Professional Documents
Culture Documents
000152883
000152883
CONTENTS
Preface ...................................................... i
Supplement I to The Japanese Pharmacopoeia,
Sixteenth Edition ............................. 23212545
General Notices ................................... 2321
General Rules for Crude Drugs ............... 2323
General Rules for Preparations ............... 2325
General Tests, Processes and Apparatus ... 2327
2.22 Fluorometry................................. 2327
2.47 Osmolarity Determination............... 2327
2.49 Optical Rotation Determination ....... 2328
2.62 Mass Spectrometry ........................ 2328
2.63 Inductively Coupled Plasma-Atomic
Emission Spectrometry and Inductively Coupled Plasma-Mass Spectrometry...................................... 2333
3.01 Determination of Bulk and Tapped
Densities .................................... 2338
4.01 Bacterial Endotoxins Test ............... 2338
6.10 Dissolution Test............................ 2339
9.01 Reference Standards ...................... 2339
9.22 Standard Solutions ........................ 2339
9.41 Reagents, Test Solutions................. 2340
9.42 Solid Supports/Column Packings for
Chromatography........................... 2358
Ocial Monographs ................................ 2359
Crude Drugs ....................................... 2495
Infrared Reference Spectra ................ 25292538
Ultraviolet-visible Reference Spectra .... 25392545
General Information
G1 Physics and Chemistry
Inductively Coupled Plasma Atomic
Emission Spectrometry ....................
Near Infrared Spectrometry.................
G2 Solid-state Properties
Measurement of the Diameter of Particles Dispersed in Liquid by Dyanamic
Light Scattering .............................
Water-Solid Interactions: Determination of Sorption-Desorption Isotherms and of Water Activity ...........
G3 Biotechnological/Biological Products
Mass Spectrometry of Peptides and
Proteins .......................................
G4 Microorganisms
Microbiological Environmental Monitoring Methods of Processing Areas
for Sterile Pharmaceutical Products
(Former name: Microbiological Evaluation of Processing Areas for
Sterile Pharmaceutical Products) .......
G5 Crude Drugs
Quantitative Analytical Technique Utilizing Nuclear Magnetic Resonance
(NMR) Spectroscopy and Its Application to Reagents in the Japanese
Pharmacopoeia..............................
G8 Water
Quality Control of Water for Pharmaceutical Use ..............................
Water to be used in the Tests of Drugs ..
G9 Others
International Harmonization Implemented in the Japanese Pharmacopoeia Sixteenth Edition ................
2547
2547
2551
2554
2556
2558
2564
2566
2574
2575
Index.................................................... 2587
Index in Latin Name................................ 2605
Index in Japanese.................................... 2607
PREFACE
The 16th Edition of the Japanese Pharmacopoeia
(JP) was promulgated by Ministerial Notification No.
65 of the Ministry of Health, Labour and Welfare
(MHLW) on March 24, 2011.
In July 2011, the Committee on JP established the
basic principles for the preparation of the JP 17th Edition, setting out the roles and characteristics of the JP,
the definite measures for the revision, and the date of
the revision.
At the Committee, the five basic principles of JP,
which we refer to as the ``five pillars'', were established as follows: 1) Including all drugs which are important from the viewpoint of health care and medical
treatment; 2) Making qualitative improvement by introducing the latest science and technology; 3)
Promoting internationalization; 4) Making prompt
partial revision as necessary and facilitating smooth
administrative operation; and 5) Ensuring transparency regarding the revision, and disseminating the JP to
the public. It was agreed that the Committee on JP
should make efforts, on the basis of these principles,
to ensure that the JP is used more effectively in the
fields of health care and medical treatment by taking
appropriate measurements, including getting the understanding and cooperation of other parties concerned.
It was agreed that the JP should provide an official
standard, being required to assure the quality of medicines in Japan in response to the progress of science
and technology and medical demands at the time. It
should define the standards for specifications, as well
as the methods of testing to assure overall quality of
all drugs in principle, and it should have a role in
clarifying the criteria for quality assurance of drugs
that are recognized to be essential for public health
and medical treatment.
The JP has been prepared with the aid of the
knowledge and experience of many professionals in
the pharmaceutical field. Therefore, the JP should
have the characteristics of an official standard, which
might be widely used by all parties concerned, and it
should play an appropriate role of providing information and understanding about the quality of drugs to
the public. Moreover, as a pharmaceutical quality
standard, it should contribute promoting and maintaining of advancedness as well as international consistency and harmonization of technical requirements
in the international community.
ii
Preface
Supplement I, JP XVI
tems are omitted depending on the nature of the drug:
(1) English title
(2) Commonly used name(s)
(3) Latin title (only for crude drugs)
(4) Title in Japanese
(5) Structural formula or empirical formula
(6) Molecular formula and molecular mass
(7) Chemical name
(8) CAS Registry Number
(9) Origin
(10) Limits of the content of the ingredient(s) and/or
the unit of potency
(11) Labeling requirements
(12) Method of preparation
(13) Description/Description of crude drugs
(14) Identification tests
(15) Specific physical and/or chemical values
(16) Purity tests
(17) Loss on drying or Ignition, or Water
(18) Residue on ignition, Total ash or Acid-insoluble
ash
(19) Tests being required for pharmaceutical preparations and other special tests
(20) Assay
(21) Containers and storage
(22) Expiration date
(23) Others
4. In each monograph, the following physical and
chemical values representing the properties and quality of the drug are given in the order indicated below,
except that unnecessary items are omitted depending
on the nature of drug:
(1) Alcohol number
(2) Absorbance
(3) Congealing point
(4) Refractive index
(5) Osmolar ratio
(6) Optical rotation
(7) Constituent amino acids
(8) Viscosity
(9) pH
(10) Content ratio of the active ingredients
(11) Specific gravity
(12) Boiling point
(13) Melting point
(14) Acid value
(15) Saponification value
(16) Ester value
(17) Hydroxyl value
(18) Iodine value
Supplement I, JP XVI
5. Identification tests comprise the following items, which are generally put in the order given below:
(1) Coloration reactions
(2) Precipitation reactions
(3) Decomposition reactions
(4) Derivatives
(5) Infrared and/or ultraviolet-visible absorption
spectrometry
(6) Nuclear magnetic resonance spectrometry
(7) Chromatography
(8) Special reactions
(9) Cations
(10) Anions
6. Purity tests comprise the following items, which
are generally put in the order given below, except that
unnecessary items are omitted depending on the nature of drug:
(1) Color
(2) Odor
(3) Clarity and/or color of solution
(4) Acidity or alkalinity
(5) Acidity
(6) Alkalinity
(7) Chloride
(8) Sulfate
(9) Sulfite
(10) Nitrate
(11) Nitrite
(12) Carbonate
(13) Bromide
(14) Iodide
(15) Soluble halide
(16) Thiocyanate
(17) Selenium
(18) Cationic salts
(19) Ammonium
(20) Heavy metals
(21) Iron
(22) Manganese
(23) Chromium
(24) Bismuth
(25) Tin
(26) Aluminum
(27) Zinc
(28) Cadmium
(29) Mercury
(30) Copper
(31) Lead
(32) Silver
(33) Alkaline earth metals
(34) Arsenic
(35) Free phosphoric acid
Preface
(36)
(37)
(38)
(39)
(40)
(41)
(42)
(43)
(44)
iii
Foreign matters
Related substances
Isomer
Optical isomer
Polymer
Residual solvent
Other impurities
Residue on evaporation
Readily carbonizable substances
iv
Preface
Carboplatin
Cetotiamine Hydrochloride
Dorzolamide Hydrochloride
Epalrestat
Epoetin Alfa
Epoetin Beta
Ethyl Parahydroxybenzoate
Filgrastim
Lenograstim
Methyl Parahydroxybenzoate
Nartograstim
Propyl Parahydroxybenzoate
Quetiapine Fumarate
Tacalcitol
Valsartan
Supplement I, JP XVI
Filgrastim (Genetical Recombination)
Filgrastim (Genetical Recombination) Injection
Hypromellose Acetate Succinate
Ibuprofen Piconol
Ibuprofen Piconol Cream
Ibuprofen Piconol Ointment
Iohexol
Iohexol Injection
Isosorbide Mononitrate 70z/Lactose 30z
Isosorbide Mononitrate Tablets
Lafutidine
Lafutidine Tablets
Lenograstim (Genetical Recombination)
Levofloxacin Fine Granules
Levofloxacin Ophthalmic Solution
Levofloxacin Tablets
Lobenzarit Sodium
Losartan Potassium Tablets
Morphine Sulfate Hydrate
Nartograstim (Genetical Recombination)
Nartograstim for Injection (Genetical Recombination)
Nifedipine Extended-release Capsules
Nifedipine Enteric Fine Granules
Nifedipine Fine Granules
Omeprazole Enteric-coated Tablets
Pemirolast Potassium Ophthalmic Solution
Pilocarpine Hydrochloride Tablets
Quetiapine Fumarate
Quetiapine Fumarate Fine Granules
Quetiapine Fumarate Tablets
Simvastatin Tablets
Tacalcitol Hydrate
Tacalcitol Lotion
Taltirelin Hydrate
Taltirelin Orally Disintegrating Tablets
Taltirelin Tablets
Tranilast
Tranilast Capsules
Tranilast Fine Granules
Tranilast for Syrup
Tranilast Ophthalmic Solution
Valsartan
Valsartan Tablets
Artemisia Leaf
Cherry Bark
Hangeshashinto Extract
Malt
Tokishakuyakusan Extract
15. The following monographs were revised:
Acrinol Hydrate
Acrinol and Zinc Oxide Oil
Supplement I, JP XVI
Actinomycin D
Aldioxa
Amiodarone Hydrochloride Tablets
Atorvastatin Calcium Hydrate
Azathioprine Tablets
Aztreonam
Benzyl Alcohol
Bisoprolol Fumarate Tablets
Butyl Parahydroxybenzoate
Calcium Pantothenate
Anhydrous Dibasic Calcium Phosphate
Dibasic Calcium Phosphate Hydrate
Candesartan Cilexetil
Cefazolin Sodium
Cefdinir
Cefditoren Pivoxil Fine Granules
Cefoperazone Sodium
Cefteram Pivoxil
Ceftibuten Hydrate
Cellacefate
Chlordiazepoxide Tablets
Chlorpheniramine Maleate Powder
Anhydrous Citric Acid
Citric Acid Hydrate
Clindamycin Hydrochloride
Clomifene Citrate
Clomifene Citrate Tablets
1z Codeine Phosphate Powder
10z Codeine Phosphate Powder
Corn Starch
Daunorubicin Hydrochloride
Dibekacin Sulfate
Diethylcarbamazine Citrate Tablets
1z Dihydrocodeine Phosphate Powder
10z Dihydrocodeine Phosphate Powder
Donepezil Hydrochloride
10z Ephedrine Hydrochloride Powder
Ethanol
Anhydrous Ethanol
Ethanol for Disinfection
Ethyl Parahydroxybenzoate
Fexofenadine Hydrochloride
Glimepiride Tablets
Human Menopausal Gonadotrophin
Heparin Calcium
Heparin Sodium
Heparin Sodium Injection
Hydralazine Hydrochloride Powder
Josamycin
Josamycin Propionate
Kanamycin Sulfate
Anhydrous Lactose
Magnesium Stearate
Preface
Mefloquine Hydrochloride
10z dl-Methylephedrine Hydrochloride Powder
Methyl Parahydroxybenzoate
Mizoribine
Nateglinide
Norethisterone
Parnaparin Sodium
Piperacillin Sodium
Potato Starch
Pravastatin Sodium Fine Granules
Pravastatin Sodium Tablets
Propyl Parahydroxybenzoate
Rabeprazole Sodium
0.1z Reserpine Powder
Riboflavin Powder
Ribostamycin Sulfate
Rice Starch
Sarpogrelate Hydrochloride
Streptomycin Sulfate
Streptomycin Sulfate for Injection
Sucrose
Titanium Oxide
Trichlormethiazide Tablets
Vasopressin Injection
Voglibose Tablets
Wheat Starch
Zolpidem Tartrate
Akebia Stem
Alisma Tuber (Former name: Alisma Rhizome)
Powdered Alisma Tuber (Former name: Powdered
Alisma Rhizome)
Alpinia Officinarum Rhizome
Powdered Amomum Seed
Apricot Kernel
Aralia Rhizome
Asparagus Tuber
Powdered Atractylodes Lancea Rhizome
Atractylodes Rhizome
Powdered Atractylodes Rhizome
Bearberry Leaf
Belladonna Root
Benincasa Seed
Bupleurum Root
Powdered Capsicum
Chrysanthemum Flower
Cinnamon Bark
Citrus Unshiu Peel
Powdered Clove
Cnidium Monnieri Fruit
Cnidium Rhizome
Powdered Cnidium Rhizome
Powdered Coix Seed
Condurango
vi
Preface
Coptis Rhizome
Powdered Coptis Rhizome
Corydalis Tuber
Powdered Corydalis Tuber
Crataegus Fruit
Digenea
Ephedra Herb
Epimedium Herb
Powdered Fennel
Fritillaria Bulb
Powdered Gambir
Powdered Gardenia Fruit
Gentian
Powdered Geranium Herb
Ginger
Powdered Ginger
Ginseng
Powdered Ginseng
Glycyrrhiza
Powdered Glycyrrhiza
Hemp Fruit
Ipecac
Powdered Ipecac
Japanese Angelica Root
Powdered Japanese Angelica Root
Leonurus Herb
Lycium Bark
Magnolia Bark
Powdered Magnolia Bark
Powdered Moutan Bark
Orengedokuto Extract
Panax Japonicus Rhizome
Powdered Panax Japonicus Rhizome
Peach Kernel
Powdered Peach Kernel
Peucedanum Root
Pharbitis Seed
Phellodendron Bark
Powdered Phellodendron Bark
Picrasma Wood
Plantago Herb
Polygala Root
Powdered Polygala Root
Polygonum Root
Processed Ginger
Pueraria Root
Red Ginseng
Rehmannia Root
Powdered Rose Fruit
Saireito Extract
Schizonepeta Spike
Scutellaria Root
Powdered Scutellaria Root
Supplement I, JP XVI
Powdered Senega
Senna Leaf
Powdered Senna Leaf
Shosaikoto Extract
Sinomenium Stem and Rhizome
Smilax Rhizome
Powdered Smilax Rhizome
Sweet Hydrangea Leaf
Powdered Sweet Hydrangea Leaf
Swertia Herb
Toad Cake (Former name: Toad Venom)
Turmeric
Powdered Turmeric
Uncaria Hook
Zanthoxylum Fruit
Powdered Zanthoxylum Fruit
16. The following monographs were deleted:
Amobarbital Sodium for Injection
Flurazepam
Flurazepam Capsules
Trimethadione Tablets
17. The descriptions of following monographs
were revised according to the provision of crystal
forms:
Atorvastatin Calcium Hydrate
Candesartan Cilexetil
Donepezil Hydrochloride
Fexofenadine Hydrochloride
Nateglinide
Rabeprazole Sodium
Sarpogrelate Hydrochloride
Those who were engaged in the preparation of the
Supplement I to JP 16 are as follows:
Hiroyuki Fuchino
Fumiaki Akahori
Kiyoshi Fukuhara
Teruo Amagasa
Yukihiro Goda
Mitsuo Aoki
**
Takashi Goto
Nobuo Aoyagi
Noriaki Habasaki
Hiroyuki Arai
Yuji Haishima
Keiko Arimoto
Takashi Hakamatsuka
Yuichi Arimoto
Kentaro Hanada
Naoki Aruga
Ruri Hanajiri
Naoki Asai
Toshikazu Harada
Hiroshi Asama
Akira Harazono
Toshiki Asano
Mitsuru Hashida*
Kazuhide Ashizawa
Noritaka Hashii
Yukio Aso
Rika Hatano
Toshio Azuma
Takao Hayakawa*
Takashi Bamba
Masahiro Hayashi
Yosuke Demizu
Yoshinori Hayashi
Makoto Emura
Supplement I, JP XVI
Kenji Higuchi
Yuuki Hirata
Yukio Hiyama
Masatoshi Hori
Naoki Hosono
Kenji Hosoya
Masashi Hyuga
Nobukazu Igoshi
Kazuhiko Ikegami
Koichi Inubushi
Akiko Ishii
Tsuneo Ishizuka
Shigeru Itai
Chizuko Itoh
Takashi Itoh
Kenichi Izutsu
Kazuaki Kakehi
Takemine Kanai
Norio Karibe
Hirohito Katayama
Haru Kato
Kumiko Kato
Yoshiaki Kato
Noriko Katori
Nobuo Kawahara
Urao Kawakami
Toru Kawanishi
Yoshihiko Kawarasaki
Nana Kawasaki
Keiji Kijima
Yutaka Kikuchi
Yuuichi Kikuchi
Kimio Kiryu
Yasuhiro Kishimoto
Mitsukazu Kitada
Atsushi Kittaka
Fumiyuki Kiuchi
Junko Kizu
Yukari Koga
Masayoshi Kohase
Preface
Tatsuo Koide
Shigeo Kojima
Hiroyasu Kokubo
Katsuko Komatsu
Toshifumi Konda
Kenji Kondo
Seizo Kondo
Kenichi Kumasaka
Masaaki Kurihara
Fumiyo Kusu
Midori Makita
Eiichi Mikami
Takao Mitsuhashi
Naoki Miyata
Tamaki Miyazaki
Mitsuo Mori
Nobuaki Moriguchi
Seiki Morimoto
Katsuhiro Morisawa
Osamu Morita
Takashi Morita
Toshimi Murai
Masashi Muroi
Takashi Nagashima
Takahiro Naito
Shinsaku Nakagawa
Emi Nakajima
Hiroshi Nakamura
Tatsuya Nakano
Tatsumi Nakashima
Mitsuo Nanaura
Masao Nasu
Shingo Niimi
Yasuhiko Nishi
Yutaka Nishihara
Atsushi Nukanobu
Sumiaki Oba
Yasumitsu Ogura
Ryozo Oishi
Akira Okonogi
Tsuneo Okubo
Haruhiro Okuda
Takamasa Okugawa
Yuko Osumi
Masami Otsuka
Tadashi Ouchi
Yukio Saito
Yoshikazu Sakagami
Eiji Sakai
Tomoaki Sakamoto
Shingou Sakurai
Tomofumi Santa
Hiroshi Sasaki
Kunio Sasaki
Tomoko Sasaki
Tsuguo Sasaki
Kazumichi Sasaoki
Kyoko Sato
Michiko Sekiguchi
Setsuko Sekita
Yasuo Shimada
Kozo Shimoda
Osamu Shirokizawa
Osamu Shirota
Takuji Shoda
Junya Souma
Keiichi Sudo
Naoki Sugimoto
Daisuke Sugiura
Mikio Suzuki
Sumiko Suzuki
Shinichi Tadaki
Nobuo Taguchi
Wataru Takada
Yoshikazu Takahashi
Kunihiro Takai
Masaki Takao
vii
Kikuo Takatera
Osami Takeda
Tadahiro Takeda
Hirohumi Takeuchi
Toyoshige Tanabe
Masakazu Tanaka
Toshihiro Tanaka
Kenichi Tanamoto
Tsuyoshi Tanimoto
Susumu Terabayashi
Katsuhide Terada
Reiko Teraoka
Hiroshi Tokunaga
Kiyoshi Tomioka
Hiroyuki Tomitsuka
Shigeki Tsuda
Hideya Tsuge
Hiroyuki Tsujimoto
Eriko Uchida
Yoshimasa Uehara
Atsuhiro Uetake
Eiji Watanabe
Takehiko Yajima
Toshiyasu Yamada
Teruhide Yamaguchi
Tetsuji Yamaguchi
Hiroki Yamaji
Keiji Yamamoto
Tosuke Yamamoto
Chikamasa Yamashita
Takeshi Yamazaki
Masato Yasuhara
Shiho Yasuo
Hikaru Yoden
Chikako Yomota
Etsuo Yonemochi
Kumi Yoshida
GENERAL NOTICES
Change the paragraph 4 as follows:
4. ``Crude Drugs and related drugs'' are placed
together in the posterior part of the Official Monographs. These include: Extracts, Powders, Tinctures,
Syrups, Spirits, Fluidextracts or Suppositories containing Crude Drugs as the active ingredient, and combination preparations containing Crude Drugs as the
principal active ingredient.
Abbreviations
CS: Colorimetric Stock Solution
RS: Reference Standard
TS: Test Solution
VS: Refer to a solution listed in Standard Solutions for Volumetric Analysis <9.21>.
2321
2323
GENERAL RULES
FOR PREPARATIONS
Change the paragraphs 22 to 24 under [2]
Monographs for Preparations as follows:
2-2. Liquids and Solutions for Oro-mucosal Application
(1) Liquids and Solutions for Oro-mucosal Application
are preparations in liquid form or flowable and viscous
gelatinous state, intended for oral cavity application.
(2) Liquids and Solutions for Oro-mucosal Application
are usually prepared by mixing active substance(s) with suitable excipients and Purified Water or suitable vehicles to
dissolve homogenously or to emulsify or suspend, and by
filtering if necessary.
(3) For Liquids and Solutions for Oro-mucosal Application which are apt to deteriorate, prepare before use.
(4) Unless otherwise specified, the preparations in single-dose packages meet the requirement of the Uniformity of
Dosage Units <6.02>.
(5) Tight containers are usually used for Liquids and Solutions for Oro-mucosal Application. For the preparations
susceptible to degradation by evaporation of water, a lowmoisture-permeability container or packaging may be used.
2-2-1. Preparations for Gargles
(1) Preparations for Gargles are liquid preparations intended to apply locally to the oral and throat cavities. Solid
type preparations to be dissolved in water before use are also
included in this category.
(2) Solid type preparations to be dissolved in water before use are prepared as directed under 1-1. Tablets or 1-3.
Granules.
2-3. Sprays for Oro-mucosal Application
(1) Sprays for Oro-mucosal Application are preparations that are applied active substance(s) by spraying into the
oral cavity in mist, powder, foam or paste forms.
(2) Sprays for Oro-mucosal Application are usually prepared by the following methods:
(i) Dissolve or suspend active substance(s) and suitable excipients in a solvent, filter, where necessary, and fill
into a container together with liquefied or compressed
gas.
(ii) Dissolve or suspend active substance(s) and suitable excipients in a solvent, fill into a container, and fit
with a pump for spraying.
(3) Unless otherwise specified, metered-dose types
among Sprays for Oro-mucosal Application have an appropriate uniformity of delivered dose.
(4) Tight containers or pressure-resistant containers are
usually used for Sprays for Oro-mucosal Application.
2-4. Semi-solid Preparations for Oro-mucosal Application
(1) Semi-solid Preparations for Oro-mucosal Application are preparations in cream, gel or ointment forms, intended for application to the oral mucosa.
(2) Semi-solid Preparations for Oro-mucosal Application are usually prepared by emulsifying active substance(s)
together with excipients using ``Purified Water'' and oil
component such as petrolatum, or by homogenizing active
substance(s) together with suitable excipients using polymer
gel or oil and fats as the base.
(i) Creams for oro-mucosal application are prepared
as directed under 11-5. Creams.
(ii) Gels for oro-mucosal application are prepared as
directed under 11-6. Gels.
(iii) Ointments for oro-mucosal application are prepared as directed under 11-4. Ointments.
For Semi-solid Preparations for Oro-mucosal Application which are apt to deteriorate, prepare before use.
(3) Sufficient amounts of suitable preservatives to prevent the growth of microorganisms may be added for Semisolid Preparations for Oro-mucosal Application filled in
multiple-dose containers.
(4) Semi-solid Preparations for Oro-mucosal Application have a suitable viscosity to apply to the oral mucosa.
(5) Tight containers are usually used for Semi-solid
Preparations for Oro-mucosal Application. For the preparations susceptible to degradation by evaporation of water, a
low-moisture-permeability container or packaging may be
used.
2325
Fats and Fatty Oils Test, and sampling, preparation of sample for analysis, microscopic examination, purity test, loss
on drying, total ash, acid-insoluble ash, extract content, and
essential oil content of crude drugs are performed as directed
in the corresponding items under the Crude Drugs Test.
The number of each test method is a category number
given individually. The number in blackets (< >) appeared
in monograph indicates the number corresponding to the
general test method.
2.22
Fluorometry
F kI0qecl
k: Constant
I0: Intensity of exciting light
q: Quantum yield of fluorescence or phosphorescence
Quantum yield of fluorescence or phosphorescence
number of quanta as fluorescence or phosphorescence
2.47
Osmolarity Determination
Procedure
A fixed volume of the test solution is introduced into the
sample cell, as indicated for the individual apparatus.
The apparatus must first be calibrated by the two-point
calibration method by using osmolal standard solutions. For
the calibration, select two different standard solutions just
covering the expected osmolar concentration of a sample solution. Other than the indicated osmolal standard solutions
in the Table below, water can also be used as a standard so-
2327
2328
lution (0 mOsm) for measuring low osmolar sample solutions (0 100 mOsm). Next, after washing the sample cell
and the thermistor as indicated for the individual apparatus,
measure the degree of the freezing-point depression caused
by a sample solution. Using the above-mentioned relation of
osmolar concentration m and DT, the osmolarity of a sample solution can be obtained, and it is assumed to be numerically equal to the osmolarity.
In the case of higher osmolar solutions over 1000 mOsm,
dilute the sample with water and prepare n?/n times diluted
sample solution (n in n?). Measure the osmolarity of the
diluted solution, as described above. In this case, it is necessary to state that the calculated osmolarity for the sample
(see below) is an apparent osmolarity obtained by the dilution method. When the determination is performed using
n?/n times diluted solution, the dilution number should be
selected so that the osmolar concentration is near but not exceeding 1000 mOsm, and dilute in one step.
In the case of solid samples, such as freeze-dried medicines, prepare a sample solution by dissolving the solid using
the indicated solution for dissolution.
5.
Osmolar ratio
In this test method the osmolar ratio is defined as the ratio
of osmolarity of a sample solution to that of the isotonic sodium chloride solution. The ratio can be used as a measure
of isotonicity of sample solution. Since the osmolarity of the
isotonic sodium chloride solution (NaCl 0.900 g/100 mL) cS
(mOsm) is assumed to be constant (286 mOsm), the osmolar
ratio of a sample solution, of which the osmolarity is cT
(mOsm), can be calculated by means of the following equation,
Osmolar ratiocT/cS
2.49
Supplement I, JP XVI
quarty plate, repeat the test after refurbishing the apparatus.
2.62
Mass Spectrometry
Mass spectrometry (MS) is a method to separate and detect the ions generated from the ionization of molecules according to their m/z values, and it is used for the identification and purity test of the substances. The m/z value is the
dimensionless parameter obtained from dividing the relative
mass (m) of the ion (the ratio of the mass of the ion to the
unified atomic mass unit) by the charge number (z) of the
ion. The unified atomic mass unit is defined as one-twelfth
of the mass of a 12C atom in its ground state, and it is used to
express masses of atoms, molecules and ions. The result of
measurement is shown as the mass spectrum in which the
m/z values of the ions and the relative intensities of the signals corresponding to the ions are shown on the x-axis and
the y-axis, respectively.
The precise mass of a molecule or an ion consisting of
only a single isotope (usually, the isotope with the greatest
natural abundance) of each element comprising a sample
molecule is referred to as the ``monoisotopic mass.'' Usually
not only a monoisotopic ion but also its isotopic ions are
seen in the mass spectrum. The molecular mass of the sample substance can be determined from the m/z value of the
molecular ion. When the fragment ions are observed, the
molecular structure of the sample substance can be estimated and confirmed based on the masses of the fragment
ions and the mass differences among the molecular ion and
the fragment ions. In tandem mass spectrometry (MS/MS),
the product ions, generated by the dissociation of the selected precursor ion with m/z value, are used for the mass spectrometry. The structural estimation and confirmation of the
precursor ion can be performed using the m/z value of the
product ion observed in the measurement. The schematic diagram of the MS and the MS/MS is shown in Fig. 2.62-1.
1.
Mass Spectrometer
A mass spectrometer usually consists of a sample introduction unit, an ionization unit (ion source), a mass
analyzer, a detector and data processor, and an exhaust
Optical Rotation
Determination
Supplement I, JP XVI
system to maintain the mass analyzer under high vacuum
(Fig. 2.62-1).
1.1. Sample Introduction
For the introduction of the sample into the ion source, the
following methods are used; Direct infusion method, in
which solution samples are injected into the ion source by
using a syringe pump or capillary tip, for example; Direct inlet method, in which a liquid or solid sample is placed in a glass tube or other appropriate vessel and introduced into the
vicinity of the electron beams or reactant ion atmosphere of
the ion source. In addition, the method, in which each component separated by the chromatographic technique such as
gas chromatography or liquid chromatography and capillary
electrophoresis is introduced into the ion source successively, is also used.
1.2. Ion Source
When the sample substances are introduced into the mass
spectrometer, ions with a positive or negative charge are
generated from the substance in the ion source. There are
various ionization methods in mass spectrometry, and it is
important to select the most suitable ionization method according to the polarity and molecular mass of the sample
substance to be measured and the purpose of the measurement. Typical ionization methods are as follows.
1.2.1. Electron Ionization (EI) Method
In the EI method, the vaporized sample molecule (M) is
ionized by receiving the energy of thermal electrons (usually,
70 eV), and the molecular ion (M) and fragment ions with
the structural information of the sample molecule are generated. This method is suitable for ionizing nonpolar molecules such as volatile or gaseous samples with low molecular
mass up to approximately 1000. It is used for the identification of substances using a data library or other source, because mass spectra with reproducible fragmentation patterns
can be obtained by this method.
1.2.2. Chemical Ionization (CI) Method
In the CI method, the vaporized sample molecules are
ionized through ion/molecule reactant with reaction ions
generated from reagent gases such as methane, isobutane
and ammonia. When a reagent gas is introduced into the
ionization chamber, protonated ions of the molecules [M
H], deprotonated ions of the molecules [M H] or
reactant ion adducts of the molecules are generated. Since
the ions generated by the CI method have internal energy
values that are much lower than those obtained by the EI
method, the fragmentation of sample molecules hardly
occurs.
1.2.3. Electrospray Ionization (ESI) Method
When the sample solution is sprayed through a capillary
with a tip to which high voltage is applied, atomized charged
droplets are produced. Subsequently, the sample molecules
will be ionized when the charge density of the droplets
increases, accompanied by the evaporation of the solvent;
[M H], [M H], or alkali metal ion adduct of the
molecules is thus generated. This method is used for the ionization of sample substances from those with low molecular
mass and relatively high polarity to those with high molecular mass. The ESI method can also be applied for the meas-
2329
urement of biopolymers such as peptides, proteins and polysaccharides, because the method makes it easy to generate
multiply-charged ions such as [M nH]n and [M
nH]n.
1.2.4. Atmospheric Pressure Chemical Ionization (APCI)
Method
In the APCI method, the sample solution is sprayed and
vaporized by passing through a heated capillary using nitrogen as the carrier, and the corona discharge is induced at the
time with a high-voltage needle electrode, and the solvent
molecules are thus ionized. The sample molecules will be
ionized through the ion/molecule reaction with the solvent
ions, and [M H], [M H], or alkali metal ion adduct
of the molecules will be generated. This method is suitable
for ionizing nonpolar to highly polar compounds with a
molecular mass up to approximately 1500.
1.2.5. Matrix-assisted
Laser
Desorption/Ionization
(MALDI) Method
When a mixture of the sample and a matrix such as acyano-4-hydroxycinnamic acid or sinapinic acid is irradiated
with a pulsed laser, the sample molecules will be vaporized
quickly and ionized, accompanied by the electronic excitation of the matrix. At that time, the proton transfer occurs
between the matrix and the sample molecules, and [M
H], [M H], or alkali metal ion adduct of the molecules
is generated. With the MALDI method, it is possible to
ionize the compounds from low molecular mass of several
hundreds to high molecular mass of several hundred thousand by selecting the appropriate matrix. Since the amount
of the sample required for the measurement is very small,
this method is used for the ionization of samples of biological origin such as peptides and proteins.
1.2.6. Other Ionization Methods
Various other ionization methods have been developed,
including the field ionization (FI) method, the field desorption (FD) method, the fast atom bombardment (FAB)
method, the secondary ion mass spectrometry (SIMS)
method, the atmospheric pressure photoionization (APPI)
method, and an ionization method in which the volatile substances on the material surface can be directly ionized using
the ionization by the collision reaction with helium in the excited state in the open space.
1.2.7. Sample Introduction Method and Ionization
Method
Each ionization technique is closely related to the sample
introduction methods. In the case of the gas chromatography mass spectrometry (GC-MS), vaporized substances separated by a capillary column are directly introduced into a high-vacuum ion source and ionized by the
EI method or CI method, for example. In the case of liquid
chromatography mass spectrometry (LC-MS), the liquid
phase containing sample substances separated by the LC
column is sprayed under atmospheric pressure, and the sample substances are ionized by an ionization method described
above at the interface to introduce the ions to the high-vacuum mass analyzer. At that time, it is necessary to ensure that
the mobile phase to be used has an appropriate composition
for both the column separation and the ionization. In the
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Supplement I, JP XVI
show cyclotron movement due to the effect of the Lorenz
force. Here, the angular frequency (v) can be expressed by
the following equation.
v qB/m
where m is the mass in atomic mass units of the ion, q is the
electric charge of the ion, and B is the magnetic flux density.
When the high-frequency electric field with this frequency is
applied to the magnetic field, the ions move along the spiral
orbital. These rotating ion groups induce the electric current, which changes periodically according to its respective
m/z value in the detecting electrode. The mass spectrum can
be obtained by Fourier-transforming the signals measured
above and further converting the frequencies to the m/z
values. The Penning ion-trap is used for precise structural
studies in combination with various dissociation techniques
for precursor ions, since an FT-ICR analyzer has extremely
high mass resolving power and mass accuracy.
1.3.3. Time-of-flight (TOF) Analyzer
In the time-of-flight (TOF) analyzer, the ions are separated based on the difference of the flight times necessary for
reaching the detector. For the ions with the mass m accelerated by the constant voltage V, the time t necessary for the
ions to fly a distance L and reach the detector can be expressed by the following equation.
t m/z
L
2eV
mv
qB
Supplement I, JP XVI
magnetic sector, and the analyzer is used for both qualitative
and quantitative analyses, since it has high mass resolving
power and is also highly quantitative.
1.4. Detectors
Ions that have passed through a mass analyzer are usually
transduced to the electric signal by releasing the electrons at
the detector. The following detectors are in current use. In
Fourier-transform-type instruments, the electric current induced by the movement of the ions at the detector is identified with a detection electrode.
1.4.1. Secondary Electron Multiplier (SEM)
A secondary electron multiplier (SEM) has a multistage
arrangement of electrodes called dynodes. The secondary
electrons emitted by the collision of the ions that enter the
multiplier to the first dynode are sequentially multiplied,
and finally transduced to the electric signal and recorded.
This multiplying effect of the secondary electrons enables
the detection of small amounts of ions.
1.4.2. Channel Electron Multiplier (CEM)
A channel electron multiplier (CEM) has a pipe-shaped
channel configuration, and the secondary electrons are emitted by the collision of the ions that entered the multiplier to
the inner wall of the channel. Multiple amplification is
achieved by repeating this process at every opposite side of
the inner wall. A CEM is simpler compared to SEMs, and
with a CEM it is possible to downsize.
1.4.3. Microchannel Plate (MCP)
A microchannel plate (MCP) has a configuration in which
many very small CEMs are accumulated to form a detector.
It is used for the detector of TOF-type instruments, since an
MCP has a wide ion-receiving surface, and the time dispersion of the secondary electrons is small because of the very
thin structure of the MCP.
1.4.4. Faraday Cup (FC)
A Faraday cup (FC) is a simple detector that receives the
charge of the ions that have entered an ion detector, and it
transduces the charge to the electric current. It has a cupshaped configuration so that the secondary electrons emitted
from the ions can be captured.
2.
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2332
Supplement I, JP XVI
the identification and purity tests of molecules as a specific
detection method based on the mass and the structural information of the molecules.
4.1. Optimization of Instruments
In mass spectrometry, in order to obtain a good shape,
sensitivity, and mass accuracy of the ion peak it is necessary
to pre-optimize the measurement parameters of each component unit of the instrument by using an appropriate standard
material in accord with the ionization method and mass
range.
4.1.1. Tuning
The shape, sensitivity, and relative intensity of the ion
peak detected are optimized by adjusting the parameters
such as the gas pressure, temperature, and voltage of the ion
source, mass analyzer, and detector. The various parameters
of the ion source affect the generation of ion species, the
species transported to the mass analyzer, and the relative intensity. The parameters related to the mass analyzer influence the peak width, mass accuracy, resolving power, and
sensitivity, and the detector parameters affect the signal intensity and system sensitivity.
4.1.2. Calibration
The mass calibration of a mass spectrometer is carried out
based on the mass of standard material. The reproducibility
of the measurement mass values is affected by the electrical
variation of the instrument, the surface cleanliness of each
component unit such as the ion source, and the room temperature. There are the external and internal standard techniques for mass calibration. The number of points for the
calibration differs according to the type of mass spectrometer.
4.1.3. Mass Resolving Power
The ability to separate two adjacent ion peaks from each
other is referred to as the mass resolving power. Higher mass
resolving power capacitates to separate and detect the ion
peaks with a small mass difference. In magnetic-sector mass
spectrometry, the mass resolving power R is calculated by
the following equation when two peaks with the mass of M
and M DM overlap each other to 10z of either peak
height.
R M / DM
When an instrument other than a magnetic-sector mass
spectrometer is used, such as a quadrupole mass spectrometer or a time-of-flight mass spectrometer, the mass resolving
power can usually be calculated by the method using peak
width at half-height. When the width of the ion peak with
the mass of m is Dm, the mass resolving power is calculated
by R m/Dm, and is discriminated from that of the magnetic-sector mass spectrometer.
4.2. Test for Identification
The identification of a test substance using mass spectrometry is usually performed by the confirmation of the mass
of the test substance molecule. The test should be performed
after confirming in advance that the measurement value is
within the range specified in the monograph using the standard solutions defined in the monograph, or the specified
ion can be detected. According to the mass resolving power
Supplement I, JP XVI
of the instrument and the mass of the test substance molecule, the mass of the test substance molecule obtained from
mass spectrometry can be adjusted to the monoisotopic mass
or the average mass.
In general, the mass of the molecule consisting of only
principle isotopes should be obtained from the monoisotopic
peak. However, when the monoisotopic peak cannot be
identified because, for example, the molecular mass is high
or the resolution is not sufficient, the average mass should
be calculated from the weighted average of the peak. When
samples with high molecular mass such as proteins are analyzed by ESI/MS, the average mass should be calculated by
the deconvolution technique, because the ESI mass spectra
would show a series of multiply charged ions with different
charge states. It may be combined with the detection of the
fragment ions or the product ions generated from the test
substance molecule, which includes characteristic partial
structural information.
4.3. Purity test
The purity test of a test substance using mass spectrometry
is usually performed in combination with a separation technique such as chromatography using a standard solution
with a concentration corresponding to the specified limit of
the impurity in the sample. The peak responses of the
molecular ions or the characteristic fragment ions and
product ions generated from the specified impurity in the
sample solution should be compared with those of the ions
generated from the substance in the standard solution. To
obtain more precise values, the method in which the stable
isotope-labeled compound of the analyte is added to the
sample solution as the internal standard is also important.
When the test is performed using mass spectrometry in combination with, for example, chromatography, a system
suitability test should also be required in accord with the
chromatography.
2333
DE hn hc/l
Since there are many excited states with various energy
levels to which peripheral electrons might transit, many
emission lines with various levels of energy can generate
from one element, although some lines are strong and others
are weak. However, there is only a limited number of emission lines observed in the ultraviolet/visible region and with
enough sensitivity for the qualitative and quantitative analyses of each element. Since each element exhibits its own
spectral line with a characteristic frequency (or wavelength)
in the atomic emission spectrum, the elements contained in
the sample solution can be identified by determining the
wavelengths of spectral lines in the spectrum. Quantitative
analyses of the elements in the sample solution can also be
performed by determining the intensity of the spectral line
characteristic of each element. The elemental analysis
method using this principle is ICP-AES.
ICP-MS is the elemental analysis method alternative to
optical analysis methods such as atomic absorption spectrometry and ICP-AES. In ICP-MS, the element ions generated
by the ICP are separated into those with each m/z value and
the intensities of the separated ions are counted with a mass
spectrometer. Compared to ICP-AES, ICP-MS is higher
sensitive, and with it an isotope analysis can be performed.
ICP-AES and ICP-MS are both excellent trace analysis
methods specific for the inorganic impurities or coexisting
elements in drug substances and drug products. Therefore,
using these methods, qualitative and quantitative analyses
can be performed not only for alkaline/alkaline-earth metals
and heavy metals, but also for many elements for which adequate control is required to ensure the safety of pharmaceutical products. It would be useful for the quality assurance
of drug substances to apply these methods to the profile analyses of inorganic elements contained in the substances, because these methods enable the simultaneous analysis of
many elements.
1. Instruments
1.1. Instrument Configuration of ICP-AES
An ICP-AES is composed of an excitation source, a sam-
2334
ple introduction system, a light emission unit, a spectroscope, a photometer and a data processor.
The excitation source consists of a high-frequency power
generator, a control circuit to supply and control the electric
energy to the light emission unit, and a gas source. The sample introduction system, the main components of which are
a nebulizer and a spray chamber, is used for introducing
sample solutions to the light emission unit after nebulizing
the solutions.
The main components of the light emission unit, in which
the elements containing in the sample solution are atomized
and excited to induce light emission, are a torch and a highfrequency induction coil. The torch has a triple tube structure, and the sample solution is introduced through the
central tube. Argon gas is used to form the plasma and to
transport the sample solution. For the observation method
of the light emitted from the light emission unit, there are
two viewing modes: the lateral viewing mode in which the
radial light of the plasma is observed, and the axial viewing
mode in which the central light of the plasma is observed.
The spectroscope separates the light from the light emission unit to the spectral lines, and is composed of optical
devices such as a light-converging system and diffraction
grating. There are two types of spectrometers: wavelengthscanning spectrometers (monochromators) and simultaneously measuring spectrometers (polychromators) of the
wavelength-fixed type. In addition, it is necessary to form a
vacuum or to substitute the air in the chamber of the photometer with argon or nitrogen gas, when it is required to
measure the spectral lines of the vacuum ultraviolet region
(190 nm or shorter).
The photometer, which consists of a detector and a signal
processing system, transduces the light energy of incident
light to the electric signal proportional to the intensity of the
light. For the detector, a photomultiplier or a semiconductor
detector is used.
The data processor is used to process the data obtained by
the measurements, and it displays the calibration curves and
measurement results.
1.2. Instrument Configuration of ICP-MS
An ICP-MS system is composed of an excitation source, a
sample introduction system, an ionization port, an interface,
an ion lens, a mass analyzer, an ion detector and a data processor.
The excitation source, sample introduction system and
ionization port have the same configuration as their counterparts in an ICP-AES system.
The interface is the boundary component for introducing
the ions generated by the plasma under atmospheric pressure
into a high-vacuum mass analyzer, and is composed of the
sampling cone and skimmer cone.
The ion lens brings the ions introduced via the interface
into focus and helps introduce the focused ions into the mass
analyzer efficiently.
For the mass analyzer, a common choice is a quadrupole
mass analyzer. The interference caused by the polyatomic
ions described later can be suppressed by placing a collision/reaction cell within the vacuum region before the
Supplement I, JP XVI
mass analyzer, and introducing a gas such as hydrogen, helium, ammonia or methane into the cell.
The ion detector transduces the energy of the ions that
reached the detector to an electric signal which is amplified
by the multiplier. The data processor is used to process the
data of the electric signal from the ion detector, and to display the calibration curves and measurement results, etc.
2.
Pretreatment of Sample
When the samples to be analyzed are organic compounds
such as pharmaceutical drug substances, they are usually
digested and ashed by the dry ash method or the wet digestion method, and the sample solutions for ICP-AES or ICPMS are prepared by dissolving the residues in small quantities of nitric acid or hydrochloric acid. When a sample is
difficult to digest in the usual manner, the sample can be
sealed in a closed, pressurized container and digested using
microwave digestion equipment. Although liquid samples
containing small amounts of organic solvents can be introduced directly into an ICP-AES or ICP-MS instrument
without pretreatment, another alternative is introducing
oxygen as the option gas to prevent the build-up of carbon
generated from the solvent onto the torch and the interface
by contributing to the incineration of organic solvents.
3.
Operation of ICP-AES
The operation of an ICP-AES system is as follows. The
argon plasma is formed by setting the argon gas flow at the
specified rate and turning the high-frequency power source
on. After confirmation that the state of the plasma is stable,
a quantity of the sample solution or the standard solution
prepared by the method prescribed in the monograph is introduced into the instrument via the sample injection port,
and the emission intensity of the analytical line specified for
the element is measured. When it is necessary to perform a
test for the confirmation or identification of some elements,
the emission spectrum in the wavelength range in which analytical lines specified for the elements that appear is measured.
3.1. Performance Evaluations of Spectrometers
Since each spectrometer requires its own calibration
method that accords with its properties, a wavelength
calibration must be performed according to the procedure
indicated by the manufacturer.
For expressing the wavelength-resolving power of a spectrometer, the half height width of the analytical line in the
emission spectrum of a specified element is usually defined
in the form of ``not more than xxx nm (a constant value).''
The following emission lines, from the line with a low
wavelength to that with a high wavelength, are usually
selected for the above purpose: arsenic (As: 193.696 nm),
manganese (Mn: 257.610 nm), copper (Cu: 324.754 nm) and
barium (Ba: 455.403 nm).
3.2. Optimization of Operating Conditions
The operating conditions usually adopted are as follows.
The operating conditions of the instrument should be optimized after stabilizing the state of the plasma by warming
up the instrument for 15 30 min. The operating parameters
should usually be set as follows: high frequency power, 0.8
Supplement I, JP XVI
1.4 kW; argon gas flow rate, 10 18 L/min for the coolant
gas (plasma gas), 0 2 L/min for the auxiliary gas, and 0.5
2 L/min for the carrier gas. In the lateral viewing mode, the
point for measuring the light emitted from the plasma
should be set within the range of 10 25 mm from the top
edge of the induction coil, and the aspiration rate of the
sample solution should be set at 0.5 2 mL/min. In the axial
viewing mode, the optical axis should be adjusted so that the
maximum value can be obtained for the intensity of emission
line measured. The integration time should be set within the
range of one to several tens of seconds, taking the stability
of the intensity of the emission line measured into account.
When a test using an ICP-AES system is defined in a JP
monograph, the operating conditions such as the analytical
line (nm), high-frequency power (kW), and argon gas flow
rate (L/min) should be prescribed in the monograph.
However, it is necessary to optimize the operating conditions
individually for each instrument and for each viewing mode
used for the measurement.
3.3. Interference and Its Suppression or Correction
In the term ICP-AES, the word ``interference'' is used as
a general term that indicates the influence of the coexisting
components or matrix on the measurement results. Various
interferences are roughly classified as either non-spectral interference (such as physical interference and ionization interference) or spectral interference. Their effects can be eliminated or reduced by applying the appropriate suppression or
correction methods for the measurement.
Physical interference means that the measurement results
are influenced by the difference between the spray efficiencies of the sample solution and the standard solution used
for its calibration in the light emission unit, when the physical properties (such as viscosity, density and surface tension)
of the solutions differ. The effective methods for eliminating
or reducing this type of physical influence are as follows.
The sample solution should be diluted to the level at which
such interference will not occur; the properties between the
sample solution and the standard solution used for its
calibration should be matched as much as possible (matrixmatching method); and the internal standard method (intensity ratio method) or the standard addition method should
be used.
Ionization interference indicates the influence due to the
change in the ionization rate caused by the increase of electron density in the plasma, which is induced by a large number of electrons generated from the elements coexisting in
the sample solution at a high concentration. The suppression
or correction method against the ionization interference is
essentially the same as the method used in the case of physical interference. The measurement conditions with low ionization interference can also be set by the selection and adjustment of the observation method of emitted light, the
height for viewing, high-frequency power and carrier gas
flow rate, and so on.
Spectral interference is the phenomenon which influences
the analytical results of the sample by overlapping the various emission lines and/or the light with a continuous spectrum with the analytical line of the analyte element. To
2335
Operation of ICP-MS
In the operation of an ICP-MS system, after the confirmation that the state of the plasma is stable, the optimization of the instrument is performed and the system's
suitability is confirmed. A quantity of the sample solution or
the standard solution prepared by the method prescribed in
the monograph is introduced, and the ion count numbers of
the signal at the m/z value specified for the analyte element
are determined. When it is necessary to perform a test for
the confirmation or identification of some elements, the
mass spectrum in the m/z value range specified for the analyte elements is measured.
4.1. Performance Evaluation of Mass Spectrometer
The performance evaluation items for mass spectrometers
are the mass accuracy and the mass resolving power. The
mass accuracy should be adjusted by matching the m/z value
of the mass axis of the mass analyzer to that of the standard
element in the standard solution for the optimization specified in the operating conditions section of the monograph.
With quadrupole mass spectrometers, it is preferable that
the mass accuracy be within 0.2. For the mass resolving
power, it is preferable that the peak width at 10z of the
peak height in the observed ion peak is not more than 0.9.
4.2. Optimization of Operating Conditions
When a limit test or a quantitative test is performed, the
sensitivity, background and generation ratio of oxide ions
and doubly charged ions defined below should be optimized
previously to assure that the performance of the instrument
is suitable. For the optimization of operating conditions, the
solutions of the elements which represent the low mass number elements, intermediate mass number elements and high
mass number elements and are unlikely to be contaminated
from the environment (e.g., 7Li, 9Be, 59Co, 89Y, 115In, 140Ce,
205Tl and 209Bi) are usually used as the standard solutions
after adjusting to adequate concentrations.
The sensitivity is evaluated by the ion count numbers per
second of integration time (cps). When a limit test or quantitative test is performed, it is preferable to have the sensitivity of several tens of thousands cps per 1 mg/L (ppb) for each
element with a low mass number, intermediate mass number
or high mass number.
For the background, it is preferable to be not more than
10 cps, when the measurement is performed at the m/z value
at which no elements exist naturally (e.g., m/z value of 4, 8
or 220).
For the generation ratio of oxide ions and doubly charged
2336
System Suitability
When a limit test or quantitative test is performed using
these methods, it is necessary to confirm that the performance of the instrument is suitable by carrying out a system
suitability test as defined below in advance of the limit test
or quantitative test.
5.1. Evaluation for Required Detectability and Linearity
In an evaluation of an ICP-MS system for the required
detectability and linearity, a solution is prepared in which
Supplement I, JP XVI
the analyte element is not contained and the standard solution with the concentration of the specification limit of the
analyte element, and these solutions are used as the blank solution and the solution for the system suitability test, respectively. The spectra obtained with these solutions are measured according to the test conditions optimized individually
for each instrument, and it must be confirmed whether the
emission line (or ion peak) of the analyte element is clearly
observed at the specified wavelength (or m/z value) in the
solution for system suitability test when compared with the
blank solution. In this regard, the limit of the analyte element should be specified at the concentration of more than
the quantitation limit (10s). The test for required detectability is not required in the assay.
For the evaluation of linearity, it should be confirmed that
the correlation coefficient of the calibration curve prepared
by the procedure described in the section below, ``6.2. Quantitative Analysis'' is not less than 0.99. The confirmation of
linearity is not required in quantitative analyses in the section 6.1. or when isotope dilution in the section 6.2. is performed.
5.2. Evaluation for System Repeatability
Unless otherwise specified, when the test is repeated six
times using the solution with the lowest concentration
among those used for plotting the calibration curve according to the test conditions optimized individually for each
instrument, it should be confirmed that the relative standard
deviation of the observed values for the emission intensity
(or ion count number) of the analyte element is not more
than the specified value (e.g., not more than 3z for an assay, and not more than 5z for a purity test).
6. Qualitative and Quantitative Analyses
6.1. Qualitative Analyses
In ICP-AES, when the wavelengths and relative emission
intensities of multiple emission lines from the sample solution conform to those of the emission lines from the elements contained in the standard solution, the presence of the
elements can be confirmed. In addition, the library of ICPemission spectra attached to each instrument or the
wavelength table of the spectra can also be used instead of
the standard solution. Since the mass number region covering all the elements can be scanned in a short time in ICPMS, the elements contained in the sample solution can be
analyzed qualitatively based on the m/z value of the ion
peak in the mass spectrum obtained from the sample solution.
It would be feasible to list the metal catalysts and inorganic elements that might be contained in the sample as impurities, and for some elements (such as arsenic and lead) it
might be necessary to monitor them in a routine manner
from the point of view of safety, and to carry out the profile
of these inorganic impurities as a part of the manufacturing
controls for a drug substance. In addition, the standard solution of each element should be prepared at an appropriate
concentration considering the acceptance limit of each element to be specified separately.
Supplement I, JP XVI
6.2. Quantitative Analyses
The quantitative analysis of an inorganic element in the
sample solution is usually performed by one of the following
methods based on the emission intensity or ion count numbers obtained by the integration of measurement data in a
specified time.
(i) Calibration curve method: Prepare standard solutions for plotting a calibration curve with different concentrations (four or more) of the analyte element. Using these
standard solutions, the emission intensities at the analytical
line specified for the analyte element by ICP-AES or the ion
count numbers at the m/z value specified for the analysis of
the element by ICP-MS are measured. The data obtained are
then plotted against the concentrations, and this plot is used
as the calibration curve. The concentration of the analyte
element in the sample solution is determined by using this
calibration curve.
(ii) Internal standard method: Prepare standard solutions for plotting a calibration curve with a fixed concentration of the internal standard element and different concentrations (four or more) of the analyte element. Using these
standard solutions, the ratios of the emission intensities (or
ion count numbers) of the analyte element to those of the internal standard element are determined. The data obtained
are plotted against the concentrations, and this plot is used
as the calibration curve. The internal standard element is
also added to the sample solution, so that the concentration
of internal standard element in the solution becomes the
same as that in the standard solution. The concentration of
the analyte element in the sample solution is determined by
using the calibration curve plotted above.
Before this method is applied, it is necessary to verify that
the internal standard element to be added is not contained in
the sample solution. If the internal standard element to be
added is present in the sample solution, it is necessary to
verify that the contaminated amount of standard element is
negligible compared to the amount to be added. In addition,
in ICP-AES, the following requirements are to be met for
the internal standard element: the changes in the emission intensity due to the measurement conditions and properties of
the solution should be similar to those of the analyte element, and the emission line which does not cause spectral interference to the analytical line of the analyte element should
be selected for the analysis. In contrast, in ICP-MS, it is
preferable to select an internal standard element which does
not cause spectral interference to the analyte element and
has the ionization efficiency and mass number equivalent to
the analyte element.
(iii) Standard addition method: Take 4 portions or more
of the sample solution with the same volume, and prepare
the following solutions; the solution in which the analyte element is not added; the standard solutions for plotting
calibration curve in which the analyte element is added at
different concentrations (3 or more). Measure the emission
intensities at the specified analytical line or the ion count
numbers at the specified m/z value for these solutions. Plot
the obtained data against the concentrations calculated from
the added amount of the analyte element. Calibrate the con-
2337
Note
Water and reagents and the standard solutions used in this
test are as follows.
(i) For water, water for an ICP analysis should be used.
It should be verified prior to the test that the impurities contained in the water do not interfere with the analysis of the
analyte element. Here, the water for an ICP analysis has the
electric conductivity of 1 mScm1 or less (259
C).
(ii) Reagents that are suitable for ICP analyses and are
of high quality should be used.
(iii) For argon gas, either liquefied argon or compressed
argon gas with the purity of 99.99 volz or higher should be
used.
(iv) For the standard solutions, they should be prepared
by diluting the Standard Solution (e.g., the Standard Solution defined in the JP, or a standard solution with a concentration certified by a public institution or scientific organization) to the specified concentration using the water for ICP
analysis. However, in cases in which interference with the
analysis might occur, it is preferable to match the properties
of the standard solution to those of the sample solution.
(v) When a standard solution containing multiple elements is prepared, a combination of the test solutions and
elements should be selected so that precipitation and/or
mutual interference does not occur.
2338
3.01
Supplement I, JP XVI
to 1 mL. The modified test conditions are specified in the expression of the results.
4.01
Fig. 3.01-1
Volumeter
2.1.2. Procedure
Proceed as described above for the determination of the
bulk volume (V0).
Secure the cylinder in the holder. Carry out 10, 500 and
1250 taps on the same powder sample and read the corresponding volumes V10, V500 and V1250 to the nearest graduated unit. If the difference between V500 and V1250 is less than
or equal to 2 mL, V1250 is the tapped volume. If the difference between V500 and V1250 exceeds 2 mL, repeat in increments such as 1250 taps, until the difference between succeeding measurements is less than or equal to 2 mL. Fewer
taps may be appropriate for some powders, when validated.
Calculate the tapped density (g/mL) using the formula m/Vf
in which Vf is the final tapped volume. Generally, replicate
determinations are desirable for the determination of this
property. Specify the drop height with the results.
If it is not possible to use a 100 g test sample, use a
reduced amount and a suitable 100 mL graduated cylinder
(readable to 1 mL) weighing 130 16 g and mounted on a
holder weighing 240 12 g. If the difference between V500
and V1250 is less than or equal to 1 mL, V1250 is the tapped
volume. If the difference between V500 and V1250 exceeds 1
mL, repeat in increments such as 1250 taps, until the difference between succeeding measurements is less than or equal
Apparatus
Depyrogenate all glassware and other heat-stable materials in a hot-air oven using a validated process. Commonly
used minimum time and temperature settings are 30 minutes
at 2509C. If employing plastic apparatus, such as multi-well
plates and tips for micropipettes, use only that which has
been shown to be free of detectable endotoxin and which
does not interfere with the test.
2. Preparation of Solutions
2.1. Standard Endotoxin Stock Solution
Prepare Standard Endotoxin Stock Solution by dissolving
Japanese Pharmacopoeia Reference Standard Endotoxin
that has been calibrated to the current WHO International
Standard for Endotoxin, using water for bacterial endotoxins test (BET). Endotoxin is expressed in Endotoxin Units
(EU). One EU is equal to one International Unit (IU) of endotoxin.
2.2. Standard Endotoxin Solution
After mixing Standard Endotoxin Stock Solution thoroughly, prepare appropriate serial dilutions of Standard Endotoxin Solution, using water for BET. Use dilutions as
soon as possible to avoid loss of activity by adsorption.
2.3. Sample Solutions
Unless otherwise specified, prepare sample solutions by
dissolving or diluting drugs, using water for BET. By the
Supplement I, JP XVI
sample, an aqueous solution other than water for BET may
be used to dissolve or dilute. If necessary, adjust the pH of
the sample solution so that the pH of the mixture of the lysate TS and sample solution falls within the specified pH
range for the lysate to be used. The pH of the sample solution may be in the range of 6.0 to 8.0. For adjustment of pH,
acid, base or a suitable buffer solution may be used. The
acid and base are prepared from their concentrated solutions
or solids using water for BET, and then stored in containers
free of detectable endotoxin. The buffer solutions must be
validated to be free of detectable endotoxin and interfering
factors.
6.10
Dissolution Test
2339
9.01
Reference Standards
9.22
Standard Solutions
Fig. 6.10-1
Standard Sulfite Solution Dissolve exactly 3.150 g of anhydrous sodium sulfite in freshly prepared distilled water to
make exactly 100 mL. Pipet 0.5 mL of this solution, add
2340
Supplement I, JP XVI
volumetric analysis may be used.
9.41
Supplement I, JP XVI
Absorbance <2.24> E 11zcm (280 nm): 70 76 [4 mg, previously dried in a desiccator (in vaccum, silica gel) for 12
hours, water, 100 mL].
Purity Related substancesDissolve 40 mg of arbutin
for assay in 100 mL of water, and use this solution as the
sample solution. Pipet 1 mL of the sample solution, add
water to make exactly 100 mL, and use this solution as the
standard solution (1). Perform the test with exactly 10 mL
each of the sample solution and standard solution (1) as
directed under Liquid Chromatography <2.01> according to
the following conditions, and determine each peak area of
the both solutions by the automatic integration method: the
total area of the peaks other than arbutin from the sample
solution is not larger than the peak area of arbutin from the
standard solution (1).
Operating conditions
Proceed the operating conditions in the Assay under
Bearberry Leaf except detection sensitivity and time span of
measurement.
Detection sensitivity: Pipet 1 mL of the standard solution
(1), add water to make exactly 20 mL, and use this solution
as the standard solution (2). Adjust the detection sensitivity
so that the peak area of arbutin obtained from 10 mL of the
standard solution (2) can be measured by the automatic integration method and the peak height of arbutin obtained
from 10 mL of the standard solution (1) is about 20z of the
full scale.
Time span of measurement: About 3 times as long as the
retention time of arbutin beginning after the solvent peak.
Arbutin for thin-layer chromatography C12H16O7
Colorless to white crystals or crystalline powder, and odorless. Freely soluble in water, soluble in methanol, sparingly
soluble in ethanol (95), and practically insoluble in ethyl
acetate and in chloroform.
Melting point <2.60>: 199 2019C
Purity Related substancesDissolve 1.0 mg of arbutin
for thin-layer chromatography in exactly 1 mL of a mixture
of ethanol (95) and water (7:3). Perform the test with 20 mL
of this solution as directed in the Identification (2) under
Bearberry Leaf: any spot other than the main spot with an
Rf value of about 0.4 does not appear.
Atractylenolide III for thin-layer chromatography
C15H20O3 White crystals or crystalline powder. Freely soluble in methanol, soluble in ethanol (99.5), and practically insoluble in water. Melting point: 193 1969C
Identification(1) Determine the absorption spectrum of
a solution of atractylenolide III for thin-layer chromatography in methanol (1 in 100,000) as directed under
Ultraviolet-visible Spectrophotometry <2.24>: it exhibits a
maximum between 217 nm and 221 nm.
(2) Determine the infrared absorption spectrum of atractylenolide III for thin-layer chromatography as directed in
the potassium bromide disk method under Infrared Spectrophotometry <2.25>: it exhibits absorption at the wave
numbers of about 3350 cm1, 1742 cm1, 1641 cm1 and
1384 cm1.
Purity Related substancesDissolve 2 mg of atrac-
2341
2342
than 4, respectively.
System repeatability: When the test is repeated 6 times
with 20 mL of aconitum monoester alkaloids standard TS for
assay under the above operating conditions, the relative
standard deviations of the peak areas of benzoylmesaconine,
benzoylhypaconine and 14-anisoylaconine are not more than
1.5z, respectively.
Benzoylmesaconine hydrochloride for thin-layer chromatography C31H43NO10.HCl White crystals or crystalline powder. Soluble in water and in ethanol (99.5) and sparingly soluble in methanol. Melting point: about 2509
C (with
decomposition).
Absorbance <2.24> E 11zcm (230 nm): 217 231 (5 mg calculated on the anhydrous basis, methanol, 200 mL).
Purity Related substancesDissolve 1.0 mg of benzoylmesaconine hydrochloride for thin-layer chromatography
in exactly 1 mL of ethanol (99.5). Perform the test with 5 mL
of this solution as directed in the Identification under Processed Aconite Root: no spot other than the principal spot
with an Rf value of about 0.4 appears.
Benzyl parahydroxybenzoate C14H12O3 White, fine
crystals or crystalline powder. Freely soluble in ethanol (95),
and very slightly soluble in water.
Melting point <2.60>: 109 1129C
Residue on ignition <2.44>: not more than 0.1z.
Content: not less than 99.0z. AssayWeigh accurately
about 1 g of benzyl parahydroxybenzoate, add exactly 20
mL of 1 mol/L sodium hydroxide VS, heat at about 709
C
for 1 hour, and immediately cool in ice. Titrate <2.50> the
excess sodium hydroxide with 0.5 mol/L sulfuric acid VS up
to the second equivalent point (potentiometric titration).
Perform a blank determination.
Each mL of 1 mol/L sodium hydroxide VS
228.2 mg of C14H12O3
Bovine serum albumin-isotonic sodium chloride solution
Dissolve 0.1 g of bovine serum albumin in 100 mL of isotonic sodium chloride solution. Prepare before use.
Bromocresol green-sodium hydroxide-ethanol TS Dissolve 50 mg of bromocresol green in 0.72 mL of 0.1 mol/L
sodium hydroxide VS and 20 mL of ethanol (95), and add
water to make 100 mL.
Test for sensitivityTo 0.2 mL of the bromocresol greensodium hydroxide-ethanol TS add 100 mL of freshly boiled
and cool water: the solution is blue, and not more than 0.2
mL of 0.02 mol/L hydrochloric acid VS is required to
change the color of this solution to yellow.
Color change: pH 3.6 (yellow) to pH 5.2 (blue).
Cephaeline hydrobromate C28H38N2O4.2HBr A white
or light-yellow crystalline powder.
PurityDissolve 10 mg of cephaeline hydrobromate in 10
mL of the mobile phase, and use this solution as the sample
solution. Pipet 1 mL of the sample solution, add the mobile
phase to make exactly 10 mL, and use this solution as the
standard solution. Perform the test with exactly 10 mL each
Supplement I, JP XVI
of the sample solution and standard solution as directed in
the Assay under Ipecac: when measure the peak areas for 2
times the retention time of emetine, the total area of the
peaks other than cephaeline obtained from the sample solution is not larger than the peak area of cephaeline from the
standard solution.
Chikusetsusaponin IV for thin-layer chromatography
C47H74O18 White crystalline powder. Freely soluble in
methanol and in ethanol (95), and practically insoluble in
diethyl ether. Melting point: about 2159
C (with decomposition).
Purity Related substancesDissolve 2 mg of chikusetsusaponin IV for thin-layer chromatography in 1 mL of
methanol, and perform the test with 5 mL of this solution as
directed in the Identification under Panax Japonicus Rhizome: any spot other than the principal spot with an Rf
value of about 0.4 does not appear.
(E)-Chlorogenic acid for thin-layer chromatography
C16H18O9 A white powder. Freely soluble in methanol and
in ethanol (99.5), and sparingly soluble in water. Melting
point: about 2059
C (with decomposition).
Purity Related substancesDissolve 1.0 mg of (E )chlorogenic acid for thin-layer chromatography in 2 mL of
methanol, and use this solution as the sample solution. Perform the test with the sample solution as directed under
Thin-layer Chromatography <2.03>. Spot 10 mL of the sample solution on a plate of silica gel for thin-layer chromatography, develop the plate with a mixture of ethyl
acetate, water and formic acid (6:1:1) to a distance of about
10 cm, and air-dry the plate. Examine under ultraviolet light
(main wavelength: 365 nm): no spot other than the principal
spot with an Rf value of about 0.5 appears.
Cinobufagin for assay C26H34O6 A white crystalline
powder. It is odorless.
Absorbance <2.24> E 11zcm (295 nm): 125 137 (10 mg,
methanol, 250 mL). Use the sample dried in a desiccator (silica gel) for 24 hours for the test.
Purity Related substancesProceed with 40 mg of
cinobufagin for assay as directed in the Purity under bufalin
for assay.
Content: not less than 98.0z. AssayWeigh accurately
about 10 mg of cinobufagin for assay, previously dried in a
desiccator (silica gel) for 24 hours, dissolve in methanol to
make exactly 10 mL, and use this solution as the sample solution. Perform the test with 20 mL of the sample solution as
directed under Liquid Chromatography <2.01> according to
the following conditions. Determine each peak area by the
automatic integration method and calculate the amount of
cinobufagin by the area percentage method.
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 295 nm).
Column: A stainless steel column 4 to 6 mm in inside diameter and 15 to 30 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (5 to 10 mm in
particle diameter).
Supplement I, JP XVI
Column temperature: A constant temperature of about
409C.
Mobile phase: A mixture of water and acetonitrile (1:1).
Flow rate: Adjust the flow rate so that the retention time
of cinobufagin is about 7 minutes.
Selection of column: Dissolve 10 mg each of cinobufagin
for assay, bufalin for assay and resibufogenin for assay in
methanol to make 200 mL. Proceed with 20 mL of this solution under the above operating conditions. Use a column
giving elution of bufalin, cinobufagin and resibufogenin in
this order, and clearly dividing each peak.
Detection sensitivity: Pipet 1 mL of the sample solution,
add methanol to make exactly 100 mL, and use this solution
as the standard solution (1). Pipet 1 mL of the standard solution (1), add methanol to make exactly 20 mL, and use this
solution as the standard solution (2). Adjust the detection
sensitivity so that the peak area of cinobufagin obtained
from 20 mL of the standard solution (2) can be measured by
the automatic integration method, and the peak height of
cinobufagin from 20 mL of the standard solution (1) is about
20z of the full scale.
Time span of measurement: About twice as long as the
retention time of cinobufagin beginning after the solvent
peak.
Copper (standard reagent) Cu In addition to JIS K
8005 standard reagent for volumetric analysis, certified
reference material which can be used for volumetric analysis
may be used.
Diethyl phthalate C6H4(COOC2H5)2 A colorless, clear
liquid.
Refractive index <2.45> n20
D : 1.500 1.505
Eleutheroside B for liquid chromatography C17H24O9
A white crystalline powder. Sparingly soluble in methanol,
slightly soluble in water, and very slightly soluble in ethanol
(99.5). Melting point: 190 1949
C
IdentificationDetermine the absorption spectrum of a
solution of eleutheroside B for liquid chromatography in
methanol (1 in 200,000) as directed under Ultraviolet-visible
Spectrophotometry <2.24>: it exhibits a maximum between
261 nm and 265 nm.
Purity Related substancesDissolve 1.0 mg of eleutheroside B for liquid chromatography in 10 mL of
methanol, and use this solution as the sample solution. Pipet
1 mL of the sample solution, add methanol to make exactly
50 mL, and use this solution as the standard solution. Perform the test with exactly 10 mL each of the sample solution
and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions.
Determine each peak area by the automatic integration
method: the total area of the peaks other than eleutheroside
B obtained with the sample solution is not larger than the
peak area of eleutheroside B with the standard solution.
Operating conditions
Detector, column, column temperature, mobile phase,
and flow rate: Proceed as directed in the operating conditions in the Identification under Eleutherococcus Senticosus
2343
Rhizome.
Time span of measurement: About 3 times as long as the
retention time of eleutheroside B beginning after the solvent
peak.
System suitability
Test for required detectability: To exactly 1 mL of the
standard solution add methanol to make exactly 20 mL.
Confirm that the peak area of eleutheroside B obtained with
10 mL of this solution is equivalent to 3.5 to 6.5z of that
with 10 mL of the standard solution.
System performance: Proceed as directed in the system
suitability in the Identification under Eleutherococcus
Senticosus Rhizome.
Emetine hydrochloride for assay C29H40N2O4.2HCl A
white or light-yellow crystalline powder. Soluble in water.
Absorbance <2.24> E 11zcm (283 nm): 116 127 (10 mg,
diluted methanol (1 in 2), 400 mL). [after drying in a desiccator (reduced pressure below 0.67 kPa, phosphorus (V) oxide,
509C) for 5 hours].
Melting point <2.60>: about 2509C [with decomposition,
after drying in a desiccator (reduced pressure below 0.67
kPa, phosphorus (V) oxide, 509
C) for 5 hours].
Purity Related substancesDissolve 10 mg of emetine
hydrochloride for assay in 10 mL of the mobile phase, and
use this solution as the sample solution. Pipet 1 mL of the
sample solution, add the mobile phase to make exactly 100
mL, and use this solution as the standard solution (1). Perform the test with exactly 10 mL each of the sample solution
and standard solution (1) as directed under Liquid Chromatography <2.01> according to the following conditions.
Determine the peak areas from both solutions by the automatic integration method: the total area of peaks other than
emetine from the sample solution is not larger than the peak
of emetine from the standard solution (1).
Operating conditions
Proceed the operating conditions in the Assay under
Ipecac except the detection sensitivity and time span of
measurement.
Detection sensitivity: Pipet 1 mL of the standard solution
(1), add the mobile phase to make exactly 20 mL, and use
this solution as the standard solution (2). Adjust the sensitivity so that the peak area of emetine obtained from 10 mL of
the standard solution (2) can be measured by the automatic
integration method, and the peak height of emetine obtained
from 10 mL of the standard solution (1) is about 20z of the
full scale.
Time span of measurement: About 3 times as long as the
retention time of emetine.
2-Ethylhexyl parahydroxybenzoate C15H22O3 Pale yellow, clear viscous liquid. Miscible with methanol (99.5).
Practically insoluble in water.
Content: not less than 98.0z. AssayWeigh accurately
about 1 g of 2-ethylhexyl parahydroxybenzoate, add exactly
20 mL of 1 mol/L sodium hydroxide VS, heat at about 709
C
for 1 hour, and immediately cool in ice. Titrate <2.50> the excess sodium hydroxide with 0.5 mol/L sulfuric acid VS up to
the second equivalent point (potentiometric titration). Per-
2344
Supplement I, JP XVI
make 10 mL, and use this solution as the sample solution.
Perform the Liquid Chromatography <2.01> with 10 mL of
the sample solution as directed in the Assay under Magnolia
Bark: when measure the peak areas for 2 times as long as the
retention time of magnorole, the total area of peaks other
than honokiol is not larger than 1/10 times the total area of
the peaks other than the solvent peak.
Hydrazinum sulfate TS Dissolve 1.0 g of hydrazinum
sulfate in water to make 100 mL, and allow to stand for 4 6
hours.
Isobutyl
parahydroxybenzoate C11H14O3 Colorless
crystals or white crystalline powder. Freely soluble in
ethanol (95), and practically insoluble in water.
Melting point <2.60>: 75 789C
Residue on ignition <2.44>: not more than 0.1z.
Content: not less than 99.0z. AssayWeigh accurately
about 1 g of isobuthyl parahydroxybenzoate, add exactly 20
mL of 1 mol/L sodium hydroxide VS, heat at about 709
C
for 1 hour, and immediately cool in ice. Titrate <2.50> the
excess sodium hydroxide with 0.5 mol/L sulfuric acid VS up
to the second equivalent point (potentiometric titration).
Perform a blank determination.
Each mL of 1 mol/L sodium hydroxide VS
194.2 mg of C11H14O3
Isopropyl parahydroxybenzoate C10H12O3 Colorless
fine crystals, or white, crystalline powder. Freely soluble in
ethanol (95), and very slightly soluble in water.
Melting point <2.60>: 84 869C
Residue on ignition <2.44>: not more than 0.1z.
Content: not less than 99.0z. AssayWeigh accurately
about 1 g of isopropyl parahydroxybenzoate, add exactly 20
mL of 1 mol/L sodium hydroxide VS, heat at about 709
C
for 1 hour, and immediately cool in ice. Titrate <2.50> the
excess sodium hydroxide with 0.5 mol/L sulfuric acid VS up
to the second equivalent point (potentiometric titration).
Perform a blank determination.
Each mL of 1 mol/L sodium hydroxide VS
180.2 mg of C10H12O3
Liquiritin for thin-layer chromatography C21H22O9
White crystals or crystalline powder. Sparingly soluble in
methanol, slightly soluble in ethanol (99.5), and practically
insoluble in water. Melting point: about 2109
C (with decomposition).
IdentificationDetermine the absorption spectrum of a
solution of liquiritin for thin-layer chromatography in diluted methanol (1 in 2) (1 in 100,000) as directed under Ultraviolet-visible Spectrophotometry <2.24>: it exhibits maxima
between 215 nm and 219 nm, and between 275 nm and 279
nm.
Purity Related substancesDissolve 1.0 mg of liquiritin
for thin-layer chromatography in 1 mL of methanol, and
perform the test with 1 mL of this solution as directed in the
Identification (5) under Kakkonto Extract: no spot other
than the principal spot with an Rf value of about 0.4 ap-
Supplement I, JP XVI
pears.
Naringin for thin-layer chromatography C27H32O14
White to light yellow crystalline powder. Freely soluble in
ethanol (95) and in acetone, and slightly soluble in water.
Melting point: about 1709C (with decomposition).
Optical rotation <2.49> [a]20
D : 87 939(0.1 g, ethanol
(95), 10 mL, 100 mm).
Purity Related substancesProceed with 10 mL of a solution, prepared by dissolving 10 mg of naringin for thinlayer chromatography in 10 mL of ethanol (95), as directed
in the Identification under Bitter Orange Peel: any spot
other than the principal spot with an Rf value of about 0.4
does not appear.
Paeoniflorin for thin-layer chromatography C23H28O11
Colorless, odorless powder. Freely soluble in water and in
methanol, and practically insoluble in diethyl ether. Melting
point: 123 1259
C (with decomposition).
Purity Related substancesDissolve 1.0 mg of paeoniflorin for thin layer chromatography in exactly 1 mL of
methanol. Perform the test with 20 mL of this solution as
directed in the Identification (2) under Peony Root: any spot
other than the principal spot with an Rf value of about 0.3
does not appear.
Palmatin chloride C21H22ClNO4 A yellow-brown crystalline powder.
Purity Related substancesDissolve 1 mg of palmatin
chloride in 10 mL of methanol, and use this solution as the
sample solution. Proceed with 20 mL of the sample solution
as directed in the Assay under Phellodendron Bark: when
measure the peak areas for 2 times the retention time of berberine, the total area of the peaks other than palmatin is not
larger than 1/10 times the total area except the area of solvent peak.
Potassium dichromate (standard reagent) K2Cr2O7 In
addition to JIS K 8005 standard reagent for volumetric
analysis, certified reference material which can be used for
volumetric analysis may be used.
Potassium hydrogen phthalate (standard reagent)
C6H4(COOK)(COOH) In addition to JIS K 8005 standard
reagent for volumetric analysis, certified reference material
which can be used for volumetric analysis may be used.
Potassium iodate (standard reagent) KIO3 In addition
to JIS K 8005 standard reagent for volumetric analysis, certified reference material which can be used for volumetric
analysis may be used.
Resibufogenin for assay C24H32O4 Odorless white crystalline powder.
Absorbance <2.24> E 11zcm (300 nm): 131 145 (10 mg,
methanol, 250 mL), dried in a desiccator (silica gel) for 24
hours.
Purity Related substancesWeigh accurately 40 mg of
resibufogenin for assay and proceed as directed in the Purity
under bufalin for assay.
Content: not less than 98.0z. AssayWeigh accurately
2345
2346
Supplement I, JP XVI
other than the principal spot at an Rf value of about 0.2 obtained from the sample solution are not more intense than
the spot from the standard solution.
Zinc (standard reagent) Zn In addition to JIS K 8005
standard reagent for volumetric analysis, certified reference
material which can be used for volumetric analysis may be
used.
CH3COCl
Supplement I, JP XVI
C11H19NO9
0.4 mmol/L N-Acetylneuraminic acid TS Weigh accurately about 15.5 mg of N-acetylneuraminic acid for epoetin alfa, dissolve in water to make exactly 50 mL. To exactly
V mL of this solution add water to make exactly 100 mL.
2347
Operating conditions
Column, column temperature and mobile phase: Proceed
as directed in the operating conditions in the Assay (3) under
Tokishakuyakusan Extract.
Detector: An ultraviolet absorption photometer (wavelength: 220 nm).
Flow rate: Adjust the flow rate so that the retention time
of atractylenolide III is about 11 minutes.
Time span of measurement: About 5 times as long as the
retention time of atractylenolide III, beginning after the solvent peak.
System suitability
Test for required detectability: To exactly 1 mL of the
standard solution add methanol to make exactly 20 mL.
Confirm that the peak area of atractylenolide III obtained
with 10 mL of this solution is equivalent to 3.5 to 6.5z of
that with 10 mL of the standard solution.
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of atractylenolide III are not less than
5000 and not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of atractylenolide III is not more than 1.5z.
Atractylodin for assay C13H10O White to pale yellowish crystals. Freely soluble in methanol and in ethanol (99.5),
and practically insoluble in water. Melting point: about
549C.
IdentificationConduct this procedure without exposure
to light, using light-resistant vessels. Determine the absorption spectrum of a solution of atractylodin for assay in
methanol (1 in 250,000) as directed under Ultraviolet-visible
Spectrophotometry <2.24>: it exhibits maxima between 256
nm and 260 nm, between 270 nm and 274 nm, between 332
nm and 336 nm and between 352 nm and 356 nm.
Absorbance <2.24> E 11zcm (272 nm): 763 819 (2 mg,
methanol, 250 mL). Conduct this procedure without exposure to light, using light-resistant vessels.
Purity Related substances
(i) Conduct this procedure without exposure to light, using light-resistant vessels.
Dissolve 2 mg of atractylodin for assay in 2 mL of
methanol, and use this solution as the sample solution. To
exactly 1 mL of the sample solution add methanol to make
exactly 100 mL, and use this solution as the standard solution. Perform the test with these solutions as directed under
Thin-layer Chromatography <2.03>. Spot 10 mL each of the
sample solution and standard solution on a plate of silica gel
for thin-layer chromatography and immediately develop the
plate with a mixture of hexane and acetone (7:1) to a distance of about 10 cm, and air-dry the plate. Spray evenly
vanillin-sulfuric acid-ethanol TS for splaying on the plate,
and heat at 1059C for 5 minutes: the spot other than the
principle spot which appears at an Rf value of about 0.4 obtained from the sample solution is not more intense than the
2348
Supplement I, JP XVI
hydrogen phosphate in water to make 500 mL to adjust to
pH 4.3. To 20 mL of this solution add 15 mg of 2,2?azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt. To this solution add 14 mL of hydrogen peroxide TS
before use.
Blocking TS for epoetin alfa
Blocking TS for nartograstim test Dissolve 1.0 g of bovine serum albumin in phosphate-buffered sodium chloride
TS to make 100 mL.
Blotting TS Dissolve 5.81 g of 2-amino-2-hydroxymethyl-1,3-propanediol, 2.93 of glycine and 0.38 g of sodium lauryl sulfate in a suitable amount of water, add 200 mL
of methanol, and add water to make 1000 mL.
Bovine serum albumin for gel filtration molecular mass
marker Albumin obtained from bovine serum. For gel
filtration chromatography.
0.1 w/v% Bovine serum albumin-sodium chloridephosphate buffer solution Dissolve 8.0 g of sodium chloride, 0.2 g of potassium chloride, 1.15 g of anhydrous disodium hydrogen phosphate and 0.2 g of potassium dihydrogen phosphate in water to make 1000 mL. To this solution
add a solution of bovine serum albumin dissolved 1.0 g in 10
mL of water.
Bovine serum albumin TS for nartograstim test Dissolve
0.5 g of bovine serum albumin and 0.5 mL of polysorbate 20
in phosphate-buffered sodium chloride TS to make 500 mL.
Buffer solution for enzyme digestion Dissolve 0.30 g of
urea in a mixture of 100 mL of 2-amino-2-hydroxymethyl1,3-propanediol solution containing 6.06 g in 100 mL of
water, 100 mL of 2-amino-2-hydroxymethyl-1,3-propanediol
hydrochloride solution containing 7.88 g in 100 mL of
water, 100 mL of methylamine hydrochloride solution containing 2.70 g in 100 mL of water, 50 mL of dithiothreitol in
solution containing 30.9 mg in 1 mL of water and 420 mL of
water.
Buffer solution for epoetin alfa sample Dissolve 1.2 g of
2-amino-2-hydroxymethyl-1,3-propanediol and 3.2 g of sodium lauryl sulfate in a suitable amount of water, adjust to
pH 6.8 with 6 mol/L hydrochloric acid TS, 1 mol/L
hydrochloric acid TS or 0.1 mol/L hydrochloric acid TS,
add 32 mg of bromophenol blue and 16 mL of glycerin, and
add water to make 40 mL. Before use, dissolve 50 mg of
dithiothreitol in 10 mL of this solution.
Buffer solution for filgrastim sample Dissolve 1.2 g of 2amino-2-hydroxymethyl-1,3-propanediol and 3.2 g of sodium lauryl sulfate in a suitable amount of water, adjust to pH
6.8 with 6 mol/L hydrochloric acid TS, 1 mol/L hydrochloric acid TS or 0.1 mol/L hydrochloric acid TS, add 32 mg of
bromophenol blue and 16 mL of glycerin, and add water to
make 40 mL.
Buffer solution for nartograstim sample Mix 0.8 mL of
sodium lauryl sulfate solution (1 in 10), 0.5 mL of 0.5 mol/L
tris buffer solution, pH 6.8, 0.4 mL of glycerin and 0.1 mL
Supplement I, JP XVI
C6H12N2O4Pt
32D Clone3 cells A cloned cell line established by culturing mouse bone marrow origin 32D cell line in the presence
of G-CSF.
3-Chloro-1,2-propanediol C3H7ClO2 A
clear
and
colorless viscous liquid.
Purity Dissolve 0.20 g of 3-chloro-1,2-propanediol in
100 mL of diethyl ether, and use this solution as the sample
solution. Pipet 1 mL of the sample solution, add diethyl
ether to make exactly 100 mL, and use this solution as the
standard solution. Perform the test with exactly 5 mL each of
the sample solution and standard solution as directed under
Gas Chromatography <2.02> according to the following conditions, and determine each peak area by the automatic integration method: the total area of the peaks other than 3chloro-1,2-propanediol obtained from the sample solution is
not larger than 2 times the peak area from the standard solution.
Operating conditions
Proceed as directed in the operating conditions in the
Purity (6) under Iohexol except the time span of measurement.
Time span of measurement: About 5 times as long as the
retention time of 3-chloro-1,2-propanediol, beginning after
the solvent peak.
System suitability
Test for required detectability: To exactly 5 mL of the
standard solution add diethyl ether to make exactly 20 mL.
Confirm that the peak area of 3-chloro-1,2-propanediol obtained with 5 mL of this solution is equivalent to 20 30z of
that with 5 mL of the standard solution.
System performance and system repeatability: Proceed as
directed in the system suitability in the Purity (6) under Iohexol.
Chlorotrimethylsilane (CH3)3SiCl A colorless or practically colorless liquid, having a pungent odor. Evolves
fumes in a damp atmosphere. Very soluble in diethyl ether,
and reactable with water or with ethanol. Boiling point:
about 589
C.
Chymotrypsinogen for gel filtration molecular mass marker A chymotrypsinogen obtained from bovine spleen. For
gel filtration chromatography.
Cyclobutanecarboxylic acid C5H8O2
less liquid. Congealing point: 7.59C
2349
[Same as the
Prepared
2350
C27H29NO11.HCl
[Same as
Edaravone for assay C10H10N2O [Same as the monograph Edaravone. When dried, it contains not less than
99.5z of edaravone (C10H10N2O).]
Emedastine fumarate for assay C17H26N4O.2C4H4O4
[Same as the monograph Emedastine Fumarate. When dried
it contains not less than 99.5z of emedastine fumarate
(C17H26N4O.2C4H4O4).]
Ethyl formate HCOOC2H5 A clear and colorless liquid. Miscible with ethanol (95) and with acetone, and soluble
in water.
IdentificationDetermine the infrared absorption spectrum of ethyl formate as directed in the liquid film method
under Infrared Spectrophotometry <2.25>: it exhibits absorption at the wave numbers of about 2980 cm1, 2930
cm1, 1718 cm1, 1470 cm1, 1449 cm1, 1387 cm1, 1302
cm1, 1181 cm1, 1004 cm1, 840 cm1 and 747 cm1.
Purity(1) Perform the test with 1 mL of ethyl formate
as directed under Gas Chromatography <2.02> according to
the following conditions, determine each peak area by the
automatic integration method, and calculate the amount of
ethyl formate by the area percentage method: not less than
97.0z.
Operating conditions
Detector: A thermal conductivity detector.
Column: A fused silica column 0.25 mm in inside diameter and 30 m in length, coated the inside surface with a
layer about 0.25 mm thick of polyethylene glycol 20M for gas
chromatography.
Column temperature: Maintain at 509
C for 1 minute after
injecting sample, then rise to 1509C at the rate of 109C per
minute, and maintain at 1509C for 1 minute.
Carrier gas: Helium.
Flow rate: 41 cm per second.
Split ratio: 1:110.
Time span of measurement: About 5 times as long as the
retention time of ethyl formate.
(2) Acid (as formic acid) Dissolve 0.5 g of potassium
iodate and 5 g of potassium iodide in 50 mL of water, and
add 2 g of ethyl formate. After allowing to stand for 10
minutes, add 2 drops of starch TS and 1.30 mL of 0.1 mol/L
sodium thiosulfate VS: the solution is colorless (not more
than 0.3z).
Water <2.48>: not more than 0.5z (1 g, coulometric titration).
Supplement I, JP XVI
of sodium hydrogen carbonate and 36 mL of 2-mercapto
ethanol solution (1 in 10) in water to make 1000 mL, and
sterilize by filtration. To this solution add fetal bovine serum, previously heated at 569C for 30 minutes, so that the
concentration of the serum is 10 volz.
(E)-Ferulic acid for assay C10H10O4 Use (E )-ferulic
acid. It meets the following additional requirements.
Absorbance <2.24> E 11zcm (320 nm): 878 969 (5 mg,
methanol, 1000 mL).
Purity Related substancesConduct this procedure
without exposure to light, using light-resistant vessels. Dissolve 5 mg of (E )-ferulic acid for assay in 10 mL of a mixture of water and methanol (1:1), and use this solution as the
sample solution. Pipet 1 mL of the sample solution, add a
mixture of water and methanol (1:1) to make exactly 100
mL, and use this solution as the standard solution. Perform
the test with exactly 10 mL each of the sample solution and
standard solution as directed under Liquid Chromatography
<2.01> according to the following conditions, and determine
the peak areas of each peak by the automatic integration
method: the total area of the peaks other than (E )-ferulic
acid obtained from the sample solution is not larger than the
peak area of (E )-ferulic acid from the standard solution.
Operating conditions
Detector, column, column temperature, mobile phase,
and flow rate: Proceed as directed in the operating conditions in the Assay (1) under Tokishakuyakusan Extract.
Time span of measurement: About 6 times as long as the
retention time of (E )-ferulic acid, beginning after the solvent
peak.
System suitability
Test for required detectability: To exactly 1 mL of the
standard solution add a mixture of water and methanol (1:1)
to make exactly 20 mL. Confirm that the peak area of (E )ferulic acid obtained with 10 mL of this solution is equivalent
to 3.5 to 6.5z of that with 10 mL of the standard solution.
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of (E )-ferulic acid are not less than 5000
and not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of (E )-ferulic acid is not more than 1.5z.
Fluorescence TS Mix 400 mL of sodium dithionite solution containing 6.27 g in 200 mL of water, 210 mL of 2-mercaptoethanol, 321 mL of acetic acid (100), 400 mL of 1,2-diamino-4,5-methylenedioxybenzene solution containing 31.1
mg in 1.0 mL of water and 2669 mL of water. Prepare before
use.
Fluorogenic substrate TS
idation-reduction indicator.
Supplement I, JP XVI
N-Glycolylneuraminic acid
crystalline powder.
C11H19NO10
White needle
0.1 mmol/L N-Glycolylneuraminic acid TS Weigh accurately about 16.5 mg of N-glycolylneuraminic acid, and
dissolve in water to make exactly 50 mL. To exactly V mL of
this solution add water to make exactly 100 mL.
C19H23NO2
2351
from the sample solution is not larger than the peak area of
ibuprofen piconol from the standard solution.
Operating conditions
Detector, column, column temperature, mobile phase,
and flow rate: Perform as directed in the operating conditions in the Assay under Ibuprofen Piconol Ointment.
Time span of measurement: About 2 times as long as the
retention time of ibuprofen piconol.
System suitability
Test for required detectability: To exactly 1 mL of the
standard solution add the mobile phase to make exactly 20
mL. Confirm that the peak area of ibuprofen piconol obtained with 5 mL of this solution is equivalent to 3.5 6.5z
of that with 5 mL of the standard solution.
System performance: When the procedure is run with 5 mL
of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of ibuprofen piconol are not less than
5000 and not more than 1.3, respectively.
System repeatability: When the test is repeated 6 times
with 5 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of ibuprofen piconol is not more than 2.0z.
Iodoacetic acid
white crystals.
ICH2COOH
White
or
practically
2352
Supplement I, JP XVI
tions in the Assay under Isosorbide Mononitrate 70z/Lactose 30z.
Time span of measurement: About 5 times as long as the
retention time of isosorbide mononitrate, beginning after
the solvent peak.
System suitability
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of isosorbide mononitrate are not less
than 2000 and not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of isosorbide mononitrate is not more than 2.0z.
Loss on drying <2.41>: not more than 0.5z (1 g, in vacuum, silica gel, 4 hours).
Content: not less than 99.0z. AssayWeigh accurately
about 0.2 g of previously dried isosorbide mononitrate for
assay, put in a Kjeldahl flask, dissolve in 10 mL of water,
add 3 g of Devarda's alloy and 40 mL of water, and set the
flask on the apparatus as shown in the figure under Nitrogen
Determination <1.08>. Put exactly 25 mL of 0.05 mol/L sulfuric acid VS and 5 drops of bromocresol green-methyl red
TS in a absorption flask, and set to the apparatus to immerse
the lower end of the condenser. Add 15 mL of sodium
hydroxide solution (1 in 2) through the funnel, rinse cautiously the funnel with 20 ml of water, immediately close the
clamp attached to the rubber tubing, then begin the distillation with steam, and continue until the distillate measures
about 100 mL. Remove the absorption flask from the lower
end of the condenser, rinse the end part of the condenser
with a small quantity of water, and titrate <2.50> with 0.1
mol/L sodium hydroxide VS until the color of the solution
changes from red to light blue-green through a light red-purple. Perform a blank determination in the same manner.
Each mL of 0.05 mol/L sulfuric acid VS
19.11 mg of C6H9NO6
Lafutidine for assay C22H29N3O4S [Same as the monograph Lafutidine. When dried, it contains not less than
99.5z of lafutidine (C22H29N3O4S).]
Lecithin A pale yellow to yellow-brawn, powder or
grains, having a characteristic odor.
It is emulsified with water.
It is hygroscopic.
Levofloxacin hydrate for assay C18H20FN3O4.1/2H2O
[Same as the monograph Levofloxacin Hydrate]
Losartan potassium
namesake monograph]
C22H22ClKN6O
[Same
as
the
Lysyl endopeptidase A protease obtained from Lysobacter enzymogenes. It contains about 150 units per mg, where
1 unit is an enzyme amount which hydrolyzes 1 mmol of
tosyl-glycyl-prolyl-lysine-4-nitroanilide acetate per minute at
pH 7.7 and 259
C.
Supplement I, JP XVI
Myoinositol
powder.
Naphazoline hydrochloride
the namesake monograph]
HSCH2CH2OH
C14H12O
White crystals.
2353
[Same as
b-Nicotinamide adenine dinucleotide reduced form (bNADH) C21H27N7O14P2.Na2 A white to light yellowish
white powder.
Absorbance ratio: Determine the absorbances at 260 nm
and at 340 nm, A260 and A340, of a solution of bnicotinamide adenine dinucleotide reduced form (b-NADH)
in pH 7.4 phosphate buffer solution (1 in 50,000) as directed
under Ultraviolet-visible Spectrophotometry <2.24>: the
result of A260/A340 is between 2.2 and 2.4.
Water <2.48>: not more than 8.0z (0.3 g, volumetric titration, direct titration).
b-Nicotinamide adenine dinucleotide reduced form TS
Dissolve 0.4 mg of b-nicotinamide adenine dinucleotide
reduced form (b-NADH) in 1 mL of 0.6 mol/L 2,2?,2!nitrilotriethanol hydrochloride buffer solution, pH 8.0. Prepare before use.
Nifedipine for assay C17H18N2O6 [Same as the monograph Nifedipine. When dried, it contains not less than
99.0z of nifedipine (C17H18N2O6) and meets the following
requirement.]
2354
Dissolve 1 g of nin-
2,2?,2!-Nitrilotriethanol hydrochloride
(CH2CH2OH)3N.HCl White, crystals or powder.
Purity Clarity of solutionA solution (1 in 20) is clear.
Content: not less than 98z. AssayDissolve 0.3 g of
2,2?,2!-nitrilotriethanol hydrochloride, accurately weighed,
in 50 mL of water, add 5 mL of diluted nitric acid (1 in 3),
and titrate <2.50> with 0.1 mol/L silver nitrate VS (potentiometric titration).
Supplement I, JP XVI
Each mL of 0.1 mol/L silver nitrate VS
18.57 mg of (CH2CH2OH)3N.HCl
0.6 mol/L 2,2?,2!-Nitrilotriethanol hydrochloride buffer
solution, pH 8.0 Dissolve 5.57 g of 2,2?,2!-nitrilotriethanol hydrochloride in 40 mL of water, adjust to pH 8.0
with dilute sodium hydroxide TS, and add water to make 50
mL.
Omeprazole for assay
monograph Omeprazole]
C17H19N3O3S
[Same as the
C10H7KN6O
[Same
as
the
Supplement I, JP XVI
2355
of a solution dissolved 1.0 105 units of potassium benzylpenicillin and 0.1 g (potency) of streptomycin sulfate in 10
mL of isotonic sodium chloride solution, and add 5 mL of 2mercaptoethanol solution (9 in 125). Sterilize this solution
by filtration.
Primary antibody TS To a mixture of 1.5 mL of blocking TS for epoetin alfa and 13.5 mL of sodium azidephosphate-buffered sodium chloride TS add a volume of
mouse anti-epoetin alfa monoclonal antibody corresponding
to 100 mg of protein, 50 mL of a solution of aprotinin containing 1 105 units in 5 mL of water and 100 mL of
phenylmethylsulfonyl fluoride solution containing 1.74 mg
in 100 mL of methanol.
Rabbit anti-nartograstim antibody Dissolve the antibody obtained from rabbit antiserum, prepared by immunizing with Nartograstim (Genetical Recombination), in trisacetic acid buffer solution, pH 8.0, so that each mL contains
1 mg of rabbit anti-nartograstim antibody. Storage at
809
C.
Performance test: When perform the test by Ouchterlony
method, a precipitation line is appeared against Nartograstim (Genetical Recombination).
Protein concentration: Determine the absorbance at 280
nm as directed under Ultraviolet-visible Spectrophotometry
<2.24>, and calculate the protein concentration using the
specific absorbance E 11zcm 15.
Rabbit anti-nartograstim antibody TS To rabbit antinartograstim antibody add bovine serum albumin TS for
nartograstim test so that each mL contains 0.2 mg of rabbit
anti-nartograstim antibody. Prepare before use.
Reference suspension 1 To 5.0 mL of formazin opalescence standard solution add 95.0 mL of water. Mix and
shake before use.
Resazurin solution
ment of living cell.
Potency measuring medium for nartograstim test Dissolve 10.4 g of RPMI-1640 medium in a suitable amount of
water, add 16 mL of sodium hydrogen carbonate solution (3
in 40), then add water to make 1000 mL, adjust to pH 7.0 by
passing carbon dioxide through the solution, and sterilize by
filtration. To 90 mL of this solution add 10 mL of fetal
bovine serum, previously heat at 569C for 30 minutes, 1 mL
2356
Supplement I, JP XVI
hydroxide in water to make 1000 mL. Preserve in a polyethylene bottle.
Stachyose for thin-layer chromatography C24H42O21 A
white powder. Very soluble in water, and practically insoluble in ethanol (99.5). It is deliquescence with the atmospheric
moisture.
Optical rotation <2.49> [a]20
D : 144 1549(50 mg calculated on the anhydrous basis, diluted ammonia solution (28)
(1 in 1000), 5 mL, 100 mm).
Purity Related substancesDissolve 2 mg of stachyose
for thin-layer chromatography in 1 mL of a mixture of water
and methanol (1:1), and use this solution as the sample solution. Perform the test with the sample solution as directed
under Thin-layer chromatography <2.03>. Spot 2 mL of the
sample solution on a plate of silica gel for thin-layer chromatography. Develop the plate with a mixture of 2propanol, water and methanol (3:2:2) to a distance of about
7 cm, and air-dry the plate. Spray evenly 1,3-naphthalenediol TS to the plate, and heat at 1059
C for 10 minutes: a
spot other than the principle spot with an Rf value of about
0.5 is not observed.
Subculture medium for nartograstim test Dissolve an
amount of Nartograstim (Genetical Recombination),
equivalent to 0.20 mg in 20 mL of phosphate-buffered sodium chloride TS. To 0.1 mL of this solution add 100 mL of
potency measuring medium for nartograstim test.
Substrate TS for epoetin alfa Dissolve 30 mg of 4-chloro-1-naphthol in 10 ml of methanol, and use as Solution A.
Mix 30 mL of hydrogen peroxide (30) and 50 mL of 0.02
mol/L tris buffer solution, pH 7.5, and use as Solution B.
Mix Solutions A and B before use.
Succinic acid C4H6O4 Colorless or white crystalline
powder. Very soluble in hot water, soluble in water and in
ethanol (99.5), and sparingly soluble in diethyl ether.
Melting point <2.60>: About 1859C.
Residue on ignition <2.44>: not more than 0.02z (1 g).
Content: not less than 99.5z. AssayWeigh accurately
about 1 g of succinic acid, dissolve in 50 mL of water, add 5
drops of phenolphthalein TS, and titrate <2.50> with 1
mol/L sodium hydroxide VS. Perform a blank titration in
the same manner, and make any necessary correction.
Each mL of 1 mol/L sodium hydroxide VS
59.05 mg of C4H6O4
Sucrose for optical rotation
crose, Special class]
C12H22O11
[K 8383, Su-
Sulfite oxidase One unit indicates an amount of the enzyme which consumes 1 mmol of oxygen in 1 minute at 259
C
and pH 8.0 using sulfur dioxide and oxygen as the substrate.
Sulfite oxidase TS Suspend sulfite oxidase in ammonium
sulfate TS so that each mL contains 2.5 units of the activity.
StorageBetween 0 and 89C.
System suitability test solution for filgrastim Filgrastim
(Genetical Recombination) containing about 2z charge
Supplement I, JP XVI
isomer.
Taltirelin hydrate for assay C17H23N7O5.4H2O [Same
as the monograph Taltirelin Hydrate. It contains not less
than 99.0z of taltirelin (C17H23N7O5), calculated on the anhydrous basis.]
Thermolysin It has the activity of 50 100 units per mg
protein. Origin: Bacillus thermoproteolyticus rokko.
Tranilast for assay C18H17NO5 [Same as the monograph Tranilast. When dried, it contains not less than 99.5z
of tranilast (C18H17NO5).]
Trichloroethylene
C2HCl3
A clear and
2357
2358
Supplement I, JP XVI
pared for liquid chromatography.
Gel type strong basic ion-exchange resin for liquid chromatography Prepared for liquid chromatography.
Porous styrene-divinylbenzene copolymer for gas chromatography (0.3 0.4 mm in mean pore size, not exceeding
50 m2/g) Prepared for gas chromatography.
Pre-
Official Monographs
Add the following:
Water <2.48> Not more than 7.5z (0.1 g, volumetric titration, direct titration).
Less than 0.25 EU/mg.
ContainersHermetic containers.
acid TS to make exactly 100 mL, and use this solution as the
sample solution. Separately, weigh accurately about 20 mg
of Aciclovir RS (separately determine the water <2.48> in the
same manner as Aciclovir), and dissolve in dilute sodium
hydroxide TS to make exactly 20 mL. Pipet 15 mL of this
solution, add 70 mL of water and 5 mL of 2 mol/L hydrochloric acid TS, then add water to make exactly 100 mL.
Pipet 5 mL of this solution, add 0.1 mol/L hydrochloric
acid TS to make exactly 100 mL, and use this solution as the
standard solution. Determine the absorbances, AT and AS,
at 255 nm of the sample solution and standard solution as
directed under Ultraviolet-visible Spectrophotometry <2.24>,
using 0.1 mol/L hydrochloric acid TS as the blank.
Sterility <4.06> Perform the test according to the Membrane filtration method: it meets the requirement.
Assay Weigh accurately the mass of the contents of not
less than 10 Aciclovir for Injection. Weigh accurately an
amount of the contents, equivalent to about 0.1 g of
aciclovir (C8H11N5O3), and dissolve in dilute sodium hydroxide TS to make exactly 100 mL. Pipet 15 mL of this
solution, add 70 mL of water and 5 mL of 2 mol/L hydrochloric acid TS, then add water to make exactly 100 mL.
Pipet 5 mL of this solution, add 0.1 mol/L hydrochloric
Aciclovir Ointment
2359
2360
Official Monographs
Supplement I, JP XVI
Actinomycin D
ContainersTight containers.
Acrinol Hydrate
Aldioxa
[6402-23-9]
10 g
990 g
To make
1000 g
Dihydroxo[(4RS)-5-oxo-4-ureido-4,5-dihydro-1H-imidazol2-yl]oxoaluminium
Description Aldioxa occurs as a white powder.
It is practically insoluble in water and in ethanol (99.5).
It dissolves in dilute hydrochloric acid.
A solution of Aldioxa in sodium fluoride-hydrochloric
acid TS (1 in 100) shows no optical rotation.
Melting point: about 2309
C (with decomposition).
Identification (1) Determine the infrared absorption
spectrum of Aldioxa, previously dried, as directed in the
potassium bromide disk method under Infrared Spectrophotometry <2.25>, and compare the spectrum with the
Reference Spectrum: both spectra exhibit similar intensities
of absorption at the same wave numbers.
Purity (1) Chloride <1.03>To 0.10 g of Aldioxa add 6
mL of dilute nitric acid, boil to dissolve with shaking for 5
minutes, cool, and add water to make 50 mL. Perform the
test using this solution as the test solution. Prepare the control solution with 0.40 mL of 0.01 mol/L hydrochloric acid
VS (not more than 0.142z).
(2) Heavy metals <1.07>To 1.0 g of Aldioxa add 3 mL
of hydrochloric acid and 3 mL of water, heat gently to boil
with shaking, and evaporate on a water bath to dryness. To
the residue add 30 mL of water, shake under warming, cool,
filter, and to the filtrate add 2 mL of dilute acetic acid (31)
Supplement I, JP XVI
and water to make 50 mL. Perform the test using this solution as the test solution. Prepare the control solution as follows: to 3 mL of hydrochloric acid add 3 mL of water,
evaporate on a water bath to dryness, and add 2.0 mL of
Standard Lead Solution, 2 mL of dilute acetic acid (31) and
water to make 50 mL (not more than 20 ppm).
Aldioxa Granules
Official Monographs
2361
ContainersTight containers.
Aldioxa Tablets
2362
Official Monographs
Supplement I, JP XVI
50 mg of aldioxa for assay, previously dried at 1059
C for 2
hours, and dissolve in sodium fluoride-hydrochloric acid TS
to make exactly 100 mL. Pipet 4 mL of this solution, add
diluted ammonia-ammonium chloride buffer solution, pH
10.0 (1 in 10) to make exactly 100 mL, and use this solution
as the standard solution. Determine the absorbances, AT and
AS, at 223 nm of the sample solution and standard solution
as directed under Ultraviolet-visible Spectrophotometry
<2.24>.
Amount (mg) of aldioxa (C4H7AlN4O5)
M S A T/ A S 2
ContainersTight containers.
Supplement I, JP XVI
Add the following:
Official Monographs
2363
Mobile phase
A (volz)
Mobile phase
B (volz)
0 10
10 35
35 50
80
80 0
0
20
20 100
100
Flow rate: Adjust the flow rate so that the retention time
of amlodipine is about 10 minutes.
Time span of measurement: About 5 times as long as the
retention time of amlodipine.
System suitability
Test for required detectability: Pipet 10 mL of the standard solution, and add a mixture of methanol and the mobile phase A (3:2) to make exactly 50 mL. Confirm that the
peak area of amlodipine obtained with 30 mL of this solution
is equivalent to 14 to 26z of that with 30 mL of the standard
solution.
System performance: When the procedure is run with 30
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of amlodipine are not less than 3000 and
not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 30 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of amlodipine is not more than 2.0z.
Uniformity of dosage units <6.02> Perform the test according to the following method: it meets the requirement of the
Content uniformity test.
To 1 tablet of Amlodipine Besilate Orally Disintegrating
Tablets add 4V/5 mL of a mixture of the mobile phase and
methanol (1:1), disperse the particles with the aid of ultrasonic waves, add a mixture of the mobile phase and
methanol (1:1) to make exactly V mL so that each mL of the
solution contains about 0.14 mg of amlodipine besilate
(C20H25ClN2O5.C6H6O3S). Centrifuge this solution, and use
the supernatant liquid as the sample solution. Then, proceed
as directed in the Assay.
Amount (mg) of amlodipine besilate
(C20H25ClN2O5.C6H6O3S)
MS AT/AS V 1/250
2364
Official Monographs
on the anhydrous basis
Disintegration
Dissolution
Supplement I, JP XVI
Containers and storage
ContainersTight containers.
Assay Accurately weigh the mass of not less than 20 Amlodipine Besilate Orally Disintegrating Tablets, and powder
them. Weigh accurately a portion of this powder, equivalent
to about 7 mg of amlodipine besilate (C20H25ClN2O5.
C6H6O3S), add 40 mL of a mixture of the mobile phase and
methanol (1:1), disperse the particles with the aid of ultrasonic waves, and add a mixture of the mobile phase and
methanol (1:1) to make exactly 50 mL. Centrifuge this solution, and use the supernatant liquid as the sample solution.
Separately, weigh accurately about 35 mg of Amlodipine
Besilate RS (separately, determine the water <2.48> in the
same manner as Amlodipine Besilate), add 150 mL of a mixture of the mobile phase and methanol (1:1), dissolve with
the aid of ultrasonic waves, then add a mixture of the mobile
phase and methanol (1:1) to make exactly 250 mL, and use
this solution as the standard solution. Perform the test with
exactly 30 mL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01>, and
determine the peak areas, AT and AS, of amlodipine from
both solutions.
Amount (mg) of amlodipine besilate
(C20H25ClN2O5.C6H6O3S)
MS AT/AS 1/5
Auranofin
C20H34AuO9PS: 678.48
(2,3,4,6-Tetra-O-acetyl-1-thiob-D-glucopyranosato)(triethylphosphine)gold
[34031-32-8]
Supplement I, JP XVI
Official Monographs
2365
113 1169
C
2366
Official Monographs
ContainersTight containers.
Auranofin Tablets
Supplement I, JP XVI
30 mg of Auranofin RS, previously dried at 1059C for 3
hours, and dissolve in acetonitrile to make exactly 50 mL.
Pipet 5 mL of this solution, and add water to make exactly
100 mL. Pipet 10 mL of this solution, add water to make
exactly 100 mL, and use this solution as the standard solution. Perform the test with exactly 50 mL each of the sample
solution and standard solution as directed under Liquid
Chromatography <2.01> under the following conditions, and
determine the peak areas, AT and AS, of auranofin from
both solutions.
Dissolution rate (z) with respect to the labeled amount of
auranofin (C20H34AuO9PS)
MS AT/AS V?/V 1/C 9
Supplement I, JP XVI
Operating conditions
Proceed as directed in the operating conditions in the
Assay under Auranofin.
System suitability
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, auranofin and the internal standard are eluted in
this order with the resolution between these peaks being not
less than 9.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the ratio of
the peak area of auranofin to that of the internal standard is
not more than 1.0z.
Containers and storage
ContainersTight containers.
Official Monographs
2367
Azelnidipine
C33H34N4O6: 582.65
3-[1-(Diphenylmethyl)azetidin-3-yl] 5-(1-methylethyl)
(4RS)-2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine3,5-dicarboxylate
[123524-52-7]
Azathioprine Tablets
2368
Official Monographs
Assay Weigh accurately about 0.4 g of Azelnidipine, dissolve in 50 mL of acetic acid (100), and titrate <2.50> with
0.1 mol/L perchloric acid VS (potentiometric titration). Perform a blank determination in the same manner, and make
any necessary correction.
Each mL of 0.1 mol/L perchloric acid VS
29.13 mg of C33H34N4O6
Containers and storage
ContainersTight containers.
Supplement I, JP XVI
Aztreonam
Supplement I, JP XVI
Benzyl Alcohol
Official Monographs
2369
2370
Official Monographs
Brotizolam
C15H10BrClN4S: 393.69
2-Bromo-4-(2-chlorophenyl)-9-methyl6H-thieno[3,2-f ][1,2,4]triazolo[4,3-a][1,4]diazepine
[57801-81-7]
Supplement I, JP XVI
crystalline powder.
It is sparingly soluble in methanol, slightly soluble in
acetonitrile and in ethanol (99.5), and practically insoluble
in water.
Identification (1) Determine the absorption spectrum of
a solution of Brotizolam in methanol (1 in 100,000) as directed under Ultraviolet-visible Spectrophotometry <2.24>, and
compare the spectrum with the Reference Spectrum: both
spectra exhibit similar intensities of absorption at the same
wavelengths.
(2) Determine the infrared absorption spectrum of
Brotizolam as directed in the potassium bromide disk
method under Infrared Spectrophotometry <2.25>, and compare the spectrum with the Reference Spectrum: both spectra exhibit similar intensities of absorption at the same wave
numbers.
Melting point <2.60>
208 2129
C
Supplement I, JP XVI
Official Monographs
Mobile phase
A (volz)
Mobile phase
B (volz)
04
4 15
63
63 12
37
37 88
Assay Weigh accurately about 0.15 g of Brotizolam, previously dried, dissolve in 75 mL of a mixture of acetic anhydride and acetic acid (100) (2:1), and titrate <2.50> with 0.1
mol/L perchloric acid VS (potentiometric titration). Perform a blank determination in the same manner, and make
any necessary correction.
Each mL of 0.1 mol/L perchloric acid VS
19.68 mg of C15H10BrClN4S
Containers and storage ContainersTight containers.
StorageLight-resistant.
2371
Bupivacaine Hydrochloride
Hydrate
C18H28N2O.HCl.H2O: 342.90
(2RS)-1-Butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide
monohydrochloride monohydrate
[14252-80-3]
2372
Official Monographs
Supplement I, JP XVI
with 1 mL of the solution for system suitability test under the
above operating conditions, the relative standard deviation
of the ratio of the peak area of bupivacaine to that of the internal standard is not more than 2.0z.
(5) Residual solvent Being specified separately.
Water <2.48> 4.0 6.0z (0.25 g, volumetric titration,
direct titration).
Residue on ignition <2.44>
ContainersTight containers.
Butyl Parahydroxybenzoate
68 719C
Supplement I, JP XVI
Official Monographs
acetic acid and water to make 50 mL, and perform the test
using this solution as the test solution. Prepare the control
solution as follows: to 2.0 mL of Standard Lead Solution
add 25 mL of acetone, 2 mL of dilute acetic acid, and water
to make 50 mL (not more than 20 ppm).
(4) Related substancesDissolve 50 mg of Butyl Parahydroxybenzoate in 2.5 mL of methanol, and add the mobile phase to make exactly 50 mL. Pipet 10 mL of this solution, add the mobile phase to make exactly 100 mL, and use
this solution as the sample solution. Pipet 1 mL of the sample solution, and add the mobile phase to make exactly 20
mL. Pipet 1 mL of this solution, add the mobile phase to
make exactly 10 mL, and use this solution as the standard
solution. Perform the test with exactly 10 mL each of the
sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions, and determine each peak area by the automatic integration method: the peak area of parahydroxybenzoic acid
having a relative retention time of about 0.1 to butyl parahydroxybenzoate obtained from the sample solution is not
larger than the peak area of butyl parahydroxybenzoate
from the standard solution (0.5z). For this calculation use
the peak area of parahydroxybenzoic acid after multiplying
by the relative response factor, 1.4. Furthermore, the area of
the peak other than butyl parahydroxybenzoate and parahydroxybenzoic acid from the sample solution is not larger
than the peak area of butyl parahydroxybenzoate from the
standard solution (0.5z), and the total area of the peaks
other than butyl parahydroxybenzoate and parahydroxybenzoic acid is not larger than 2 times the peak area of butyl
parahydroxybenzoate from the standard solution (1.0z).
For this calculation the peak area not larger than 1/5 times
the peak area of butyl parahydroxybenzoate from the standard solution is excluded (0.1z).
Operating conditions
Detector, column, column temperature, mobile phase,
and flow rate: Proceed as directed in the operating conditions in the Assay.
Time span of measurement: About 1.5 times as long as the
retention time of butyl parahydroxybenzoate.
System suitability
Assay Weigh accurately about 50 mg each of Butyl Parahydroxybenzoate and Butyl Parahydroxybenzoate RS, dissolve separately in 2.5 mL each of methanol, and add the
mobile phase to make exactly 50 mL. Pipet 10 mL each of
2373
tainers.
and storage
ContainersWell-closed con-
2374
Official Monographs
Calcium Pantothenate
Supplement I, JP XVI
is not larger than 3/10 times the peak area of pantothenic
acid from the standard solution. Additionally, the total area
of the peaks other than pantothenic acid is not larger than
2.4 times the peak area of pantothenic acid from the standard solution. For these calculations use the areas of the
peaks, having the relative retention time of about 0.6 and
about 0.8 to pantothenic acid, after multiplying by their relative response factors, 19 and 13, respectively.
Operating conditions
Detector, column, column temperature, mobile phase,
and flow rate: Proceed as directed in the operating conditions in the Assay.
Time span of measurement: About 2 times as long as the
retention time of pantothenic acid, beginning after the solvent peak.
System suitability
Test for required detectability: To exactly 2 mL of the
standard solution add water to make exactly 10 mL. Confirm that the peak area of pantothenic acid obtained with 10
mL of this solution is equivalent to 14 26z of that with 10
mL of the standard solution.
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of pantothenic acid are not less than
10,000 and not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of pantothenic acid is not more than 2.0z.
(3) AlkaloidsDissolve 50 mg of Calcium Pantothenate
in 5 mL of water, add 0.5 mL of hexaammonium heptamolybdate TS and 0.5 mL of a solution of phosphoric acid
(1 in 10): no white turbidity is produced.
Loss on drying <2.41>
hours).
MS: Amount (mg) of Calcium Pantothenate RS, calculated on the dried basis
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 210 nm).
Column: A stainless steel column 4.6 mm in inside diameter and 25 cm in length, packed with octadecylsilanized
Supplement I, JP XVI
silica gel for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
409C.
Mobile phase: Dissolve 0.81 g of sodium 1-heptanesulfonate and 1.36 g of potassium dihydrogen phosphate in
water to make 1000 mL, and adjust to pH 2.1 with phosphoric acid. To 980 mL of this solution add 10 mL of
acetonitrile and 10 mL of methanol.
Flow rate: Adjust the flow rate so that the retention time
of pantothenic acid is about 17 minutes.
System suitability
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of pantothenic acid are not less than
10,000 and not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of pantothenic acid is not more than 1.0z.
Containers and storage
Official Monographs
2375
ContainersTight containers.
2376
Official Monographs
Candesartan Cilexetil
Carboplatin
C6H12N2O4Pt: 371.25
(SP-4-2)-Diammine[cyclobutan-1,1-dicarboxylato(2-)-O,O?]platinum
[41575-94-4]
Supplement I, JP XVI
Identification (1) To 2 mL of a solution of Carboplatin
(1 in 100) add 2 to 3 drops of diluted tin (II) chloride TS (1 in
15), and allow to stand for 30 minutes: a yellowish brown
precipitate is formed.
(2) Determine the infrared absorption spectrum of Carboplatin as directed in the potassium bromide disk method
under Infrared Spectrophotometry <2.25>, and compare the
spectrum with the Reference Spectrum or the spectrum of
Carboplatin RS: both spectra exhibit similar intensities of
absorption at the same wave numbers.
pH <2.54> Dissolve 0.10 g of Carboplatin in 10 mL of
water: the pH of this solution is 5.0 to 7.0.
Purity (1) 1,1-Cyclobutanedicarboxylic acidWeigh accurately about 40 mg of Carboplatin, dissolve in the mobile
phase to make exactly 20 mL, and use this solution as the
sample solution. Separately, weigh accurately about 25 mg
of 1,1-cyclobutanedicarboxylic acid, and dissolve in the mobile phase to make exactly 100 mL. Pipet 4 mL of this solution, add the mobile phase to make exactly 50 mL, and use
this solution as the standard solution. Perform the test with
exactly 25 mL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions. Determine the peak
areas, AT and AS, of 1,1-cyclobutanedicarboxylic acid of
these solutions, and calculate the amount of 1,1-cyclobutanedicarboxylic acid by the following formula: it is
not more than 0.2z.
Amount (z) of 1,1-cyclobutanedicarboxylic acid
MS/MT AT/AS 8/5
Supplement I, JP XVI
Official Monographs
Mobile phase
A (volz)
Mobile phase
B (volz)
0 15
15 35
35 50
100
100 0
0
0
0 100
100
2377
Mobile phase
A (volz)
Mobile phase
B (volz)
0 15
15 35
100
100 0
0
0 100
2378
Official Monographs
Carboplatin Injection
Supplement I, JP XVI
Operating conditions
Proceed as directed in the operating conditions in the
Purity (1) under Carboplatin.
System suitability
Proceed as directed in the system suitability in the Purity
(1) under Carboplatin.
(2) Related substancesTo a volume of Carboplatin Injection, equivalent to 10 mg of Carboplatin, add water to
make 10 mL, and use this solution as the sample solution.
Perform the test with 10 mL of the sample solution as directed under Liquid Chromatography <2.01> according to the
following conditions, and determine each peak area by the
automatic integration method. Calculate the amounts of
these peaks by the area percentage method: the total amount
of the peaks other than carboplatin is not more than 2.0z.
Operating conditions
Detector, column, column temperature, mobile phases A
and B, and flow rate: Proceed as directed in the operating
conditions in the Assay under Carboplatin.
Flowing of the mobile phase, and time span of measurement: Proceed as directed in the operating conditions in the
Purity (2) under Carboplatin.
System suitability
Test for required detectability, and system repeatability:
Proceed as directed in the system suitability in the Purity (2)
under Carboplatin.
System performance: Proceed as directed in the system
suitability in the Assay under Carboplatin.
Bacterial endotoxins <4.01>
Sterility <4.06> Perform the test according to the Membrane filtration method: it meets the requirement.
Assay To an exact volume of Carboplatin Injection,
equivalent to about 20 mg of carboplatin (C6H12N2O4Pt),
add water to make exactly 20 mL, and use this solution as
the sample solution. Separately, weigh accurately about 25
mg of Carboplatin RS (separately determine the loss on
drying <2.41> under the same conditions as Carboplatine),
dissolve in water to make exactly 25 mL, and use this solution as the standard solution. Perform the test with exactly
10 mL each of the sample solution and standard solution as
directed under Liquid Chromatography <2.01> according to
the following conditions, and determine the peak areas, AT
and AS, of carboplatin of these solutions.
Amount (mg) of carboplatin (C6H12N2O4Pt)
MS AT/AS 4/5
Supplement I, JP XVI
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 230 nm).
Column: A stainless steel column 4.0 mm in inside diameter and 25 cm in length, packed with octadecylsilanized
silica gel for liquid chromatography (10 mm in particle diameter).
Column temperature: A constant temperature of about
359C.
Mobile phase: Dissolve 8.5 g of tetrabutylammonium
hydrogensulfate in 80 mL of water, add 3.4 mL of phosphoric acid, and adjust to pH 7.5 with a solution of sodium
hydroxide (43 in 100). To 10 mL of this solution add 880 mL
of water and 10 mL of acetonitrile.
Flow rate: Adjust the flow rate so that the retention time
of carboplatin is about 4 minutes.
System suitability
System performance: To a solution of 25 mg of carboplatin in 20 mL of water add 2.5 mL of a solution of 65 mg of
1,3-phenylenediamine hydrochloride in 50 mL of water, and
add water to make 25 mL. When the procedure is run with
10 mL of this solution under the above operating conditions,
carboplatin and 1,3-phenylenediamine are eluted in this order with the resolution between these peaks being not less
than 2.0.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of carboplatin is not more than 1.0z.
Containers and storage ContainersHermetic containers.
StorageLight-resistant.
Expiration date
Official Monographs
Cefdinir
Cefazolin Sodium
2379
2380
Official Monographs
standard solution as directed under Ultraviolet-visible Spectrophotometry <2.24>, using water as the control.
Dissolution rate (z) with respect to the labeled amount of
cefditoren pivoxil (C25H28N6O7S3)
MS/MT AT/AS 1/C 450
Cefoperazone Sodium
Supplement I, JP XVI
ameter).
Column temperature: A constant temperature of about
359C.
Mobile phase: To 57 mL of acetic acid (100) add 139 mL
of triethylamine and water to make 1000 mL. To 20 mL of
this solution add 835 mL of water, 140 mL of acetonitrile
and 5 mL of dilute acetic acid.
Flow rate: Adjust the flow rate so that the retention time
of cefoperazone is about 10 minutes.
System suitability
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, the internal standard and cefoperazone are eluted in
this order with the resolution between these peaks being not
less than 5.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the ratios
of the peak area of cefoperazone to that of the internal standard is not more than 1.0z.
Supplement I, JP XVI
equivalent to about 60 mg (potency), dissolve in 60 mL of a
mixture of water, acetonitrile and acetic acid (100) (99:99:2),
add exactly 12 mL of the internal standard solution, then
add a mixture of water, acetonitrile and acetic acid (100)
(99:99:2) to make 100 mL, and use this solution as the standard solution. Then, proceed as directed in the Assay under
Cefpodoxime Proxetil.
Amount [mg (potency)] of cefpodoxime (C15H17N5O6S2)
MS (QT1 QT2)/(QS1 QS2) 10/V
Official Monographs
2381
409C.
Mobile phase: A mixture of water and methanol (11:9).
Flow rate: Adjust the flow rate so that the retention time
of one of the two peaks that elutes firster is about 24
minutes.
System suitability
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, the resolution between the two peaks of cefpodoxime proxetil is not less than 4.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the total
area of the two peaks of cefpodoxime proxetil is not more
than 2.0z.
Assay Weigh accurately the mass of not less than 20 Cefpodoxime Proxetil Tablets, and powder. Weigh accurately a
portion of the powder, equivalent to about 0.3 g (potency)
of Cefpodoxime Proxetil, add 80 mL of a mixture of water,
acetonitrile and acetic acid (100) (99:99:2), agitate for 10
minutes with the aid of ultrasonic waves, and add a mixture
of water, acetonitrile and acetic acid (100) (99:99:2) to make
exactly 100 mL. Filter the solution through a membrane
filter with a pore size not exceeding 0.45 mm. Discard the
first 10 mL of the filtrate, pipet 10 mL of the subsequent
filtrate, add exactly 6 mL of the internal standard solution,
then, add a mixture of water, acetonitrile and acetic acid
(100) (99:99:2) to make 50 mL, and use this solution as the
sample solution. Separately, weigh accurately an amount of
Cefpodoxime Proxetil RS, equivalent to about 60 mg
(potency), dissolve in 60 mL of a mixture of water, acetonitrile and acetic acid (100) (99:99:2), add exactly 12 mL of the
internal standard solution, then add a mixture of water,
acetonitrile and acetic acid (100) (99:99:2) to make 100 mL,
and use this solution as the standard solution. Then, proceed
as directed in the Assay under Cefpodoxime Proxetil.
Amount [mg (potency)] of cefpodoxime (C15H17N5O6S2)
MS (QT1 QT2)/(QS1 QS2) 5
ContainersTight containers.
2382
Official Monographs
Cefteram Pivoxil
Change the origin/limits of content, the Identification and the Purity as follows:
Cefteram Pivoxil contains not less than 743 mg
(potency) and not more than 824 mg (potency) per mg,
calculated on the anhydrous basis. The potency of
Cefteram Pivoxil is expressed as mass (potency) of
cefteram (C16H17N9O5S2: 479.49).
Identification (1) Determine the absorption spectrum of
a solution of Cefteram Pivoxil in 0.05 mol/L hydrochloric
acid-methanol TS (1 in 100,000) as directed under Ultraviolet-visible Spectrophotometry <2.24>, and compare the
spectrum with the Reference Spectrum: both spectra exhibit
similar intensities of absorption at the same wavelengths.
(2) Determine the infrared absorption spectrum of
Cefteram Pivoxil as directed in the potassium bromide disk
method under Infrared Spectrophotometry <2.25>, and compare the spectrum with the Reference Spectrum: both spectra exhibit similar intensities of absorption at the same wave
numbers.
(3) Determine the 1H spectrum of a solution of Cefteram
Pivoxil in deuterated chloroform for nuclear magnetic
resonance spectroscopy (1 in 10) as directed under Nuclear
Magnetic Resonance Spectroscopy <2.21>, using tetramethylsilane for nuclear magnetic resonance spectroscopy as an internal reference compound: it exhibits single signals A, B
and C, at around d 1.2 ppm, at around d 2.5 ppm and at
around d 4.0 ppm, respectively. The ratio of the integrated
intensity of these signals, A:B:C, is about 3:1:1.
Purity (1) Heavy metals <1.07>Proceed with 1.0 g of
Cefteram Pivoxil according to Method 2, and perform the
test. Prepare the control solution with 2.0 mL of Standard
Lead Solution (not more than 20 ppm).
(2) Related substancesDissolve 50 mg of Cefteram
Pivoxil in 50 mL of the mobile phase, and use this solution
as the sample solution. Pipet 1 mL of the sample solution,
add the mobile phase to make exactly 50 mL, and use this solution as the standard solution. Perform the test with exactly
10 mL each of the sample solution and standard solution as
directed under Liquid Chromatography <2.01> according to
the following conditions, and determine each peak area by
the automatic integration method: the area of the peak, having the relative retention time of about 0.9 with respect to
cefteram pivoxil from the sample solution is not larger than
1.25 times the peak area of cefteram pivoxil from the standard solution, the area of the peak, having the relative retention time of about 0.1 is not larger than 1/4 times the peak
area of cefteram pivoxil from the standard solution, and the
total area of the peaks other than cefteram pivoxil is not
larger than 2.75 times the peak area of cefteram pivoxil from
the standard solution. For the above calculation, use the
area of the peak, having the relative retention time of about
Supplement I, JP XVI
0.1, after multiplying by its relative response factor, 0.74.
Operating conditions
Detector, column, column temperature, mobile phase,
and flow rate: Proceed as directed in the operating conditions in the Assay.
Time span of measurement: About 2 times as long as the
retention time of cefteram pivoxil.
System suitability
Test for required detectability: Measure exactly 1 mL of
the standard solution, and add the mobile phase to make exactly 10 mL. Confirm that the peak area of cefteram pivoxil
obtained from 10 mL of this solution is equivalent to 7 to
13z of that from 10 mL of the standard solution.
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of cefteram pivoxil are not less than 5000
and not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of cefteram pivoxil is not more than 3.0z.
Ceftibuten Hydrate
Supplement I, JP XVI
System suitability
Test for required detectability: Pipet 2 mL of the standard
solution, and add 0.1 mol/L phosphate buffer solution for
antibiotics, pH 8.0 to make exactly 20 mL. Confirm that the
peak area of ceftibuten obtained from 5 mL of this solution
is equivalent to 7 to 13z of that of ceftibuten obtained from
5 mL of the standard solution.
System performance: Dissolve 5 mg of Ceftibuten Hydrate in 20 mL of 0.1 mol/L hydrochloric acid TS, and allow to stand at 409
C for 1 hour. To 4 mL of this solution
add 0.1 mol/L phosphate buffer solution for antibiotics, pH
8.0 to make 25 mL. When the procedure is run with 5 mL of
this solution under the above operating conditions, transisomer of ceftibuten and ceftibuten are eluted in this order
with the resolution between these peaks being not less than
2.0.
System repeatability: When the test is repeated 5 times
with 5 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of ceftibuten is not more than 2.0z.
(ii) Keep the sample solution at not exceeding 59C, and
use within 24 hours after preparation. To 5 mg of Ceftibuten
Hydrate add 20 mL of the mobile phase, agitate with the aid
of ultrasonic waves, if necessary, then shake to dissolve,
filter through a membrane filter with a pore size not exceeding 0.45 mm, and use the filtrate as the sample solution. Perform the test with 10 mL of the sample solution as directed
under Liquid Chromatography <2.01> according to the following conditions. Determine each peak area by the automatic integration method, and calculate their amounts by
the area percentage method: the total amount of the peaks
that are eluted faster than ceftibuten is not more than 5.0z.
For these calculations use the areas of these peaks after multiplying by their relative response factors, 1.63, respectively.
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 263 nm).
Column: A stainless steel column 7.5 mm in inside diameter and 60 cm in length, packed with glycol etherifized
silica gel for liquid chromatography (10 mm in particle diameter).
Column temperature: A constant temperature of about
259C.
Mobile phase: Dissolve 1.05 g of disodium hydrogen
phosphate dodecahydrate and 0.58 g of potassium dihydrogen phosphate in water to make 1000 mL.
Flow rate: Adjust the flow rate so that the retention time
of ceftibuten is about 20 minutes.
Time span of measurement: About 1.6 times as long as the
retention time of ceftibuten.
System suitability
Test for required detectability: To 1 mL of the sample solution add the mobile phase to make 20 mL, and use this solution as the solution for system suitability test. Pipet 2 mL
of the solution for system suitability test, and add the mobile
phase to make exactly 20 mL. Confirm that the peak area of
ceftibuten obtained from 10 mL of this solution is equivalent
to 7 to 13z of that of ceftibuten obtained from 10 mL of the
Official Monographs
2383
2384
Official Monographs
Change to read:
Cellacefate
Cellulose Acetate Phthalate
Supplement I, JP XVI
Amount (z) of free acids 0.8306A/M
[9004-38-0]
The amount of free acids is not more than 3.0z, calculated as phthalic acid (C8H6O4: 166.13).
This monograph is harmonized with the European Pharmacopoeia and the U.S. Pharmacopeia. The parts of the text
that are not harmonized are marked with symbols (
).
Water <2.48> Not more than 5.0z (0.5 g, volumetric titration, direct titration, using a mixture of ethanol (99.5) and
dichloromethane (3:2) instead of methanol for Karl Fischer
method).
100
100 B
Viscosity <2.53> Weigh accurately a quantity of Cellacefate, equivalent to 15 g calculated on the anhydrous basis,
dissolve in 85 g of a mixture of acetone and water (249: 1 in
mass), and use this solution as the sample solution. Perform
the test with the sample solution at 25 0.29C as directed in
Method 1 to obtain the kinematic viscosity n. Separately, determine the density, r, of the sample solution as directed under Determination of Specific Gravity and Density <2.56>,
and calculate the viscosity of the sample solution, h, as h
rn: not less than 45 mPas and not more than 90 mPas.
(2) Acetyl groupWeigh accurately about 0.1 g of Cellacefate, put in a glass-stoppered conical flask, add exactly
25 mL of 0.1 mol/L sodium hydroxide VS, and boil for 30
minutes under a reflux condenser. After cooling, add 2 3
drops of phenolphthalein TS, and titrate <2.50> the excess of
sodium hydroxide with 0.1 mol/L hydrochloric acid VS.
Perform a blank determination.
A: Amount (mL) of 0.1 mol/L sodium hydroxide VS consumed, corrected by the blank determination
M: Amount (g) of Cellacefate, calculated on the anhydrous basis
and storage
ContainersTight containers.
Supplement I, JP XVI
Add the following:
Cetotiamine Hydrochloride
Hydrate
C18H26N4O6S.HCl.H2O: 480.96
(3Z)-4-s
N-[(4-Amino-2-methylpyrimidin-5-yl)methyl]-Nformylaminot
-3-(ethoxycarbonylsulfanyl)pent-3-enyl ethyl
carbonate monohydrochloride monohydrate
[616-96-6, anhydride]
Official Monographs
2385
2386
Official Monographs
Amount (mg) of cetotiamine hydrochloride
(C18H26N4O6S.HCl)
M S Q T/Q S
ContainersTight containers.
Chlordiazepoxide Tablets
Supplement I, JP XVI
Amount (mg) of chlordiazepoxide (C16H14ClN3O)
MS QT/QS 5/V
Uniformity of dosage units <6.02> Perform the test according to the following method: it meets the requirement of the
Content uniformity test.
Conduct this procedure without exposure to light using
light-resistant vessels. To 1 tablet of Chlordiazepoxide
Tablets add 1 mL of water, shake to disintegrate the tablet,
then add 20 mL of methanol, shake, add methanol to make
exactly 25 mL, and filter through a membrane filter with a
pore size not exceeding 0.5 mm. Discard the first 5 mL of the
filtrate, take exactly V mL of the subsequent filtrate equivalent to about 2 mg of chlordiazepoxide (C16H14ClN3O), add
exactly 1 mL of the internal standard solution, then add
methanol to make 20 mL, and use this solution as the sample
solution. Then, proceed as directed in the Assay.
Supplement I, JP XVI
Chlorpheniramine Maleate RS, previously dried at 1059C
for 3 hours, and dissolve in water to make exactly 100 mL.
Pipet 2 mL of this solution, add water to make exactly 100
mL, and use this solution as the standard solution. Perform
the test with exactly 50 mL each of the sample solution and
standard solution as directed under Liquid Chromatography
<2.01> according to the following conditions, and determine
the peak areas, AT and AS, of chlorpheniramine of each solution.
Dissolution rate (z) with respect to the labeled amount of
chlorpheniramine maleate (C16H19ClN2.C4H4O4)
MS/MT AT/AS 1/C 18
Official Monographs
2387
2388
Official Monographs
TS).
Each mL of 1 mol/L sodium hydroxide VS
64.04 mg of C6H8O7
ContainersTight containers.
Citric Acid Hydrate occurs as colorless crystals, white granules or crystalline powder.
It is very soluble in water, and freely soluble in ethanol
(99.5).
It is efflorescent in dry air.
Supplement I, JP XVI
in 4 mL of water, add 3 mL of hydrochloric acid and 1 g of
zinc, and boil for 1 minute. After allowing to stand for 2
minutes, take the supernatant liquid, add 0.25 mL of a solution of phenylhydrazinium chloride (1 in 100), heat to boil,
and then cool quickly. To this solution add the equal volume
of hydrochloric acid and 0.25 mL of a solution of potassium
hexacyanoferrate (III) (1 in 20), mix, and allow to stand for
30 minutes: the solution has no more color than the following control solution prepared at the same time (not more
than 360 ppm expressed as oxalic anhydride).
Control solution: To 4 mL of a solution of oxalic acid dihydrate (1 in 10,000) add 3 mL of hydrochloric acid and 1 g
of zinc, and proceed in the same manner as the test solution.
(4)
Heavy metals <1.07>Proceed with 2.0 g of Citric
Acid Hydrate according to Method 2, and perform the test.
Prepare the control solution with 2.0 mL of Standard Lead
Solution (not more than 10 ppm).
(5) Readily carbonizable substancesPlace 1.0 g of
Citric Acid Hydrate in a Nessler tube, add 10 mL of sulfuric
acid, immediately heat in a 90 19
C water bath for 60
minutes, and cool quickly. Compare the color of 2.0 mL
each of this solution and Matching Fluid K, using test tubes
12 mm in outside diameter, from a side against white background: the solution is not more colored than the matching
fluid.
Water <2.48> Not less than 7.5z and not more than 9.0z
(0.5 g, volumetric titration, direct titration).
Residue on ignition <2.44>
Assay Weigh accurately about 0.55 g of Citric Acid Hydrate, dissolve in 50 mL of water, and titrate <2.50> with 1
mol/L sodium hydroxide VS (indicator: 1 drop of phenolphthalein TS).
Each mL of 1 mol/L sodium hydroxide VS
64.04 mg of C6H8O7
ContainersTight containers.
Clindamycin Hydrochloride
Supplement I, JP XVI
time of about 0.7 to clindamycin, and that of 7-epiclindamycin, having the relative retention time of about 0.8 to clindamycin, obtained from the sample solution are not larger
than 2 times the peak area of clindamycin from the standard
solution, the area of the peak other than clindamycin and
the peaks mentioned above is not larger than the peak area
of clindamycin from the standard solution, and the total
area of the peaks other than clindamycin from the sample
solution is not larger than 4 times the peak area of clindamycin from the standard solution.
Operating conditions
Detector, column, column temperature, mobile phase,
and flow rate: Proceed as directed in the operating conditions in the Assay.
Time span of measurement: About 2 times as long as the
retention time of clindamycin, beginning after the solvent
peak.
System suitability
Test for required detectability: Pipet 1 mL of the standard
solution, and add the mobile phase to make exactly 10 mL.
Confirm that the peak area of clindamycin obtained from 20
mL of this solution is equivalent to 7 to 13z of that of clindamycin obtained from 20 mL of the standard solution.
System performance: When the procedure is run with 20
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of clindamycin are not less than 6000 and
not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 20 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of clindamycin is not more than 2.0z.
Clomifene Citrate
Official Monographs
2389
C.
2309
Injection port temperature: A constant temperature of
about 2709
C.
Detector temperature: A constant temperature of about
3009
C.
Carrier gas: Helium.
Flow rate: Adjust the flow rate so that the retention time
of the first peak of clomifene citrate is about 7.5 minutes.
Split ratio: 1:50.
System suitability
System performance: When the procedure is run with 1 mL
of the sample solution under the above operating conditions,
the resolution between the two adjacent peaks having the
retention time of about 8 minutes is not less than 5.
System repeatability: When the test is repeated 6 times
with 1 mL of the sample solution under the above operating
conditions, the relative standard deviation of the result of
Ab/(Aa Ab) is not more than 1.0z.
2390
Official Monographs
MS: Amount (mg) of codeine phosphate hydrate for assay, calculated on the anhydrous basis
MT: Amount (g) of 1z Codeine Phosphate Powder
Operating conditions
Proceed as directed in the operating conditions in the Assay.
System suitability
System performance: When the procedure is run with 50
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of codeine are not less than 3000 and not
more than 2.0, respectively.
System repeatability: When the test is repeated 6 times
with 50 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of codeine is not more than 2.0z.
Supplement I, JP XVI
ed under Liquid Chromatography <2.01> according to the
following conditions, and determine the peak areas, AT and
AS, of codeine of each solution.
Dissolution rate (z) with respect to the labeled amount of
codeine phosphate hydrate (C18H21NO3.H3PO4.1/2H2O)
MS/MT AT/AS 18/25 1.023
MS: Amount (mg) of codeine phosphate hydrate for assay, calculated on the anhydrous basis
MT: Amount (g) of 10z Codeine Phosphate Powder
Operating conditions
Proceed as directed in the operating conditions in the Assay.
System suitability
System performance: When the procedure is run with 50
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of codeine are not less than 3000 and not
more than 2.0, respectively.
System repeatability: When the test is repeated 6 times
with 50 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of codeine is not more than 2.0z.
Colestimide
[95522-45-5]
Supplement I, JP XVI
Official Monographs
5 mL of hydrogen peroxide (30), and ignite the ethanol. After cooling, add 1 mL of sulfuric acid, then, proceed according to Method 4, and perform the test. Prepare the control
solution as follows: To 10 mL of a solution of magnesium
nitrate hexahydrate in ethanol (95) (1 in 10) add 5 mL of
hydrogen peroxide (30), and ignite the ethanol. After cooling, add 1 mL of sulfuric acid, then, proceed in the same
manner as for the test solution, and add 2.0 mL of Standard
Lead Solution and water to make 50 mL (not more than 10
ppm).
(2) Related substancesTo exactly 0.50 g of Colestimide add exactly 20 mL of water, shake for 1 hour, centrifuge, and use the supernatant liquid as the sample solution. Determine the absorbance of the sample solution at 210
nm as directed under Ultraviolet-visible Spectrophotometry
<2.24>: the absorbance is not more than 0.50.
(3) Residual solvent Being specified separately.
Loss on drying <2.41>
um, 1059
C, 4 hours).
Degree of swelling Weigh accurately about 1 g of Colestimide, put in a 25-mL glass stoppered measuring cylinder
(about 11 mm in inside diameter), add 23 mL of water,
shake for 2 minutes, and add water to make 25 mL. After
standing for 2 hours, measure the volume of the resin layer,
and determine the volume per g, calculated on the dried basis: the volume is 12 18 mL/g.
Assay (1) ChlorineWeigh accurately about 0.2 g of
Colestimide, add 50 mL of water, and shake. Add 1 mL of
nitric acid and 25 mg of potassium nitrate, shake, and titrate
<2.50> with 0.1 mol/L silver nitrate VS (potentiometric titration). Perform a blank determination in the same manner,
and make any necessary correction.
Each mL of 0.1 mol/L silver nitrate VS
3.545 mg of Cl
(2) Exchange capacityWeigh accurately about 0.45 g
of sodium cholate hydrate (separately determine the water),
dissolve in water to make exactly 100 mL, and use this solution as the sodium cholate standard stock solution.
Separately, weigh accurately about 30 mg of Colestimide,
add exactly 30 mL of the sodium cholate standard stock solution, shake for 1 hour, and centrifuge or filter through a
membrane filter with a pore size not exceeding 0.8 mm. Pipet
5 mL of the supernatant liquid or the filtrate, add exactly 5
mL of the internal standard solution, and use this solution as
the sample solution. Separately, pipet 5 mL of the sodium
cholate standard stock solution, add exactly 5 mL of the internal standard solution, and use this solution as the standard solution. Perform the test with 10 mL each of the sample solution and standard solution as directed under Liquid
Chromatography <2.01> according to the following conditions, and calculate the ratios, QT and QS, of the peak area
of cholic acid to that of the internal standard.
2391
ContainersTight containers.
Colestimide Tablets
2392
Official Monographs
ContainersTight containers.
Supplement I, JP XVI
Corn Starch
Crospovidone
This monograph is harmonized with the European Pharmacopoeia and the U.S. Pharmacopeia. The parts of the text
that are not harmonized are marked with symbols (
).
M1: The mass (g) of the residue with sieve after 5 hours
drying
Supplement I, JP XVI
M2: Amount (g) of Crospovidone, calculated on the dried
basis
M3: Mass (g) of the sieve
Purity (1) Heavy metals <1.07>Proceed with 2.0 g of
Crospovidone according to Method 2, and perform the test.
Prepare the control solution with 2.0 mL of Standard Lead
Solution (not more than 10 ppm).
(2) Water-soluble substancesPlace 25.0 g of Crospovidone in a 400-mL beaker, add 200 mL of water, and stir for
1 hour. Transfer the suspension to a 250-mL volumetric
flask, rinsing with water, and dilute to volume with water.
Allow the bulk of the solids to settle. Filter about 100 mL of
the almost clear supernatant liquid through a 0.45 mm membrane filter, protected by superimposing a 3 mm membrane
filter. Transfer exactly 50 mL of the clear filtrate to a tared
100-mL beaker, evaporate to dryness and dry at 105 1109C
for 3 hours: the mass of the residue is not more than 75 mg.
(3) 1-Vinyl-2-pyrrolidoneTo 1.250 g of Crospovidone
add exactly 50 mL of methanol, and shake for 60 minutes.
Leave bulk to settle, filter through a 0.2 mm membrane
filter, and use the filtrate as the sample solution. Separately,
dissolve 50 mg of 1-vinyl-2-pyrrolidone in methanol to make
exactly 100 mL. Pipet 1 mL of this solution, and add
methanol to make exactly 100 mL. To exactly 5 mL of this
solution add the mobile phase to make exactly 100 mL, and
use this solution as the standard solution. Perform the test
with exactly 50 mL each of the sample solution and standard
solution as directed under Liquid Chromatography <2.01>
according to the following conditions: the peak area of 1vinyl-2-pyrrolidone obtained from the sample solution is not
larger than that obtained from the standard solution (not
more than 10 ppm).
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 235 nm).
Column: Two stainless steel columns, one is 4 mm in inside diameter and 25 mm in length and the other is 4 mm in
inside diameter and 250 mm in length, they are packed with
octadecylsilanized silica gel for liquid chromatography (5
mm in particle diameter), and used them as the pre-column
and the separation column, respectively.
Column temperature: A constant temperature of about
409C.
Mobile phase: A mixture of water and acetonitrile (9:1).
Flow rate: 1.0 mL per minute.
Washing of pre-column: After each injection of the sample solution, wash the pre-column by passing the mobile
phase backwards, at the same flow rate as applied in the test,
for 30 minutes.
System suitability
System performance: Dissolve 10 mg of 1-vinyl-2-pyrrolidone and 0.50 g of vinyl acetate in methanol to make 100
mL. To 1 mL of this solution add the mobile phase to make
100 mL. When the procedure is run with 50 mL of this solution under the above operating conditions, 1-vinyl-2-pyrrolidone and vinyl acetate are eluted in this order with the resolution between these peaks being not less than 2.0.
Official Monographs
2393
2394
Official Monographs
ContainersTight containers.
L-Cystine
L-
C6H12N2O4S2: 240.30
3,3?-Disulfanediylbis[(2R)-2-aminopropanoic acid]
[56-89-3]
L-Cystine, when dried, contains not less than 99.0z
and not more than 101.0z of C6H12N2O4S2.
Supplement I, JP XVI
Solution (not more than 10 ppm).
(6) Iron <1.10>Prepare the test solution with 1.0 g of
L-Cystine according to Method 3, and perform the test according to Method A. Prepare the control solution with 1.0
mL of Standard Iron Solution (not more than 10 ppm).
(7) Related substancesDissolve 0.20 g of L-Cystine in
20 mL of 1 mol/L hydrochloric acid TS, and use this solution as the sample solution. Pipet 1 mL of the sample solution, and add water to make exactly 10 mL. Pipet 1 mL of
this solution, add water to make exactly 50 mL, and use this
solution as the standard solution. Perform the test with these
solutions as directed under Thin-layer Chromatography
<2.03>. Spot 5 mL each of the sample solution and standard
solution on a plate of silica gel for thin-layer chromatography. Develop the plate with a mixture of 1-propanol
and ammonia solution (28) (67:33) to a distance of about 10
cm, and dry the plate at 809C for 30 minutes. Spray evenly a
solution of ninhydrin in a mixture of methanol and acetic
acid (100) (97:3) (1 in 100) on the plate, and heat at 809C for
10 minutes: the spot other than the principal spot obtained
from the sample solution is not more intense than the spot
from the standard solution.
(8) Residual solvent Being specified separately.
Loss on drying <2.41>
hours).
Assay Weigh accurately about 30 mg of L-Cystine, previously dried, and perform the test as directed under Nitrogen
Determination <1.08>.
Each mL of 0.005 mol/L sulfuric acid VS
1.202 mg of C6H12N2O4S2
Containers and storage ContainersTight containers.
StorageLight-resistant.
Daunorubicin Hydrochloride
Supplement I, JP XVI
Spectrum or the spectrum of a solution of Daunorubicin
Hydrochloride RS prepared in the same manner as the sample solution: both spectra exhibit similar intensities of absorption at the same wavelengths.
(2) Determine the infrared absorption spectrum of
Daunorubicin Hydrochloride as directed in the potassium
chloride disk method under Infrared Spectrophotometry
<2.25>, and compare the spectrum with the Reference Spectrum or the spectrum of Daunorubicin Hydrochloride RS:
both spectra exhibit similar intensities of absorption at the
same wave numbers.
(3) A solution of Daunorubicin Hydrochloride (1 in 50)
responds to the Qualitative Tests <1.09> (2) for chloride.
Purity
(3) Related substancesWeigh accurately about 50 mg
of Daunorubicin Hydrochloride, dissolve in diluted acetonitrile (43 in 100) to make exactly 50 mL, and use this solution
as the sample solution. Separately, weigh accurately about
50 mg of Daunorubicin Hydrochloride RS, and dissolve in
diluted acetonitrile (43 in 100) to make exactly 50 mL. Pipet
1 mL of this solution, add diluted acetonitrile (43 in 100) to
make exactly 200 mL, and use this solution as the standard
solution (1). Separately, weigh accurately about 5 mg of
Doxorubicin Hydrochloride RS, and dissolve in diluted
acetonitrile (43 in 100) to make exactly 100 mL. Pipet 1 mL
of this solution, add diluted acetonitrile (43 in 100) to make
exactly 10 mL, and use this solution as the standard solution
(2). Perform the test with exactly 5 mL each of the sample solution and the standard solutions (1) and (2) as directed under Liquid Chromatography <2.01> according to the following conditions. Determine each peak area by the automatic
integration method, and calculate the amounts of related
substances by the following equations: each amount of the
peaks, having a relative retention time of about 0.3, about
0.6, about 0.7, about 0.8, about 1.7 and about 2.0 to
daunorubicin, is not more than 1.3z, not more than 1.0z,
not more than 0.3z, not more than 0.5z, not more than
0.4z and not more than 0.5z, respectively, and the amount
of doxorubicin is not more than 0.1z. Furthermore, the
total amount of the peaks, other than daunorubicin and the
peaks mentioned above, is not more than 0.4z. For this calculation use the area of the peak, having a relative retention
time of about 0.3 to daunorubicin, after multiplying by its
relative response factor 0.7.
Each amount (z) of related substances other
than doxorubicin
MS1/MT AT/AS1 1/2
Official Monographs
2395
Dibekacin Sulfate
2396
Official Monographs
Supplement I, JP XVI
1% Dihydrocodeine Phosphate
Powder
1%
MS: Amount (mg) of dihydrocodeine phosphate for assay, calculated on the dried basis
MT: Amount (g) of 1z Dihydrocodeine Phosphate Powder
Operating conditions
Detector, column, column temperature, mobile phase,
and flow rate: Proceed as directed in the operating conditions in the Assay.
System suitability
System performance: When the procedure is run with 20
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of diethylcarbamazine are not less than
5000 and not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 20 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of diethylcarbamazine is not more than 2.0z.
Operating conditions
Proceed as directed in the operating conditions in the Assay.
System suitability
System performance: When the procedure is run with 20
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of dihydrocodeine are not less than 3000
and not more than 2.0, respectively.
System repeatability: When the test is repeated 6 times
with 20 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of dihydrocodeine is not more than 2.0z.
Supplement I, JP XVI
MS: Amount (mg) of dihydrocodeine phosphate for assay, calculated on the dried basis
MT: Amount (g) of 10z Dihydrocodeine Phosphate Powder
Operating conditions
Proceed as directed in the operating conditions in the Assay.
System suitability
System performance: When the procedure is run with 50
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of dihydrocodeine are not less than 3000
and not more than 2.0, respectively.
System repeatability: When the test is repeated 6 times
with 50 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of dihydrocodeine is not more than 2.0z.
Official Monographs
2397
Donepezil Hydrochloride
Dorzolamide Hydrochloride
C10H16N2O4S3.HCl: 360.90
(4S,6S)-4-Ethylamino-6-methyl-5,6-dihydro4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide
monohydrochloride
[130693-82-2]
2398
Official Monographs
Supplement I, JP XVI
Mobile phase
A (volz)
Mobile phase
B (volz)
0 10
10 30
100
100 50
0
0 50
Supplement I, JP XVI
tion, respectively. Perform the test with exactly 10 mL each
of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions, and determine the peak areas, AT and AS, of
dorzolamide in both solutions.
Amount (mg) of dorzolamide hydrochloride
(C10H16N2O4S3.HCl)
M S A T/ A S
ContainersWell-closed contain-
Dorzolamide Hydrochloride
Ophthalmic Solution
Official Monographs
2399
Sterility <4.06> Perform the test according to the Direct inoculation method, using the culture medium containing
0.7z polysorbate 80 and 0.1z of lecithin: it meets the requirement.
Assay Weigh accurately a portion of Dorzolamide
Hydrochloride Ophthalmic Solution, equivalent to about 5
mg of dorzolamide (C10H16N2O4S3), add the diluting solution to make exactly 50 mL, and use this solution as the sample solution. Separately, weigh accurately about 20 mg of
Dorzolamide Hydrochloride RS (separately determine the
water <2.48> in the same manner as Dorzolamide Hydrochloride), dissolve in the diluting solution to make exactly 200
mL, and use this solution as the standard solution. Perform
the test with exactly 20 mL each of the sample solution and
standard solution as directed under Liquid Chromatography
2400
Official Monographs
ContainersTight containers.
Edaravone
C10H10N2O: 174.20
5-Methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one
[89-25-8]
Supplement I, JP XVI
white crystals or crystalline powder.
It is freely soluble in ethanol (99.5) and in acetic acid
(100), and slightly soluble in water.
Identification (1) Determine the absorption spectrum of
a solution of Edaravone (1 in 200,000) as directed under
Ultraviolet-visible Spectrophotometry <2.24>, and compare
the spectrum with the Reference Spectrum: both spectra exhibit similar intensities of absorption at the same wavelengths.
(2) Determine the infrared absorption spectrum of
Edaravone, previously dried, as directed in the potassium
bromide disk method under Infrared Spectrophotometry
<2.25>, and compare the spectrum with the Reference Spectrum: both spectra exhibit similar intensities of absorption at
the same wave numbers.
pH <2.54> The pH of a solution obtained by dissolving 20
mg of Edaravone in 20 mL of water is between 4.0 and 5.5.
Melting point <2.60>
127 1319
C
Supplement I, JP XVI
Official Monographs
Assay Weigh accurately about 0.2 g of Edaravone, previously dried, dissolve in 40 mL of acetic acid (100), and titrate
<2.50> with 0.1 mol/L perchloric acid VS (potentiometric
titration). Perform a blank determination in the same manner, and make any necessary correction.
Each mL of 0.1 mol/L perchloric acid VS
17.42 mg of C10H10N2O
Containers and storage
ers.
ContainersWell-closed contain-
Edaravone Injection
2401
Operating conditions
Detector, column, column temperature, mobile phase,
and flow rate: Proceed as directed in the operating conditions in the Purity (2) under Edaravone.
Time span of measurement: About 7 times as long as the
retention time of edaravone, beginning after the peak of
edaravone.
System suitability
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of edaravone are not less than 1500 and
not more than 1.4, respectively.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of edaravone is not more than 2.0z.
(ii) Use Edaravone Injection as the sample solution.
Pipet 1 mL of the sample solution, and add the mobile phase
to make exactly 50 mL. Pipet 1 mL of this solution, add the
mobile phase to make exactly 20 mL, and use this solution as
the standard solution. Perform the test with exactly 10 mL
each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the
following conditions. Determine each peak area by the automatic integration method: the area of the peak, having the
relative retention time of about 0.3 to edaravone, obtained
from the sample solution is not larger than 4 times the peak
area of edaravone from the standard solution, the area of
the peak, having the relative retention time of about 0.4 to
edaravone, is not larger than the peak area of edaravone
from the standard solution, and the area of the peak other
than edaravone and the peaks mentioned above is not larger
than 2 times the peak area of edaravone from the standard
solution.
Operating conditions
Detector, column, and mobile phase: Proceed as directed
in the operating conditions in the Assay.
Column temperature: A constant temperature of about
409C.
Flow rate: Adjust the flow rate so that the retention time
of edaravone is about 11 minutes.
Time span of measurement: About 2.5 times as long as the
retention time of edaravone, beginning after the solvent
peak.
System suitability
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of edaravone are not less than 2000 and
not more than 1.4, respectively.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of edaravone is not more than 2.0z.
Bacterial endotoxins <4.01>
2402
Official Monographs
Supplement I, JP XVI
Emedastine Fumarate
Sterility <4.06> Perform the test according to the Membrane filtration method: it meets the requirement.
Assay To an exact volume of Edaravone Injection, equivalent to about 3 mg of edaravone (C10H10N2O) add exactly 10
mL of the internal standard solution, add methanol to make
20 mL, and use this solution as the sample solution.
Separately, weigh accurately about 75 mg of edaravone for
assay, previously dried in vacuum for 3 hours using phosphorus (V) oxide as a desiccant, and dissolve in methanol to
make exactly 50 mL. Pipet 2 mL of this solution, add exactly
10 mL of the internal standard solution, add methanol to
make 20 mL, and use this solution as the standard solution.
Perform the test with 2 mL each of the sample solution and
standard solution as directed under Liquid Chromatography
<2.01> according to the following conditions, and calculate
the ratios, QT and QS, of the peak area of edaravone to that
of the internal standard.
Amount (mg) of edaravone (C10H10N2O)
MS QT/QS 1/25
ContainersHermetic containers.
C17H26N4O.2C4H4O4: 534.56
1-(2-Ethoxyethyl)-2-(4-methyl-1,4-diazepan-1-yl)1H-benzoimidazole difumarate
[87233-62-3]
149 1529
C
Supplement I, JP XVI
Official Monographs
the test. Prepare the control solution with 2.0 mL of Standard Lead Solution (not more than 10 ppm).
(2) Related substancesDissolve 10 mg of Emedastine
Fumarate in 10 mL of the mobile phase, and use this solution as the sample solution. Pipet 1 mL of the sample solution, and add the mobile phase to make exactly 100 mL.
Pipet 1 mL of this solution, add the mobile phase to make
exactly 10 mL, and use this solution as the standard solution. Perform the test with exactly 10 mL each of the sample
solution and standard solution as directed under Liquid
Chromatography <2.01> according to the following conditions. Determine each peak area by the automatic integration method: the area of the peak other than emedastine and
fumaric acid obtained from the sample solution is not larger
than the peak area of emedastine from the standard solution.
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 280 nm).
Column: A stainless steel column 6.0 mm in inside diameter and 15 cm in length, packed with octadecylsilanized
silica gel for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
409C.
Mobile phase: Dissolve 3.9 g of sodium dihydrogen phosphate dihydrate and 2.5 g of sodium lauryl sulfate in 1000
mL of water, and adjust to pH 2.4 with phosphoric acid. To
550 mL of this solution add 450 mL of acetonitrile.
Flow rate: Adjust the flow rate so that the retention time
of emedastine is about 18 minutes.
Time span of measurement: About 2 times as long as the
retention time of emedastine, beginning after the solvent
peak.
System suitability
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of emedastine are not less than 10,000 and
not more than 1.2, respectively.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of emedastine is not more than 2.0z.
(3) Residual solvent Being specified separately.
Loss on drying <2.41>
3 hours).
2403
ContainersTight containers.
Emedastine Fumarate
Extended-release Capsules
2404
Official Monographs
ing, and add the mobile phase to make exactly 100 mL. Centrifuge this solution, pipet 10 mL of the supernatant liquid,
add exactly 5 mL of the internal standard solution, and use
this solution as the sample solution. Separately, weigh accurately about 20 mg of emedastine fumarate for assay,
previously dried at 1059C for 3 hours, and dissolve in the
mobile phase to make 100 mL. Pipet 5 mL of this solution,
and add the mobile phase to make exactly 50 mL. Then,
pipet 10 mL of this solution, add exactly 5 mL of the internal standard solution, and use this solution as the standard
solution. Perform the test with 10 mL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01>, according to the following conditions,
and calculate the ratios, QT and QS, of the peak area of
emedastine to that of the internal standard.
Amount (mg) of emedastine fumarate
(C17H26N4O.2C4H4O4)
MS QT/QS 1/10
ContainersTight containers.
Supplement I, JP XVI
Add the following:
Epalrestat
C15H13NO3S2: 319.40
2-s(5Z)-5-[(2E )-2-Methyl-3-phenylprop-2-en-1-ylidene]-4-oxoacetic acid
2-thioxothiazolidin-3-ylt
[82159-09-9]
222 2279
C
Supplement I, JP XVI
Official Monographs
peak other than epalrestat obtained from the sample solution is not larger than 1/5 times the peak area of epalrestat
from the standard solution, and the total area of the peaks
other than epalrestat obtained from the sample solution is
not larger than the peak area of epalrestat from the standard
solution.
Operating conditions
Detector, column, column temperature, mobile phase,
and flow rate: Proceed as directed in the operating conditions in the Assay.
Time span of measurement: About 3 times as long as the
retention time of epalrestat, beginning after the solvent
peak.
System suitability
Test for required detectability: Pipet 1 mL of the standard
solution, and add N,N-dimethylformamide to make exactly
10 mL. Confirm that the peak area of epalrestat obtained
with 3 mL of this solution is equivalent to 7 to 13z of that
with 3 mL of the standard solution.
System performance: When the procedure is run with 3 mL
of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of epalrestat are not less than 6000 and
not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 3 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of epalrestat is not more than 2.0z.
(3) Residual solvent Being specified separately.
Loss on drying <2.41> Not more than 0.2z (1 g, in vacuum, silica gel, 609
C, 3 hours).
Residue on ignition <2.44>
2405
Epalrestat Tablets
Identification (1) Powder Epalrestat Tablets. To a portion of the powder, equivalent to 50 mg of Epalrestat, add
100 mL of methanol, shake thoroughly, and filter. To 1 mL
of the filtrate add methanol to make 100 mL. Determine the
absorption spectrum of this solution as directed under
Ultraviolet-visible Spectrophotometry <2.24>: it exhibits
maxima between 235 nm and 239 nm, between 290 nm and
294 nm, and between 387 nm and 391 nm.
Uniformity of dosage units <6.02> Perform the test according to the following method: it meets the requirement of the
Content uniformity test.
Conduct this procedure using light-resistant vessels. To 1
tablet of Epalrestat Tablets add exactly 30 mL of N,Ndimethylformamide, shake thoroughly to completely disintegrate the tablet, and centrifuge. Pipet 1 mL of the supernatant liquid, and add N,N-dimethylformamide to make
exactly 100 mL. Pipet V mL of this solution, add exactly V?
mL of N,N-dimethylformamide so that each mL contains
about 4.2 mg of epalrestat (C15H13NO3S2), and use this solution as the sample solution. Separately, weigh accurately
about 50 mg of Epalrestat RS, previously dried in vacuum at
609C for 3 hours with silica gel as a desiccant, and dissolve
2406
Official Monographs
Supplement I, JP XVI
the Assay under Epalrestat.
Amount (mg) of epalrestat (C15H13NO3S2)
MS QT/QS 5/2
ContainersTight containers.
Supplement I, JP XVI
area of ephedrine is not more than 2.0z.
Epoetin Alfa
(Genetical Recombination)
Epoetin Alfa (Genetical Recombination) is an aqueous solution in which a desired product is a recombinant human erythropoietin produced in Chinese
hamster ovary cells. It is a glycoprotein (molecular
weight: ca. 37,000 to 42,000) consisting of 165 amino
acid residues. It has stimulatory effects for the
differentiation and proliferation of erythroid precursor.
It contains not less than 1.1 mg and not more than
1.5 mg of protein per mL, and not less than 1.5 105
units per mg of protein.
Description Epoetin Alfa (Genetical Recombination) occurs as a clear and colorless liquid.
Identification Dilute a suitable volume of Epoetin Alfa
(Genetical Recombination) and Epoetin Alfa RS with water.
To 3 volume of these solutions add 1 volume each of buffer
solution for epoetin alfa sample, heat at 1009C for 5
minutes, and use these solutions as the sample solution and
the standard solution, respectively. Transfer a volume of the
sample solution and the standard solution, equivalent to 0.7
mg of protein, into each sample well of the polyacrylamide
gel for epoetin alfa, and start the SDS-polyacrylamide gel
electrophoresis using a vertical discontinuous buffer solution system. After the electrophoresis, immerse the gel, a
polyvinylidene fluoride membrane and a filter paper in the
blotting TS. Set them on a semi-dry blotting apparatus, and
transcribe for about 1 hour with a constant electric current
Official Monographs
2407
Mobile phase
A (volz)
Mobile phase
B (volz)
05
5 95
98
98 35
2
2 65
2408
Official Monographs
Supplement I, JP XVI
Operating conditions
Detector: A fluorophotometer (excitation wavelength: 373
nm, fluorescence wavelength: 448 nm).
Column: A stainless steel column 3.9 mm in inside diameter and 15 cm in length, packed with octadecylsilanized
silica gel for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
259C.
Mobile phase A: A mixture of water, acetonitrile and
methanol (84:9:7).
Mobile phase B: A mixture of water and methanol (1:1).
Flowing of the mobile phase: Control the gradient by mixing the mobile phases A and B as directed in the following
table.
Mobile phase
A (volz)
Mobile phase
B (volz)
0 20
20 20.1
20.1 27
100
100 0
0
0
0 100
100
5.7 6.7
Supplement I, JP XVI
ameter and 60 cm in length, packed with hydrophilic silica
gel for liquid chromatography.
Column temperature: A constant temperature of about
259C.
Mobile phase: Dissolve 91 mg of disodium hydrogen
phosphate dodecahydrate, 0.27 g of sodium dihydrogen
phosphate dihydrate and 8.77 g of sodium chloride in water
to make 1000 mL.
Flow rate: Adjust the flow rate so that the retention time
of epoetin alfa is about 16 minutes.
Time span of measurement: From the time corresponding
to the exclusion volume of the size-exclusion column until
the elution of epoetin alfa is finished.
System suitability
Test for required detectability: To 1 volume of Epoetin
Alfa (Genetical Recombination) add 49 volumes of the mobile phase, and use this solution as the solution for system
suitability test. Confirm that the peak area of epoetin alfa
obtained with a volume, equivalent to 1 mg of protein, of the
solution for system suitability test is equivalent to 1.5 to 2.5
z of that obtained with the same volume of Epoetin Alfa
(Genetical Recombination).
System performance: Dissolve 40 mg of bovine serum albumin for gel filtration molecular mass marker and 20 mg of
chymotrypsinogen for gel filtration molecular mass marker
in 100 mL of the mobile phase. When the procedure is run
with 50 mL of this solution under the above operating conditions, bovine serum albumin and chymotrypsinogen are eluted in this order with the resolution between these peaks
being not less than 4.
System repeatability: When the test is repeated 6 times
with a volume of Epoetin Alfa (Genetical Recombination),
equivalent to 50 mg of protein, under the above operating
conditions, the relative standard deviation of the area of the
principal peak of epoetin alfa is not more than 2.0z.
(2) Host-derived proteins Being specified separately.
(3) DNA Being specified separately.
Assay (1) Protein contentTake a suitable amount of
Epoetin Alfa (Genetical Recombination), dilute with phosphate buffer solution for epoetin alfa, if necessary, so that
each mL contains 0.5 0.8 mg protein and use as the sample
solution. Determine the absorbance, A, at 280 nm of the
sample solution as directed under Ultraviolet-visible Spectrophotometry <2.24>, using the phosphate buffer solution
for epoetin alfa as the blank.
Amount (mg) of protein in 1 mL of Epoetin Alfa (Genetical
Recombination)
A d 0.909
Official Monographs
2409
M log 4 Ya/Yb
Ya Y1 Y2 Y3 Y4
Yb Y1 Y2 Y3 Y4
d: Dilution factor for TH
C: Concentration (mg/mL) of protein obtained in Assay
(1)
F ? computed by the following equation should be smaller
than F shown in the table against n with which s2 is calculated. Calculate L (p 0.95) by use of the following equation:
L should be not more than 0.3. If F? exceeds F, or if L exceeds 0.3, repeat the test, arranging the assay conditions.
F ? (Y1 Y2 Y3 Y4)2/4fs2
f: Number of animals per group, which should be the
same for each group and not less than 5.
s2 (Sy 2 Y/f )/n
Sy 2: The sum of the squares of each y1, y2, y3 and y4.
Y Y 12 Y 22 Y 32 Y 42
n 4 ( f 1)
2410
Official Monographs
Supplement I, JP XVI
It contains not less than 0.5 mg and not more than
1.5 mg of protein per mL, and not less than 1.5 105
units per mg of protein.
t2 F
t2 F
t2 F
1
2
3
4
5
6
7
8
9
10
11
12
161.45
18.51
10.129
7.709
6.608
5.987
5.591
5.318
5.117
4.965
4.844
4.747
13
14
15
16
17
18
19
20
21
22
23
24
4.667
4.600
4.543
4.494
4.451
4.414
4.381
4.351
4.325
4.301
4.279
4.260
25
26
27
28
29
30
40
60
120
/
4.242
4.225
4.210
4.196
4.183
4.171
4.085
4.001
3.920
3.841
Epoetin Beta
(Genetical Recombination)
Epoetin Beta (Genetical Recombination) is an aqueous solution in which a desired product is a recombinant human erythropoietin produced in Chinese
hamster ovary cells. It is a glycoprotein (molecular
weight: ca. 30,000) consisting of 165 amino acid
residues. It has stimulatory effects for the differentiation and proliferation of erythroid progenitor cell.
Description Epoetin Beta (Genetical Recombination) occurs as a clear and colorless liquid.
Identification (1) Use Epoetin Beta (Genetical Recombination) and Epoetin Beta RS as the sample solution and the
standard solution, respectively. When perform a capillary
electrophoresis with the sample solution and standard solution according to the following conditions, the mobility of
each peak obtained from both solutions is the same and their
migrating images are similar each other.
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 200 nm).
Column: A silica capillary tube 50 mm in inside diameter
and about 50 cm in length, chemically coated inner surface
with amino groups (about 40 cm in effective length).
Electrolyte solution: Dissolve 32.8 g of sodium dihydrogen phosphate dihydrate in water to make 1000 mL, and adjust to pH 4.5 with a solution, prepared by dissolving 75.2 g
of disodium hydrogen phosphate dodecahydrate in water to
make 1000 mL. To 19 volumes of this solution add 1 volume
of ethanol (99.5).
Running temperature: A constant temperature of about
209C.
Running conditions: Migration current (a constant current of about 45 mA), migration time (30 minutes).
Injection of sample and standard solutions: 5 seconds
(pressurization: 0.5 psi).
Time span of measurement: From 10 minutes to 30
minutes after injection (excluding the peak of solvent origin).
System suitability
System performance: When the procedure is run with the
standard solution under the above operating conditions,
more than 4 major peaks of epoetin beta are detected, and
the resolution between the first and second eluted major
peaks is not less than 0.8.
System repeatability: When the test is repeated 3 times
with the standard solution under the above operating conditions, the relative standard deviation of the migration time
of the first eluted major peak is not more than 2.0z.
(2) Desalt a volume each of Epoetin Beta (Genetical
Recombination) and Epoetin Beta RS, equivalent to 600 mg
of protein, by a suitable method, and term them as the
desalted sample and the desalted reference standard, respectively. Dissolve the desalted sample and the desalted reference standard in 600 mL each of a solution, prepared by dissolving 2.3 g of N-ethylmorpholine in 100 mL of water and
adjusting to pH 8.0 with acetic acid (100), and use these solutions as the desalted sample solution and the desalted
reference standard solution, respectively. To 500 mL each of
the desalted sample solution and the desalted reference standard solution add 3.3 mL of triethylamine for epoetin beta
and 1.5 mL of 2-mercaptoethanol for epoetin beta, and react
at 379
C for 1 hour. After cooling, add 5.5 mL of 4-vinylpyri-
Supplement I, JP XVI
Official Monographs
dine to them, and react at 259C for 1 hour. To these solutions add 50 mL of diluted trifluoroacetic acid for epoetin
beta (1 in 10) to stop the reaction, remove the reagents by a
suitable method, and use the substances so obtained as the
pyridylethylated sample and the pyridylethylated reference
substance, respectively. Dissolve the pyridylethylated sample
and the pyridylethylated reference substance separately in
500 mL of sodium hydrogen carbonate solution (21 in 2500).
To 400 mL each of these solutions add 16 mL of a solution of
lysyl endopeptidase in sodium hydrogen carbonate solution
(21 in 2500) (1 in 50,000), and react at 379C for 24 hours.
While this reaction, additional two 16-mL portions of a solution of lysyl endopeptidase in sodium hydrogen carbonate
(21 in 2500) (1 in 50,000) are added at 4 hours and 20 hours
after starting the reaction. Then, stop the reaction by adding
100 mL of diluted trifluoroacetic acid for epoetin beta (1 in
10), and use these solutions as the sample solution and the
standard solution, respectively. Perform the test with 100 mL
each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the
following conditions, and compare the chromatograms obtained from these solutions: both chromatograms show the
similar peaks at the corresponding retention times.
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 214 nm).
Column: A stainless steel column 4.6 mm in inside diameter and 25 cm in length, packed with octadecylsilanized
silica gel for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
259C.
Mobile phase A: A mixture of water and trifluoroacetic
acid for epoetin beta (1000:1).
Mobile phase B: A mixture of acetonitrile for liquid chromatography, water, and trifluoroacetic acid for epoetin beta
(900:100:1).
Flowing of the mobile phase: Control the gradient by mixing the mobile phases A and B as directed in the following
table.
Time after injection
of sample (min)
Mobile phase
A (volz)
Mobile phase
B (volz)
0 10
10 30
30 50
50 130
130 140
140 150
90
90 80
80
80 40
40 10
10
10
10 20
20
20 60
60 90
90
Flow rate: Adjust the flow rate so that the retention time
of the first peak, which appears after the solvent peak, is
about 17 minutes.
System suitability
System performance: When the procedure is run with the
standard solution under the above operating conditions,
nine major peptide peaks are appeared after the solvent
2411
peak, and the resolution between the peaks eluted at the fifth
and the sixth is not less than 3.
(3) To exactly 100 mL of Epoetin Beta (Genetical Recombination) add 1 mL of resorcinol-copper (II) sulfate TS, and
heat on a water bath for 30 minutes. After ice-cooling, add 2
mL of a mixture of n-butyl acetate and 1-buthanol (4:1),
shake vigorously, and use the upper layer as the sample solution. Separately, dissolve N-acetylneuraminic acid in water
to make three solutions, containing 0.1 mg, 0.2 mg and 0.3
mg of N-acetylneuraminic acid in each mL, and use these solutions as the standard stock solution (1), the standard stock
solution (2) and the standard stock solution (3), respectively.
Pipet 100 mL each of these standard stock solutions, add 1
mL of resorcinol-copper (II) sulfate TS to them, then proceed in the same way as for the sample solution, and use
these solutions so obtained as the standard solution (1), the
standard solution (2) and the standard solution (3), respectively. Determine the absorbances of the sample solution
and the standard solutions (1), (2) and (3) at 625 nm as
directed under Ultraviolet-visible Spectrophotometry <2.24>.
Determine the amount of sialic acid (mg/mL) in the sample
solution, by using the calibration curve obtained from the
standard solutions, and calculate the amount of sialic acid in
Epoetin Beta (Genetical Recombination) by the following
equation: between 10 mol/mol and 13 mol/mol.
Amount of sialic acid (mol/mol of epoetin beta protein)
A/C 18,236/309.27
pH <2.54>
7.0 8.0
2412
Official Monographs
mL.
Flow rate: Adjust the flow rate so that the retention time
of epoetin beta is about 18 minutes.
Time span of measurement: About 2 times as long as the
retention time of epoetin beta.
System suitability
Test for required detectability: When the procedure is run
with 20 mL of diluted Epoetin Beta RS with water containing
0.05 volz polysorbate 20 for epoetin beta (1 in 1000) under
the above conditions, the peak of epoetin beta is detectable.
System performance: When the procedure is run with
Epoetin Beta RS under the above conditions, the number of
theoretical plates of the peak of epoetin beta is not less than
600.
System repeatability: When the test is repeated 6 times
with 20 mL of Epoetin Beta RS under the above operating
conditions, the relative standard deviation of the peak area
of epoetin beta is not more than 1.0z.
(2) Host-derived proteins Being specified separately.
(3) DNA Being specified separately.
Assay (1) Protein contentUse Epoetin Beta (Genetical
Recombination) and Epoetin Beta RS as the sample solution
and the standard solution, respectively. Perform the test
with exactly 15 mL each of the sample solution and standard
solution as directed under Liquid Chromatography <2.01>
according to the following conditions, and determine the
total area, AT and AS, of the main peak and the sub-peak of
epoetin beta.
Amount (mg) of protein in 1 mL of Epoetin Beta (Genetical
Recombination)
C S A T/A S
Supplement I, JP XVI
Time after injection
of sample (min)
Mobile phase
A (volz)
Mobile phase
B (volz)
0 18
18 33
33 43
65 50
50 0
0
35 50
50 100
100
Flow rate: Adjust the flow rate so that the retention time
of the main peak of epoetin beta is about 22 minutes.
System suitability
System performance: When the procedure is run with 15
mL of the standard solution under the above operating conditions, the main peak and the sub-peak of epoetin beta are
eluted in this order, and the number of theoretical plates of
the main peak is not less than 600.
System repeatability: When the test is repeated 6 times
with 15 mL of the standard solution under the above operating conditions, the relative standard deviation of the total
area of the main peak and the sub-peak of epoetin beta is not
more than 4.0z.
(2) Specific activityTo Epoetin Beta (Genetical
Recombination) add 0.1 w/vz bovine serum albumin-sodium chloride-phosphate buffer solution to make three solutions so that each mL contains epoetin beta equivalent to 5,
10 and 20 units (estimate), and use these solutions as the
sample solutions (1), (2) and (3), respectively. Separately, to
Epoetin Beta RS add 0.1 w/vz bovine serum albumin-sodium chloride-phosphate buffer solution to make three solutions so that each mL contains epoetin beta equivalent to 5,
10 and 20 units, and use these solutions as the standard
solutions (1), (2) and (3), respectively. Divide ICR strain
mice into 6 equal groups of not less than 5 mice. Inject exactly 0.2 mL each of the sample solutions and the standard
solutions to ICR strain mice of each group subcutaneously
on the 1st, 2nd and 3rd days. On the 4th day, collect the
blood from the mice, put 20 mL each of the collected blood
in 9.94 mL of blood dilution liquid, mix, and use these mixtures as the dilute blood solution. To each of the dilute
blood solution add 100 mL of a hemolytic agent, mix gently
to hemolyze, and count the particles of hemolytic agentresistant red cell by using a particle counter.
Determine the potency ratio ( Pr) of the sample solution to
the standard solution, and calculate the unit per mg protein
of Epoetin Beta (Genetical Recombination) by the following
equation.
Pr 10M
M 4/3 i Ta/Tb
i log 2
T a S1 S2 S 3 U 1 U 2 U 3
T b S1 S 3 U 1 U 3
U1: Sum of the responses obtained from the sample solution (1)
U2: Sum of the responses obtained from the sample solution (2)
U3: Sum of the responses obtained from the sample solution (3)
S1: Sum of the responses obtained from the standard solu-
Supplement I, JP XVI
tion (1)
S2: Sum of the responses obtained from the standard solution (2)
S3: Sum of the responses obtained from the standard solution (3)
Specific activity (unit/mg of protein) of Epoetin Beta
(Genetical Recombination)
S P r D T/ D S /C
Ethanol
Official Monographs
2413
Ethyl Parahydroxybenzoate
Anhydrous Ethanol
Expiration
115 1189
C
2414
Official Monographs
(3)
Heavy metals <1.07>Dissolve 1.0 g of Ethyl Parahydroxybenzoate in 25 mL of acetone, add 2 mL of dilute
acetic acid and water to make 50 mL, and perform the test
using this solution as the test solution. Prepare the control
solution as follows: to 2.0 mL of Standard Lead Solution
add 25 mL of acetone, 2 mL of dilute acetic acid, and water
to make 50 mL (not more than 20 ppm).
(4) Related substancesDissolve 50 mg of Ethyl Parahydroxybenzoate in 2.5 mL of methanol, and add the mobile phase to make exactly 50 mL. Pipet 10 mL of this solution, add the mobile phase to make exactly 100 mL, and use
this solution as the sample solution. Pipet 1 mL of the sample solution, and add the mobile phase to make exactly 20
mL. Pipet 1 mL of this solution, add the mobile phase to
make exactly 10 mL, and use this solution as the standard
solution. Perform the test with exactly 10 mL each of the
sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions, and determine each peak area by the automatic integration method: the peak area of parahydroxybenzoic acid
having a relative retention time of about 0.5 to ethyl parahydroxybenzoate obtained from the sample solution is not
larger than the peak area of ethyl parahydroxybenzoate
from the standard solution (0.5z). For this calculation use
the peak area of parahydroxybenzoic acid after multiplying
by the relative response factor, 1.4. Furthermore, the area of
the peak other than ethyl parahydroxybenzoate and parahydroxybenzoic acid from the sample solution is not larger
than the peak area of ethyl parahydroxybenzoate from the
standard solution (0.5z), and the total area of the peaks
other than ethyl parahydroxybenzoate is not larger than 2
times the peak area of ethyl parahydroxybenzoate from the
standard solution (1.0z). For this calculation the peak area
not larger than 1/5 times the peak area of ethyl parahydroxybenzoate from the standard solution is excluded (0.1z).
Operating conditions
Detector, column, column temperature, mobile phase,
and flow rate: Proceed as directed in the operating conditions in the Assay.
Time span of measurement: About 4 times as long as the
retention time of ethyl parahydroxybenzoate.
System suitability
Test for required detectability: To exactly 2 mL of the
standard solution add the mobile phase to make exactly 10
mL. Confirm that the peak area of ethyl parahydroxybenzoate obtained with 10 mL of this solution is equivalent to 14 to
26z of that with 10 mL of the standard solution.
System performance: Proceed as directed in the system
suitability in the Assay.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of ethyl parahydroxybenzoate is not more than 2.0z.
Assay Weigh accurately about 50 mg each of Ethyl Parahydroxybenzoate and Ethyl Parahydroxybenzoate RS, dissolve separately in 2.5 mL each of methanol, and add the
Supplement I, JP XVI
mobile phase to make exactly 50 mL. Pipet 10 mL each of
these solutions, add the mobile phase to make exactly 100
mL, and use these solutions as the sample solution and the
standard solution, respectively. Perform the test with exactly
10 mL each of the sample solution and standard solution as
directed under Liquid Chromatography <2.01> according to
the following conditions, and determine the peak areas, AT
and AS, of ethyl parahydroxybenzoate of each solution.
Amount (mg) of ethyl parahydroxybenzoate (C9H10O3)
M S A T /A S
and storage
ContainersWell-closed con-
tainers.
Fexofenadine Hydrochloride
Supplement I, JP XVI
in 100) shows no optical rotation.
Fexofenadine Hydrochloride shows crystal polymorphism.
Fexofenadine Hydrochloride
Tablets
Official Monographs
2415
2416
Official Monographs
mL of diluted acetic acid (100) (17 in 10,000), and shake until the tablets are disintegrated. Then, add 3V/5 mL of
acetonitrile for liquid chromatography, shake well, and add
a mixture of acetonitrile for liquid chromatography and
diluted acetic acid (100) (17 in 10,000) (3:1) to make exactly
V mL so that each mL contains about 1.2 mg of fexofenadine hydrochloride (C32H39NO4.HCl). Pipet 15 mL of this
solution, and add the mobile phase to make exactly 50 mL.
Pipet 5 mL of this solution, add the mobile phase to make
exactly 100 mL, and filter through a membrane filter with a
pore size not exceeding 0.45 mm. Discard the first 2 mL of
the filtrate, and use the subsequent filtrate as the sample
solution. Separately, weigh accurately about 45 mg of Fexofenadine Hydrochloride RS (separately determine the water
<2.48> in the same manner as Fexofenadine Hydrochloride),
and dissolve in a mixture of acetonitrile for liquid chromatography and diluted acetic acid (100) (17 in 10,000) (3:1)
to make exactly 200 mL. Pipet 20 mL of this solution, add
the mobile phase to make exactly 250 mL, and use this solution as the standard solution. Perform the test with exactly
20 mL each of the sample solution and standard solution as
directed under Liquid Chromatography <2.01> according to
the following conditions, and determine the peak areas, AT
and AS, of fexofenadine of each solution.
Amount (mg) of fexofenadine hydrochloride
(C32H39NO4.HCl) in 1 tablet
MS AT/AS V/750
ContainersTight containers.
Supplement I, JP XVI
Add the following:
Filgrastim
(Genetical Recombination)
C845H1339N223O243S9: 18798.61
[121181-53-1]
Supplement I, JP XVI
Official Monographs
cetic acid (19:1) to stop the reaction, and use these solutions
as the sample solution and the standard solution, respectively. Perform the test with 70 mL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions.
When the chromatograms obtained from these solutions are
compared, both chromatograms show the similar peaks at
the same retention time, and the ratio of the area of the
peaks that appear respectively at 8th among the major peaks
obtained from the sample solution and standard solution, is
80 to 120z.
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 214 nm).
Column: A stainless steel column 2.1 mm in inside diameter and 25 cm in length, packed with butylsilanized silica
gel for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
409C.
Mobile phase A: A mixture of water and trifluoroacetic
acid (1000:1).
Mobile phase B: A mixture of acetonitrile, water and
trifluoroacetic acid (9000:1000:9).
Flowing of the mobile phase: Control the gradient by mixing the mobile phases A and B as directed in the following
table.
Time after injection
of sample (min)
Mobile phase
A (volz)
Mobile phase
B (volz)
02
2 30
30 85
85 90
90 100
98
98 70
70 50
50 2
2
2
2 30
30 50
50 98
98
3.7 4.3
2417
2418
Official Monographs
Supplement I, JP XVI
Mobile phase
A (volz)
Mobile phase
B (volz)
Mobile phase
A (volz)
Mobile phase
B (volz)
02
2 10
10 11
11 20
100
100 40
40 100
100
0
0 60
60 0
0
02
2 13
13 15
15 18
90
90 70
70 0
0
10
10 30
30 100
100
Flow rate: Adjust the flow rate so that the retention time
of filgrastim is about 14 minutes.
Time span of measurement: From 6 minutes to 17
minutes.
System suitability
Test for required detectability: Confirm that when perform the test with 100 mL of the system suitability test solution for filgrastim under the above operating conditions, the
content of charge isomer is between 1.4 to 2.6z.
System performance: When the procedure is run with 100
mL of the system suitability test solution for filgrastim under
the above operating conditions, charge isomer peak and filgrastim are eluted in this order with the resolution between
these peaks being not less than 1.5.
System repeatability: When the test is repeated 6 times
with 100 mL of Filgrastim (Genetical Recombination) under
the above operating conditions, the relative standard deviation of the peak area of filgrastim is not more than 2.5z.
(3) Host-derived proteins Being specified separately.
(4) DNA Being specified separately.
Assay (1) Protein contentTake exactly 200 mL each of
Filgrastim (Genetical Recombination) and Filgrastim RS,
perform the test as directed under Liquid Chromatography
<2.01> according to the following conditions, and determine
the peak areas, AT and AS, of filgrastim.
Amount (mg) of protein in 1 mL of Filgrastim (Genetical
Recombination)
C A T/A S
Flow rate: Adjust the flow rate so that the retention time
of filgrastim is about 15 minutes.
System suitability
System performance: When the procedure is run with 200
mL of a solution prepared by dissolving 1 mg of uracil and 2
mg of diphenyl in 100 mL of a mixture of water, 1-propanol
and trifluoroacetic acid (649:350:1) under the above conditions except using a mixture of the mobile phase A and the
mobile phase B (9:1) as the mobile phase, uracil and
diphenyl are eluted in this order with the resolution between
these peaks being not less than 8.
System repeatability: When the test is repeated 6 times
with 200 mL of Filgrastim RS under the above operating conditions, the relative standard deviation of the peak area of
filgrastim is not more than 2.5z.
(2) Specific activity
(i) Test cell: 32D clone3 cell.
(ii) Sample dilution solution for assay: To Iscove's modified Dulbecco's fluid medium for filgrastim add 200
mmol/L L-glutamine solution and fetal calf serum to make 1
volz and 5 volz solution, respectively, and sterilize by
filtration.
(iii) Standard solutions Dilute Filgrastim RS by the
sample dilution solution for assay to prepare not less than 5
serial dilutions started from any concentration SH so that all
of their protein concentrations are within the range of 0.5 to
6 ng/mL, and use them as the standard solutions.
(iv) Sample solutions Dilute Filgrastim (Genetical
Recombination) by the sample dilution solution for assay to
prepare not less than 5 serial dilutions in equal ratio started
from any concentration UH so that all of their protein concentrations are within the range of 0.5 to 6 ng/mL, and use
them as the sample solutions.
(v) Procedure The procedure before stopping the incubation should be performed under aseptic condition.
Transfer exactly 100 mL of each concentration of the standard solutions and sample solutions to the wells of 96-well
flat bottom microplates. Not less than three plates are prepared for both standard solutions and sample solutions.
Add exactly 100 mL of a test cell suspension containing 1
105 cells per mL in the sample dilution solution for assay to
each well, and incubate under atmosphere of 5z carbon dioxide at 37 29C for 21 to 27 hours. After incubation, add
40 mL of fluorogenic substrate TS to each well, incubate under the same conditions as above for 21 to 51 hours, and
measure fluorescence intensities at excitation wavelength 530
to 560 nm and at measurement wavelength 590 nm, using
fluorescence microplate reader. Use the data from at least 3
plates and not less than 3 concentrations of the standard solution and sample solution for the calculation.
Supplement I, JP XVI
(vi) Calculation Transform each concentration of the
sample solutions and standard solutions to common
logarithm, and name them as xU and xS, respectively, and
their totals are named as XU and XS, respectively. The
fluorescence intensities obtained from the sample solution
and the standard solution are named as yU and yS, and their
totals are named as YU and YS, respectively. The numbers of
the concentrations of the sample solution and the standard
solution are named as nU and nS, respectively, the number of
the plate is r. Calculate the specific activity of Filgrastim
(Genetical Recombination) by the following equation, using
the protein content (mg/mL) obtained in the Assay (1).
Specific activity (unit/mg) of Filgrastim (Genetical Recombination)
antilog M biological activity of Filgrastim RS
dilution factor for UH
UH
(unit/mL)
dilution factor for SH
SH
1
F?S VRS/VES
VRS SxyS2/SxxS
VES (SyS2 S(YS2/r))/(nS(r 1))
F?U VRU/VEU
VRU SxyU2/SxxU
VEU sSyU2 S(YU2/r)t/snU(r 1)t
2) F? is smaller than F1 against m (nS nU)(r 1)
shown in the table below.
F? VP/VE
VP SxyS2/SxxS SxyU2/SxxU (SxyS SxyU)2/
(SxxS SxxU)
VE sSyS2 SyU2 S(YS2/r) S(YU2/r)t/s(nS
nU)(r 1)t
3)
L 0.3
Official Monographs
2419
Value of F1 against m
F1
F1
F1
1
2
3
4
5
6
7
8
9
10
11
12
161.45
18.51
10.129
7.709
6.608
5.987
5.591
5.318
5.117
4.965
4.844
4.747
13
14
15
16
17
18
19
20
21
22
23
24
4.667
4.600
4.543
4.494
4.451
4.414
4.381
4.351
4.325
4.301
4.279
4.260
25
26
27
28
29
30
40
60
120
/
4.242
4.225
4.210
4.196
4.183
4.171
4.085
4.001
3.920
3.841
Filgrastim (Genetical
Recombination) Injection
2420
Official Monographs
Supplement I, JP XVI
Flurazepam
Sterility <4.06> Perform the test according to the Membrane filtration method: it meets the requirement.
Biological activity Calculate the biological activity in 1 ampoule or syringe of Filgrastim (Genetical Recombination)
Injection by the following equation, using the biological actively in 1 mL of Filgrastim (Genetical Recombination) Injection determined as directed in the Assay (2) under Filgrastim (Genetical Recombination) and the labeled volume
of Filgrastim (Genetical Recombination) Injection: it is not
less than 70z and not more than 140z of the target biological activity (unit).
Biological activity (unit) in 1 ampoule or syringe of Filgrastim (Genetical Recombination) Injection
antilog M biological activity (unit/mL) of
Filgrastim RS dilution factor for UH/dilution factor
for SH UH/SH labeled volume (mL) of Filgrastim
(Genetical Recombination) Injection
where, the target biological activity (unit) is calculated by the
following formula.
Target biological activity (unit)
1.5 108 (unit/mg) labeled amount (mg) of
Filgrastim (Genetical Recombination) in labeled
volume (mL)
Assay Perform the test with an exact volume each of Filgrastim (Genetical Recombination) Injection and Filgrastim
RS, equivalent to about 100 mg of Filgrastim (Genetical
Recombination), as directed in the Assay (1) under Filgrastim (Genetical Recombination).
Calculate the amount of filgrastim in 1 mL of Filgrastim
(Genetical Recombination) Injection by following formula.
Amount (mg) of filgrastim in 1 mL
C A T / A S VS / V T
Flurazepam Capsules
Glimepiride Tablets
Supplement I, JP XVI
Start the test with 1 tablet of Glimepiride Tablets,
withdraw not less than 20 mL of the medium at the specified
minute after starting the test, and filter through a membrane
filter with a pore size not exceeding 0.45 mm. Discard the
first 10 mL of the filtrate, pipet V mL of the subsequent
filtrate, add the dissolution medium to make exactly V? mL
so that each mL contains about 0.56 mg of glimepiride
(C24H34N4O5S), and use this solution as the sample solution.
Separately, weigh accurately about 22 mg of Glimepiride RS
(separately determine the water <2.48> in the same manner as
Glimepiride), and dissolve in acetonitrile for liquid chromatography to make exactly 100 mL. Pipet 2 mL of this solution, add 8 mL of acetonitrile for liquid chromatography,
and add the dissolution medium to make exactly 200 mL.
Pipet 5 mL of this solution, add the dissolution medium to
make exactly 20 mL, and use this solution as the standard
solution. Perform the test with exactly 50 mL each of the
sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions, and determine the peak areas, AT and AS, of
glimepiride from each solution.
Dissolution rate (z) with respect to the labeled amount of
glimepiride (C24H34N4O5S)
MS AT/AS V?/V 1/C 9/4
Official Monographs
2421
Human Menopausal
Gonadotrophin
Change the Purity (1) (ii) and the Assay (ii) and (v)
as follows:
Purity
1. Seminal vesicle weight assay
(ii) Standard solutionsDissolve Menopausal Gonadotrophin RS in bovine serum albumin-sodium chloridephosphate buffer solution, pH 7.2, to prepare three kinds of
solutions, containing 10, 20 and 40 interstitial cell-stimulating hormone (luteinizing hormone) units per 1.0 mL, respectively. Inject these solutions into three groups consisting of
five test animals each, and weigh their seminal vesicles as
directed in (iv). According to the result of the test, designate
the concentration of the reference standard, which will make
the mass of the seminal vesicle 20 to 35 mg, as the high-dose
standard solution, SH. Dilute the SH to 1.5 to 2.0 times the
initial volume with the bovine serum albumin-sodium chloride-phosphate buffer solution, pH 7.2, and designate this
solution as the low-dose standard solution, SL.
Assay
(ii) Standard solutionsDissolve Human Menopausal
Gonadotrophin RS in human chorionic gonadotrophin TS
to make three solutions which contain 0.75, 1.5 and 3.0 follicle-stimulating hormone Units per 1.0 mL, respectively. Inject these solutions into three groups consisting of five test
animals each, and weigh their ovaries, as directed in (iv). According to the result of the test, designate the concentration
of the reference standard, which will make the mass of the
ovary about 120 to 160 mg, as the high-dose standard solution, SH. Dilute the SH to 1.5 to 2.0 times the initial volume
with the human chorionic gonadotrophin TS, and designate
the solution as the low-dose standard solution, SL.
(v) CalculationDesignate the mass of ovaries by SH,
SL, TH and TL as y1, y2, y3 and y4, respectively. Sum up y1, y2,
y3 and y4 on each set to obtain Y1, Y2, Y3 and Y4.
Units per mg of Human Menopausal Gonadotrophin
antilog M (units per mL of SH) b/a
M IYa/Yb
2422
Official Monographs
Supplement I, JP XVI
creasing the number of the test animals or arranging the assay method in a better way until F? is smaller than F1 or L is
not more than 0.3.
F? (Y1 Y2 Y3 Y4)2/(4fs2)
f: Number of test animals per group
s2 sSy2 (Y/f )t/n
Sy2: The sum of the squares of each y1, y2, y3 and y4
Y Y 12 Y 22 Y 32 Y 42
n 4( f 1)
L 2 (C 1)(CM 2 I 2)
C Yb2/(Yb2 4fs2t2)
t2: Value shown in the following table against n used to
calculate s2
n
t2 F1
t2 F 1
t2 F1
1
2
3
4
5
6
7
8
9
10
11
12
161.45
18.51
10.129
7.709
6.608
5.987
5.591
5.318
5.117
4.965
4.844
4.747
13
14
15
16
17
18
19
20
21
22
23
24
4.667
4.600
4.543
4.494
4.451
4.414
4.381
4.351
4.325
4.301
4.279
4.260
25
26
27
28
29
30
40
60
120
/
4.242
4.225
4.210
4.196
4.183
4.171
4.085
4.001
3.920
3.841
Heparin Calcium
Supplement I, JP XVI
Official Monographs
Mobile phase
A (volz)
Mobile phase
B (volz)
03
3 15
90
90 0
10
10 100
2423
Heparin Sodium
2424
Official Monographs
Supplement I, JP XVI
phosphoric acid (1 in 10).
Flowing of the mobile phase: Control the gradient by mixing the mobile phases A and B as directed in the following
table.
Time after injection
of sample (min)
Mobile phase
A (volz)
Mobile phase
B (volz)
03
3 15
90
90 0
10
10 100
Supplement I, JP XVI
ing to room temperature, evaporate the reaction solutions to
dryness. Add 200 mL of each of water and ethyl acetate to
each of the residues, shake vigorously, and then centrifuge.
After remove the upper layers, add 200 mL of ethyl acetate to
each of the lower layers, shake vigorously, and then centrifuge. These lower layers are used as the sample solution
and the standard solution. Perform the test with 5 mL each
of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions: the peak area ratio of galactosamine to
glucosamine of the sample solution is not larger than that of
the standard solution.
Operating conditions
Detector: A fluorescence photometer (excitation
wavelength: 305 nm; emission wavelength: 360 nm).
Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilanized
silica gel for liquid chromatography (3 mm in particle diameter).
Column temperature: A constant temperature of about
459C.
Mobile phase: To 100 mL of a mixture of water and
trifluoroacetic acid (1000:1) add 100 mL of acetonitrile. Add
140 mL of the solution to 860 mL of a mixture of water and
trifluoroacetic acid (1000:1).
Flow rate: 1.0 mL per minute.
Time span of measurement: About 50 minutes after injected.
System suitability
Test for required detectability: Dissolve 8.0 mg of D -mannosamine hydrochloride in 10 mL of a mixture of water and
hydrochloric acid (7:5), and use this solution as the mannosamine standard solution. Transfer 500 mL of a mixture
of the standard stock solution and the mannosamine standard solution (100:1) to a glass-stoppered test tube, stopper
tightly, and heat at 1009
C for 6 hours. After cooling this solution to room temperature, evaporate 100 mL of the reaction solution to dryness. Add 50 mL of methanol to the
residue and evaporate to dryness at room temperature. Dissolve the residue in 10 mL of water, add 40 mL of aminobenzoate derivatization TS, and heat at 809
C for 1 hour. After
cooling to room temperature, evaporate the reaction solution to dryness. Add 200 mL each of water and ethyl acetate
to the residue, shake vigorously, and then centrifuge. After
removing the upper layer, add 200 mL of ethyl acetate to the
lower layer, shake vigorously, and then centrifuge. The lower layer is used as the solution for system suitability test.
When the procedure is run with 5 mL of the solution for system suitability test under the above operating conditions, the
ratio of the peak area of galactosamine to that of glucosamine is 0.7 2.0z.
System performance: When the procedure is run with 5 mL
of the solution for system suitability test under the above
operating conditions, glucosamine, mannosamine and galactosamine are eluted in this order with the resolutions between the peaks of glucosamine and mannosamine and between the peaks of mannosamine and galactosamine being
not less than 1.5, respectively.
Official Monographs
2425
2426
Official Monographs
[71138-97-1]
Supplement I, JP XVI
mL of this solution, add water to make exactly 100 mL, and
use this solution as the acetic acid stock solution. Separately,
weigh accurately about 0.13 g of succinic acid, dissolve in
water to make exactly 100 mL, and use this solution as the
succinic acid stock solution. Pipet exactly 4 mL each of the
acetic acid stock solution and the succinic acid stock solution, add the mobile phase to make exactly 25 mL, and use
this solution as the standard solution. Perform the test with
exactly 10 mL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions. Determine the peak
areas of acetic acid and succinic acid of both solutions, ATA,
ATS and ASA, ASS, and calculate the amount of free acetic
acid and free succinic acid by the following expressions: the
total amount is not more than 1.0z.
Amount (z) of free acetic acid (C2H4O2)
MSA/MT ATA/ASA 48/625
Amount (z) of free succinic acid (C4H6O4)
MSS/MT ATS/ASS 32/25
Assay (1) Acetyl group and succinyl groupWeigh accurately about 30 mg of Hypromellose Acetate Succinate,
add exactly 10 mL of sodium hydroxide TS, stopper tightly,
and stir for 4 hours. Add exactly 10 mL of diluted phosphoric acid (1 in 50), turn the test tube upside down several times,
and filter the solution through a membrane filter with a pore
size 0.22 mm. Discard the first 1 mL of the filtrate, and use
the subsequent filtrate as the sample solution. Separately,
place 20 mL of water in a 100-mL volumetric flask, weigh
the mass of the flask accurately, then add 2.0 mL of acetic
acid (100), weigh the mass of the flask to calculate the accurate mass of added acetic acid, and dilute with water to
volume. Pipet 6 mL of this solution, add water to make exactly 100 mL, and use this solution as the acetic acid stock
Supplement I, JP XVI
solution. Separately, weigh accurately about 0.13 g of succinic acid, dissolve in water to make exactly 100 mL, and use
this solution as the succinic acid stock solution. Pipet 4 mL
each of the acetic acid stock solution and the succinic acid
stock solution, add the mobile phase to make exactly 25 mL,
and use this solution as the standard solution. Perform the
test with exactly 10 mL each of the sample solution and standard solution as directed under Liquid Chromatography
<2.01> according to the following conditions, and determine
the peak areas, ATA, ATS and ASA, ASS, of acetic acid and
succinic acid of both solutions.
Amount (z) of acetyl group (C2H3O)
(MSA/MT ATA/ASA 24/125 Afree) 0.717
Amount (z) of succinyl group (C4H5O3)
(MSS/MT ATS/ASS 16/5 Sfree) 0.856
Official Monographs
2427
2428
Official Monographs
ContainersTight containers.
Ibuprofen Piconol
C19H23NO2: 297.39
Pyridin-2-ylmethyl (2RS)-2-[4-(2-methylpropyl)phenyl]propanoate
[64622-45-3]
n20
D : 1.529 1.532
Supplement I, JP XVI
50 mL (not more than 0.021z).
(2) Sulfate <1.14>Dissolve 0.5 g of Ibuprofen Piconol
in 20 mL of acetone, add 1 mL of dilute hydrochloric acid
and water to make 50 mL. Perform the test using this solution as the test solution. Prepare the control solution as follows: to 0.40 mL of 0.005 mol/L sulfuric acid VS add 20 mL
of acetone, 1 mL of dilute hydrochloric acid and water to
make 50 mL (not more than 0.038z).
(3) Heavy metals <1.07>Proceed with 4.0 g of
Ibuprofen Piconol according to Method 2, and perform the
test. Prepare the control solution with 2.0 mL of Standard
Lead Solution (not more than 5 ppm).
(4) Related substancesDissolve 0.10 g of Ibuprofen
Piconol in 5 mL of methanol, and use this solution as the
sample solution. Pipet 1 mL of the sample solution, add
methanol to make exactly 200 mL, and use this solution as
the standard solution. Perform the test with these solutions
as directed under Thin-layer Chromatography <2.03>. Spot
10 mL each of the sample solution and standard solution on
a plate of silica gel for thin-layer chromatography. Develop
the plate with a mixture of hexane, ethyl acetate, acetic acid
(100) and methanol (30:10:2:1) to a distance of about 10 cm,
and air-dry the plate. Spray evenly a solution of phosphomolybdic acid n-hydrate in ethanol (95) (1 in 10) on the
plate, and heat at 1709C for 10 minutes: the number of spots
other than the dark brown principal spot obtained from the
sample solution is two or less, and they are not more intense
than the dark brown spot from the standard solution.
(5) Residual solvent Being specified separately.
Water <2.48> Not more than 0.1z (5 g, volumetric titration, direct titration).
Residue on ignition <2.44>
d 20
20: 1.046 1.050
Supplement I, JP XVI
Identification To an amount of Ibuprofen Piconol Cream,
equivalent to 50 mg of Ibuprofen Piconol, add 10 mL of
methanol, warm in a water bath, mix well, filter after cooling, and use the filtrate as the sample solution. Separately,
dissolve 50 mg of ibuprofen piconol in 10 mL of methanol,
and use this solution as the standard solution. Perform the
test with these solutions as directed under Thin-layer Chromatography <2.03>. Spot 10 mL each of the sample solution
and standard solution on a plate of silica gel with fluorescent
indicator for thin-layer chromatography. Develop the plate
with a mixture of hexane, ethyl acetate and acetic acid (100)
(15:5:1) to a distance of about 13 cm, and air-dry the plate.
Examine under ultraviolet light (main wavelength: 254 nm):
the principal spot obtained from the sample solution and the
spot from the standard solution show the same Rf value.
pH
MS: Amount (mg) of ibuprofen piconol for assay, calculated on the anhydrous basis
Internal standard solutionA solution of triphenylmethane
in methanol (1 in 200).
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 254 nm).
Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilanized
silica gel for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
409C.
Mobile phase: A mixture of methanol and acetic acid-sodium acetate buffer solution, pH 4.0 (3:1).
Flow rate: Adjust the flow rate so that the retention time
of ibuprofen piconol is about 6.5 minutes.
Official Monographs
2429
System suitability
System performance: When the procedure is run with 5 mL
of the standard solution under the above operating conditions, ibuprofen piconol and the internal standard are eluted
in this order with the resolution between these peaks being
not less than 8.
System repeatability: When the test is repeated 6 times
with 5 mL of the standard solution under the above operating conditions, the relative standard deviation of the ratio of
the peak area of ibuprofen piconol to that of the internal
standard is not more than 1.0z.
Containers and storage ContainersTight containers.
StorageLight-resistant.
2430
Official Monographs
solution. Perform the test with 5 mL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions,
and calculate the ratios, QT and QS, of the peak area of
ibuprofen piconol to that of the internal standard.
Supplement I, JP XVI
Add the following:
Iohexol
MS: Amount (mg) of ibuprofen piconol for assay, calculated on the anhydrous basis
Internal standard solutionA solution of triphenylmethane
in methanol (1 in 200).
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 254 nm).
Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilanized
silica gel for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
409C.
Mobile phase: A mixture of methanol and acetic acid-sodium acetate buffer solution, pH 4.0 (3:1).
Flow rate: Adjust the flow rate so that the retention time
of ibuprofen piconol is about 6.5 minutes.
System suitability
System performance: When the procedure is run with 5 mL
of the standard solution under the above operating conditions, ibuprofen piconol and the internal standard are eluted
in this order with the resolution between these peaks being
not less than 8.
System repeatability: When the test is repeated 6 times
with 5 mL of the standard solution under the above operating conditions, the relative standard deviation of the ratio of
the peak area of ibuprofen piconol to that of the internal
standard is not more than 1.0z.
Containers and storage ContainersTight containers.
StorageLight-resistant.
C19H26I3N3O9: 821.14
5-sAcetyl[(2RS)-2,3-dihydroxypropyl]aminot
-N,N ?-bis[(2RS)2,3-dihydroxypropyl]-2,4,6-triiodobenzene-1,3-dicarboxamide
5-sAcetyl[(2RS)-2,3-dihydroxypropyl]aminot
-N-[(2RS)2,3-dihydroxypropyl]-N ?-[(2SR)-2,3-dihydroxypropyl]2,4,6-triiodobenzene-1,3-dicarboxamide
-N,N ?-bis[(2SR)5-sAcetyl[(2RS)-2,3-dihydroxypropyl]aminot
2,3-dihydroxypropyl]-2,4,6-triiodobenzene-1,3-dicarboxamide
[66108-95-0]
Supplement I, JP XVI
Purity (1) Clarity and color of solutionA solution obtained by dissolving 1.0 g of Iohexol in 5 mL of water is clear
and colorless.
(2) Aromatic primary amineConduct this procedure
using light-resistant vessels. Dissolve 0.20 g of Iohexol in 15
mL of water, cool in ice for 5 minutes, add 1.5 mL of 6
mol/L hydrochloric acid TS and 1 mL of a solution of sodium nitrite (1 in 50), prepared before use, stir, and cool in ice
for 4 minutes. Add 1 mL of a solution of amidosulfuric acid
(standard reagent) (1 in 25), stir, and cool in ice for 1
minute. Then, add 0.5 mL of a solution, prepared by dissolving 0.3 g of N-1-naphthylethylenediamine dihydrochloride in diluted propylene glycol (7 in 10) to make 100 mL,
and add water to make exactly 25 mL. Perform the test with
this solution as directed under Ultraviolet-visible Spectrophotometry <2.24> within 20 minutes, using a solution
prepared in the same manner with 15 mL of water as the
blank: the absorbance at 495 nm is not more than 0.21.
(3) Chloride <1.03>Perform the test with 2.0 g of Iohexol. Prepare the control solution with 0.40 mL of 0.01
mol/L hydrochloric acid VS (not more than 0.007z).
(4) Iodine and iodideDissolve 1.0 g of Iohexol in 4 mL
of water, add 1 mL of dilute sulfuric acid, and allow to stand
for 10 minutes while occasional shaking. Add 5 mL of chloroform, shake well, and allow to stand: the chloroform layer
is colorless. Then, add 1 mL of sodium nitrite solution (1 in
50), shake, allow to stand, and determine the absorbance of
collected chloroform layer as directed under Ultraviolet-visible Spectrophotometry <2.24>, using a chloroform layer prepared in the same manner with 4.0 mL of water as the blank:
the absorbance at 510 nm is not larger than that of chloroform layer obtained from the following control solution.
Control solution: Dissolve exactly 0.131 g of potassium
iodide in water to make exactly 100 mL. Pipet 1 mL of this
solution, and add water to make exactly 100 mL. Pipet 3 mL
of this solution, add exactly 1 mL of water and 1 mL of dilute sulfuric acid, then proceed in the same manner.
(5) Heavy metals <1.07>Proceed with 2.0 g of Iohexol
according to Method 1, and perform the test. Prepare the
control solution with 2.0 mL of Standard Lead Solution (not
more than 10 ppm).
(6) 3-Chloro-1,2-propanediolTo exactly 1.0 g of Iohexol, add exactly 2 mL of diethyl ether, and treat with
ultrasonic waves for 10 minutes under cooling. Centrifuge,
and use the diethyl ether layer as the sample solution.
Separately, dissolve exactly 0.50 g of 3-chloro-1,2propanediol in diethyl ether to make exactly 50 mL. Pipet 1
mL of this solution, and add diethyl ether to make exactly
100 mL. Pipet 5 mL of this solution, add diethyl ether to
make exactly 25 mL, and use this solution as the standard
solution. Perform the test with exactly 5 mL each of the sample solution and standard solution as directed under Gas
Chromatography <2.02>, and determine the peak areas, AT
and AS, of 3-chloro-1,2-propanediol of each solution: AT is
not more than 2.5 times AS.
Operating conditions
Detector: A hydrogen flame-ionization detector.
Column: A fused silica column 0.25 mm in inside di-
Official Monographs
2431
2432
Official Monographs
Supplement I, JP XVI
Mobile phase
A (volz)
Mobile phase
B (volz)
01
1 46
1
1 10
99
99 90
Flow rate: Adjust the flow rate so that the retention time
of the second principal peak (iohexol exo-product) is about
19 minutes.
Time span of measurement: About 2 times as long as the
retention time of iohexol exo-product.
System suitability
Test for required detectability: To 1 mL of the sample solution add water to make 50 mL, and use this solution as the
solution for system suitability test. Pipet 1 mL of the solution for system suitability test, and add water to make exactly 20 mL. Confirm that the peak area of iohexol exoproduct obtained from 10 mL of this solution is equivalent to
3.5 to 6.5z of that from 10 mL of the solution for system
suitability test.
System performance: When the procedure is run with 10
mL of the solution for system suitability test under the above
operating conditions, the resolution between the adjacent
two peaks, which appear at the retention time of about 18
minutes, is not less than 1.5.
System repeatability: When the test is repeated 3 times
with 10 mL of the solution for system suitability test under
the above operating conditions, the relative standard deviation of the peak area of iohexol exo-product is not more
than 3.0z.
(8) Residual solvent Being specified separately.
Water <2.48> Not more than 4.0z (0.3 g, volumetric titration, direct titration).
Residue on ignition <2.44>
ContainersTight containers.
Iohexol Injection
Identification To a volume of Iohexol Injection, equivalent to 0.65 g of Iohexol, add water to make 500 mL. To 1
mL of this solution add water to make 100 mL, and determine the absorption spectrum of this solution as directed under Ultraviolet-visible Spectrophotometry <2.24>: it exhibits
a maximum between 243 nm and 247 nm.
pH
Sterility <4.06> Perform the test according to the Membrane filtration method: it meets the requirement.
Assay To an exactly measured volume of Iohexol Injection, equivalent to about 1.5 g of iohexol (C19H26I3N3O9) add
Supplement I, JP XVI
water to make exactly 25 mL. Pipet 10 mL of this solution,
add 25 mL of a solution of sodium hydroxide (1 in 20) and
0.5 g of zinc powder, and heat on a water bath under a reflux
condenser for 30 minutes. After cooling, wash down the inside of the condenser with 20 mL of water, and filter. Then,
proceed as directed in the Assay under Iohexol.
Each mL of 0.1 mol/L silver nitrate VS
27.37 mg of C19H26I3N3O9
Containers and storage
ContainersHermetic containers.
Isosorbide Mononitrate
70%/Lactose 30%
70%
C6H9NO6: 191.14
1,4:3,6-Dianhydro-D-glucitol 5-nitrate
[16051-77-7, Isosorbide mononitrate]
Official Monographs
2433
Purity (1) Nitrate Dissolve an exact quantity of Isosorbide Mononitrate 70z/Lactose 30z, equivalent to 50 mg of
isosorbide mononitrate (C6H9NO6), in water to make exactly
100 mL. Pipet 25 mL of this solution, add water to make exactly 50 mL, and use this solution as the sample solution.
Separately, to exactly 5 mL of Standard Nitric Acid Solution
add water to make exactly 150 mL. Pipet 25 mL of this solution, add water to make exactly 150 mL, and use this solution as the standard solution. Perform the test with exactly
100 mL each of the sample solution and standard solution as
directed under Liquid Chromatography <2.01> according to
the following conditions, and determine the peak area of
nitric acid of each solution by the automatic integration
method: the peak area of nitric acid obtained from the sample solution is not larger than the peak area of nitric acid
from the standard solution.
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 214 nm).
Column: A stainless steel column 4.6 mm in inside diameter and 5 cm in length, packed with gel type strong basic
ion-exchange resin for liquid chromatography (10 mm in particle diameter).
Column temperature: A constant temperature of about
359C.
Mobile phase: Dissolve 16.0 g of sodium gluconate, 18.0 g
of boric acid, 25.0 g of sodium tetraborate decahydrate, and
250 mL of glycerin in water to make 1000 mL. To 20 mL of
this solution add 20 mL of 1-butanol, 120 mL of acetonitrile, and add water to make 1000 mL.
Flow rate: Adjust the flow rate so that the retention time
of nitric acid is about 5.3 minutes.
System suitability
System performance: When the procedure is run with 100
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of nitric acid are not less than 800 and not
more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 100 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of nitric acid is not more than 2.0z.
(2) Heavy metals <1.07>Proceed with 1.0 g of Isosorbide Mononitrate 70z/Lactose 30z according to Method
1, and perform the test. Prepare the control solution with
1.0 mL of Standard Lead Solution (not more than 10 ppm).
(3) Isosorbide To an amount of Isosorbide Mononitrate 70z/Lactose 30z, equivalent to 1.0 g of isosorbide
mononitrate (C6H9NO6), add 10 mL of acetone, shake well,
centrifuge, and filter the supernatant liquid through a membrane filter with a pore size not exceeding 0.5 mm. To the
residue add 2 mL of acetone and proceed in the same manner, and combine the filtrates. Evaporate the combined
filtrate to dryness on a water bath, and further dry the
residue in vacuum for 30 minutes. Dissolve the residue in the
mobile phase to make 10 mL, and use this solution as the
sample solution. Pipet 1 mL of the sample solution, and add
the mobile phase to make exactly 20 mL. Pipet 1 mL of this
2434
Official Monographs
Supplement I, JP XVI
System suitability
Test for required detectability: Pipet 1 mL of the standard
solution, and add water to make exactly 10 mL. Confirm
that the peak area of isosorbide mononitrate obtained with
10 mL of this solution is equivalent to 7 to 13z of that with
10 mL of the standard solution.
System performance: Proceed as directed in the system
suitability in the Assay.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of isosorbide mononitrate is not more than 2.0z.
(5) Residual solvent Being specified separately.
Loss on drying <2.41> Not more than 0.5z (1 g, in vacuum, silica gel, 4 hours).
Water <2.48> Between 1.0 and 2.0z (0.4 g, direct titration.
Use a mixture of methanol for Karl Fischer method and formamide for Karl Fischer method (2:1) instead of methanol
for Karl Fischer method).
Residue on ignition <2.44>
Assay Weigh accurately an amount of Isosorbide Mononitrate 70z/Lactose 30z, previously dried, equivalent to
about 0.2 g of isosorbide mononitrate (C6H9NO6), and dissolve in water to make exactly 50 mL. Pipet 10 mL of this
solution, add exactly 20 mL of the internal standard solution, then add water to make 100 mL, and use this solution
as the sample solution. Separately, weigh accurately about
40 mg of isosorbide mononitrate for assay, previously dried,
and dissolve in 60 mL of water, add exactly 20 mL of the internal standard solution, then, add water to make 100 mL,
and use this solution as the standard solution. Perform the
test with 10 mL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions, and calculate the ratios,
QT and QS, of the peak area of isosorbide mononitrate to
that of the internal standard.
Amount (mg) of isosorbide mononitrate (C6H9NO6)
M S Q T /Q S 5
Supplement I, JP XVI
System suitability
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, isosorbide mononitrate and the internal standard
are eluted in this order with the resolution between these
peaks being not less than 10.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the ratio of
the peak area of isosorbide mononitrate to that of the internal standard is not more than 1.0z.
Containers and storage
ContainersTight containers.
Official Monographs
2435
isosorbide mononitrate for assay, previously dried in vacuum (silica gel) for 4 hours, add 30 mL of water and exactly
10 mL of the internal standard solution, then add water to
make 100 mL, and use this solution as the standard solution,
Then, proceed as directed in the Assay.
Amount (mg) of isosorbide mononitrate (C6H9NO6)
MS QT/QS V/100
2436
Official Monographs
ContainersTight containers.
Supplement I, JP XVI
Josamycin
Josamycin Propionate
Kanamycin Sulfate
Anhydrous Lactose
[a]20
D : 54.4 55.99 Weigh ac-
Supplement I, JP XVI
Official Monographs
2437
Operating conditions
Detector: A hydrogen flame-ionization detector.
Column: A fused silica column 0.25 mm in inside diameter and 15 m in length, coated the inside surface with 5z
diphenyl-95z dimethylpolysiloxane in 0.25 mm thickness.
Use a middle polar inertness fused silica column 0.53 mm in
inside diameter and 2 m in length as a guard column.
Column temperature: Keep at 809C for 1 minute after injection, then rise to 1509C with 359C per minute, then rise to
3009
C with 129C per minute, and keep 3009C for 2 minutes.
Injection port temperature: A constant temperature of
about 2759
C, or use cold-on column injection.
Detector temperature: A constant temperature of about
3259
C.
Carrier gas: Helium.
Flow rate: 2.8 mL per minute (Retention time of b-lactose
is about 12 minutes).
Sprit ratio: Spritless.
System suitability
System performance: Prepare a solution with 10 mg of a
mixture of a-lactose and b-lactose (1:1) in the same manner
as for preparing the sample solution, and proceed with 0.5
mL of this solution under the above operating conditions,
and determine the retention times of the peaks of a-lactose
and b-lactose: the relative retention time of a-lactose with
respect to that of b-lactose is about 0.9 with the resolution
between these peaks being not less than 3.0.
System repeatability: When the test is repeated 6 times
with 0.5 mL of the solution used in the system performance
under the above operating conditions, the relative standard
deviation of the peak area of b-lactose is not more than
1.0z.
Containers
tainers.
and storage
ContainersWell-closed con-
2438
Official Monographs
Lafutidine
C22H29N3O4S: 431.55
2-[(RS)-Furan-2-ylmethylsulfinyl]-N-s4-[4-(piperidin1-ylmethyl)pyridin-2-yl]oxy-(2Z)-but-2-en-1-yltacetamide
[206449-93-6]
Supplement I, JP XVI
lafutidine from the standard solution.
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 220 nm).
Column: A stainless steel column 6 mm in inside diameter
and 15 cm in length, packed with octadecylsilanized silica gel
for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
409C.
Mobile phase: Dissolve 0.87 g of sodium 1-pentanesulfonate in 1000 mL of diluted phosphoric acid (1 in 1000). To
850 mL of this solution add 150 mL of acetonitrile.
Flow rate: Adjust the flow rate so that the retention time
of lafutidine is about 15 minutes.
Time span of measurement: About 6 times as long as the
retention time of lafutidine.
System suitability
Test for required detectability: To exactly 1 mL of the
standard solution add the mobile phase to make exactly 20
mL. Confirm that the peak area of lafutidine obtained with
5 mL of this solution is equivalent to 3.5 to 6.5z of that with
5 mL of the standard solution.
System performance: When the procedure is run with 5 mL
of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of lafutidine are not less than 8000 and
not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 5 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of lafutidine is not more than 2.0z.
(3) Residual solvent Being specified separately.
Loss on drying <2.41> Not more than 0.5z (1 g, reduced
pressure not exceeding 0.67 kPa, phosphorus (V) oxide, 4
hours).
Residue on ignition <2.44>
Assay Weigh accurately about 0.3 g of Lafutidine, previously dried, dissolve in 50 mL of acetic acid (100), and titrate
<2.50> with 0.1 mol/L perchloric acid VS (potentiometric
titration). Perform a blank determination in the same manner, and make any necessary correction.
Each mL of 0.1 mol/L perchloric acid VS
21.58 mg of C22H29N3O4S
Containers and storage
ContainersTight containers.
Supplement I, JP XVI
Add the following:
Lafutidine Tablets
Official Monographs
2439
factor of the peak of lafutidine are not less than 8000 and
not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 5 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of lafutidine is not more than 2.0z.
Uniformity of dosage units <6.02> Perform the test according to the following method: it meets the requirement of the
Content uniformity test.
To 1 tablet of Lafutidine Tablets add exactly V mL of the
internal standard solution so that each mL contains about 2
mg of lafutidine (C22H29N3O4S), disintegrate the tablet with
the aid of ultrasonic waves, then shake vigorously for 30
minutes. Centrifuge this solution, filter the supernatant liquid through a membrane filter with a pore size not exceeding
0.45 mm, and use the filtrate as the sample solution.
Separately, weigh accurately about 0.1 g of lafutidine for assay, previously dried under a reduced pressure (not exceeding 0.67 kPa) using phosphorus (V) oxide as dessicant for 4
hours, dissolve in exactly 50 mL of the internal standard solution, and use this solution as the standard solution. Then,
proceed as directed in the Assay.
Amount (mg) of lafutidine (C22H29N3O4S)
MS QT/QS V/50
2440
Official Monographs
Supplement I, JP XVI
System suitability
System performance: When the procedure is run with 5 mL
of the standard solution under the above operating conditions, lafutidine and the internal standard are eluted in this
order with the resolution between these peaks being not less
than 6.
System repeatability: When the test is repeated 6 times
with 5 mL of the standard solution under the above operating conditions, the relative standard deviation of the ratio of
the peak area of lafutidine to that of the internal standard is
not more than 1.0z.
Containers and storage
ContainersTight containers.
Lenograstim (Genetical
Recombination)
Lenograstim (Genetical Recombination) is an aqueous solution in which a desired product is a recombinant human granulocyte colony-stimulating factor
produced in Chinese hamster ovary cells. It is a
glycoprotein (molecular mass: ca. 20,000) consisting
of 174 amino acid residues. It has a neutrophilic leucocyte induction activity.
It contains not less than 0.40 mg and not more than
0.60 mg of protein per mL, and not less than 1.02
108 units per mg of protein.
Description Lenograstim (Genetical Recombination) occurs as a clear and colorless liquid.
Identification (1) Use Lenograstim (Genetical Recombination) and Lenograstim RS as the sample solution and the
standard solution, respectively. Perform the test with a
volume each of the sample solution and standard solution,
equivalent to 20 mg of protein, as directed under Liquid
Chromatography <2.01> according to the following conditions: the retention times of the two peaks of lenograstim
Supplement I, JP XVI
Official Monographs
Mobile phase
A (volz)
Mobile phase
B (volz)
0 35
35 40
100 80
80
0 20
20
Flow rate: Adjust the flow rate so that the retention time
of the first appeared peak of lenograstim is about 27
minutes.
System suitability
System performance: When the procedure is run with a
volume of the standard solution, equivalent to 20 mg of protein, under the above operating conditions, the resolution
between the two peaks of lenograstim is not less than 4.
(2) Desalt 2 mL each of Lenograstim (Genetical Recombination) and Lenograstim RS by a suitable method, and assign them as the desalted sample and the desalted reference
standard, respectively. Add the desalted sample and the
desalted reference standard in 100 mL each of a mixture of
water and 1-propanol (3:2), add 4 mL of urea-EDTA TS,
and allow them to stand at 379C for 18 hours. Then, add 10
mL of 2-mercaptoethanol to them, and allow to stand at
379C for 4 hours. To these solutions add a solution of 27 mg
of iodoacetic acid in 150 mL of sodium hydroxide TS, and
react at 379
C for 15 minutes, avoiding exposure to light. Remove the reagents from these reaction solution by a suitable
method, and assign obtained these substances as the reduced
carboxymethylated sample and the reduced carboxymethylated reference standard. To these substances add 100 mL
each of a mixture of water and 1-propanol (3:2), and add 1
mL of 0.05 mol/L ammonium hydrogen carbonate solution.
Add 20 mL each of a solution of V8 protease in 0.05 mol/L
ammonium hydrogen carbonate solution (1 in 1000), and
react at 379
C for 18 hours. To each reaction solution add 50
mL of diluted trifluoroacetic acid (1 in 10) to stop the reaction, and use these solutions as the sample solution and the
standard solution, respectively. Perform the test with 100 mL
150 mL each of the sample solution and standard solution
as directed under Liquid Chromatography <2.01> according
to the following conditions, and compare the chromato-
2441
Mobile phase
A (volz)
Mobile phase
B (volz)
0 120
120 140
140 150
100 20
20 0
0
0 80
80 100
100
Flow rate: Adjust the flow rate so that the retention time
of the first appeared peak is about 33 minutes.
System suitability
System performance: When the procedure is run with the
standard solution under the above operating conditions, the
resolution between the first appeared peak and the second
appeared peak is not less than 15.
(3) Put exactly 2 mL of Lenograstim (Genetical Recombination) into a precolumn, packed with 0.36 g of octadecylsilanized silica gel for pretreatment, wash the column with 5
mL of a mixture of water, acetonitrile and trifluoroacetic
acid (600:400:1), then elute with a mixture of acetonitrile,
water and trifluoroacetic acid (800:200:1), and collect exactly 5 mL of the first eluate. Pipet 1.5 mL of the eluate in a
test tube, add exactly 20 mL of the internal standard solution, and lyophilize. Dissolve the lyophilized substance in
250 mL of a mixture of methanol and acetyl chloride (9:1),
seal the tube, and heat at 909
C for 2 hours. After cooling,
open the tube, and dry the content under reduced pressure.
To the residue add 200 mL of methanol, and evaporate to
dryness under reduced pressure. Dissolve the residue in 200
mL of a solution of pyridine in methanol (1 in 10) and 50 mL
of acetic anhydride, stopper the tube tightly, and allow to
stand for 10 minutes. Evaporate the solution to dryness at
about 509
C under reduced pressure, add 200 mL of methanol
to the residue, and evaporate to dryness at 509C under
reduced pressure. To the residue add 50 mL of a mixture of
pyridine, 1,1,1,3,3,3-hexamethyldisilazane and chlorotrimethylsilane (10:2:1), stopper tightly, shake vigorously
for 30 seconds, and warm at 509
C for 10 minutes. After
cooling, add 300 mL of pentane, stir gently, then add 300 mL
of water, and stir gently. Separate the upper layer, evaporate
2442
Official Monographs
Supplement I, JP XVI
System suitability
System performance: When the procedure is run with 2 mL
of the monosaccharide standard solution under the above
operating conditions, D-galactose, the internal standard, Nacetylgalactosamine and N-acetylneuraminic acid are eluted
in this order, and the resolution between the peaks of the internal standard and N-acetylgalactosamine is not less than
10.
pH <2.54>
7.7 8.3
Supplement I, JP XVI
Official Monographs
Mobile phase
A (volz)
Mobile phase
B (volz)
0 40
80 30
20 70
Flow rate: Adjust the flow rate so that the retention time
of lenograstim is about 35 minutes.
System suitability
System performance: When the procedure is run with 30
mL of the standard solution under the above operating conditions, the number of theoretical plates of the peak of
lenograstim is not less than 2900.
System repeatability: When the test is repeated 6 times
with 30 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of lenograstim is not more than 4.0z.
(2) Specific activityDilute Lenograstim (Genetical
Recombination) with FBS-IMDM so that each mL contains
an estimate amount of 7.69 units, 10.0 units and 13.0 units,
and name them as the sample solution (1), the sample solution (2) and the sample solution (3), respectively. Separately,
dilute Lenograstim RS with FBS-IMDM so that each mL
contains 7.69 units, 10.0 units and 13.0 units, and name
them as the standard solution (1), the standard solution (2)
and the standard solution (3), respectively. Put exactly 100
mL each of the sample solutions and the standard solutions
in wells of a sterile disposable multiple well plate, add 50 mL
each of NFS-60 cell suspension (prepared by adding FBSIMDM so the each mL contains about 5 105 cells) to each
well and mix to make homogenize, and place the plate in a
CO2 incubator at 379
C. After incubation for 22 hours, add
15 mL of resazurin solution to each well, and determine the
absorbances at 570 nm, AT1 and AS1, and at 600 nm, AT2 and
AS2. From the reaction values at each concentration of the
standard solution and sample solution [deference of absor-
2443
Pr anti ln (M )
M ( PT PS)/db
P T T1 T2 T 3
P S S 1 S2 S3
b HL(LS LT)/Inh
HL 12n/(d3 d)
LS 1S1 2S2 3S3 1/2(d 1)PS
LT 1T1 2T2 3T3 1/2(d 1)PT
d3
I ln 1.3
n3
h2
T1: Mean of reaction values of the sample solution (1)
T2: Mean of reaction values of the sample solution (2)
T3: Mean of reaction values of the sample solution (3)
S1: Mean of reaction values of the standard solution (1)
S2: Mean of reaction values of the standard solution (2)
S3: Mean of reaction values of the standard solution (3)
Specific activity (unit/mg of protein) of lenograstim
S P r D T /D S / C
2444
Official Monographs
Uniformity of dosage units <6.02> Perform the test according to the following method: the Granules in single-unit container meet the requirement of the Content uniformity test.
To the total amount of the content of 1 container of
Levofloxacin Fine Granules add diluted 3 mol/L
hydrochloric acid TS (1 in 100) to make exactly V mL so that
each mL of the solution contains about 1 mg of levofloxacin
(C18H20FN3O4), and stir for 20 minutes. Filter this solution
through a membrane filter with a pore size not exceeding
0.45 mm. Discard the first 10 mL of the filtrate, pipet 1 mL
of the subsequent filtrate, add diluted 3 mol/L hydrochloric
acid TS (1 in 100) to make exactly 100 mL, and use this solution as the sample solution. Separately, weigh accurately
about 25 mg of levofloxacin hydrate for assay (separately
determine the water <2.48> in the same manner as Levofloxacin Hydrate), and dissolve in diluted 3 mol/L hydrochloric
acid TS (1 in 100) to make exactly 50 mL. Pipet 2 mL of this
solution, add diluted 3 mol/L hydrochloric acid TS (1 in
100) to make exactly 100 mL, and use this solution as the
standard solution. Determine the absorbances, AT and AS,
at 327 nm of the sample solution and standard solution as
directed under Ultraviolet-visible Spectrophotometry <2.24>.
Amount (mg) of levofloxacin (C18H20FN3O4)
MS AT/AS V/25
MS: Amount (mg) of levofloxacin hydrate for assay, calculated on the anhydrous basis
Dissolution <6.10> When the tests are performed at 75
revolutions per minute according to the Paddle method, using 900 mL of water as the dissolution medium, the dissolution rate in 90 minutes of Levofloxacin Fine Granules is not
less than 70z.
Start the test with an accurately weighed amount of the
content of Levofloxacin Fine Granules, equivalent to about
0.1 g of levofloxacin (C18H20FN3O4), withdraw not less than
20 mL of the medium at the specified minute after starting
the test, and filter through a membrane filter with a pore size
not exceeding 0.45mm. Discard the first 10 mL of the filtrate,
pipet 5 mL of the subsequent filtrate, add water to make exactly 100 mL, and use this solution as the sample solution.
Separately, weigh accurately about 28 mg of levofloxacin
hydrate for assay (separately determine the water <2.48> in
the same manner as Levofloxacin Hydrate), and dissolve in
water to make exactly 100 mL. Pipet 2 mL of this solution,
add water to make exactly 100 mL, and use this solution as
the standard solution. Determine the absorbances, AT and
AS, at 289 nm of the sample solution and standard solution
as directed under Ultraviolet-visible Spectrophotometry
<2.24>.
Dissolution rate (z) with respect to the labeled amount of
levofloxacin (C18H20FN3O4)
MS/MT AT/AS 1/C 360
MS: Amount (mg) of levofloxacin hydrate for assay, calculated on the anhydrous basis
MT: Amount (g) of Levofloxacin Fine Granules
C: Labeled amount (mg) of levofloxacin (C18H20FN3O4) in
Supplement I, JP XVI
1g
Assay Weigh accurately an amount of Levofloxacin Fine
Granules, powder if necessary, equivalent to about 50 mg of
levofloxacin (C18H20FN3O4), add diluted 3 mol/L
hydrochloric acid TS (1 in 100) to make exactly 50 mL, stir
for 20 minutes, and filter this solution through a membrane
filter with a pore size not exceeding 0.45 mm. Discard the
first 10 mL of the filtrate, pipet 5 mL of the subsequent
filtrate, add diluted 3 mol/L hydrochloric acid TS (1 in 100)
to make exactly 100 mL, and use this solution as the sample
solution. Separately, weigh accurately about 50 mg of
levofloxacin hydrate for assay (separately determine the
water <2.48> in the same manner as Levofloxacin Hydrate),
and dissolve in diluted 3 mol/L hydrochloric acid TS (1 in
100) to make exactly 50 mL. Pipet 5 mL of this solution, add
diluted 3 mol/L hydrochloric acid TS (1 in 100) to make exactly 100 mL, and use this solution as the standard solution.
Perform the test with exactly 10 mL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions,
and determine the peak areas, AT and AS, of levofloxacin of
each solution.
Amount (mg) of levofloxacin (C18H20FN3O4)
M S A T/A S
MS: Amount (mg) of levofloxacin hydrate for assay, calculated on the anhydrous basis
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 340 nm).
Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilanized
silica gel for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
459C.
Mobile phase: Dissolve 1.00 g of copper (II) sulfate pentahydrate, 1.41 g of L-valine and 6.17g of ammonium acetate
in 800 mL of water, and add 200 mL of methanol.
Flow rate: Adjust the flow rate so that the retention time
of levofloxacin is about 20 minutes.
System suitability
System performance: Dissolve 10 mg of ofloxacin in 20
mL of diluted 3 mol/L hydrochloric acid TS (1 in 100). To 1
mL of this solution add diluted 3 mol/L hydrochloric acid
TS (1 in 100) to make 20 mL. When the procedure is run
with 10 mL of this solution under the above operating conditions, levofloxacin and an enantiomer are eluted in this order with the resolution between these peaks being not less
than 3.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of levofloxacin is not more than 1.0z.
Containers and storage ContainersTight containers.
StorageLight-resistant.
Supplement I, JP XVI
Add the following:
Official Monographs
2445
Sterility <4.06> Perform the test according to the Membrane filtration method: it meets the requirement.
Assay To an accurately weighed amount of Levofloxacin
Ophthalmic Solution, equivalent to about 5 mg of levofloxacin hydrate (C18H20FN3O4.1/2H2O) add exactly 2 mL of the
internal standard solution, then add the mobile phase to
make 100 mL, and use this solution as the sample solution.
Separately, weigh accurately about 25 mg of levofloxacin
hydrate for assay (separately determine the water <2.48> in
the same manner as Levofloxacin Hydrate), and dissolve in
water to make exactly 50 mL. Pipet 10 mL of this solution,
add exactly 2 mL of the internal standard solution, then add
the mobile phase to make 100 mL, and use this solution as
the standard solution. Perform the test with 10 mL each of
the sample solution and standard solution as directed under
Liquid Chromatography <2.01> according to the following
conditions, and calculate the ratios, QT and QS, of the peak
area of levofloxacin to that of the internal standard.
Amount (mg) of levofloxacin hydrate
(C18H20FN3O4.1/2H2O)
MS QT/QS 1/5 1.025
MS: Amount (mg) of levofloxacin hydrate for assay, calculated on the anhydrous basis
Internal standard solutionA solution of naphazoline
hydrochloride in the mobile phase (3 in 500).
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 280 nm).
Column: A stainless steel column 4 mm in inside diameter
and 15 cm in length, packed with octadecylsilanized silica gel
for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
409C.
Mobile phase: Dissolve 13.61 g of potassium dihydrogen
phosphate and 0.77 g of ammonium acetate in 900 mL of
water, adjust to pH 3.0 with 1 mol/L hydrochloric acid TS,
and add water to make 1000 mL. To 900 mL of this solution
add 100 mL of acetonitrile.
Flow rate: Adjust the flow rate so that the retention time
of levofloxacin is about 17 minutes.
System suitability
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, levofloxacin and the internal standard are eluted in
this order with the resolution between these peaks being not
2446
Official Monographs
less than 5.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the ratio of
the peak area of levofloxacin to that of the internal standard
is not more than 1.0z.
Containers and storage ContainersTight containers.
StorageLight-resistant.
Levofloxacin Tablets
MS: Amount (mg) of levofloxacin hydrate for assay, calculated on the anhydrous basis
Dissolution <6.10> (1) For a 100-mg Tablet When the
tests are performed at 50 revolutions per minute according
Supplement I, JP XVI
to the Paddle method, using 900 mL of water as the dissolution medium, the dissolution rate in 90 minutes is not less
than 80z.
Start the test with 1 tablet of Levofloxacin Tablets,
withdraw not less than 20 mL of the medium at the specified
minute after starting the test, and filter through a membrane
filter with a pore size not exceeding 0.45 mm. Discard the
first 10 mL of the filtrate, pipet 5 mL of the subsequent
filtrate, add water to make exactly 100 mL, and use this solution as the sample solution. Separately, weigh accurately
about 28 mg of levofloxacin hydrate for assay (separately
determine the water <2.48> in the same manner as Levofloxacin Hydrate), and dissolve in water to make exactly 100 mL.
Pipet 2 mL of this solution, add water to make exactly 100
mL, and use this solution as the standard solution. Determine the absorbances, AT and AS, at 289 nm of the sample
solution and standard solution as directed under Ultravioletvisible Spectrophotometry <2.24>.
Dissolution rate (z) with respect to the labeled amount of
levofloxacin hydrate (C18H20FN3O4.1/2H2O)
MS AT/AS 18/5 1.025
MS: Amount (mg) of levofloxacin hydrate for assay, calculated on the anhydrous basis
(2) For a 250-mg Tablet and 500-mg Tablet When the
tests are performed at 50 revolutions per minute according
to the Paddle method, using 900 mL of 2nd fluid for dissolution test as the dissolution medium, the dissolution rate in 30
minutes is not less than 80z.
Start the test with 1 tablet of Levofloxacin Tablets,
withdraw not less than 20 mL of the medium at the specified
minute after starting the test, and filter through a membrane
filter with a pore size not exceeding 0.45 mm. Discard the
first 10 mL of the filtrate, pipet V mL of the subsequent
filtrate, add the dissolution medium to make exactly V? mL
so that each mL contains about 11.2 mg of levofloxacin
(C18H20FN3O4), and use this solution as the sample solution.
Separately, weigh accurately about 28 mg of levofloxacin
hydrate for assay (separately determine the water <2.48> in
the same manner as Levofloxacin Hydrate), and dissolve in
the dissolution medium to make exactly 50 mL. Pipet 2 mL
of this solution, add the dissolution medium to make exactly
100 mL, and use this solution as the standard solution. Determine the absorbances, AT and AS, at 287 nm of the sample solution and standard solution as directed under Ultraviolet-visible Spectrophotometry <2.24>.
Dissolution rate (z) with respect to the labeled amount of
levofloxacin (C18H20FN3O4)
MS AT/AS V?/V 1/C 36
MS: Amount (mg) of levofloxacin hydrate for assay, calculated on the anhydrous basis
C: Amount (mg) of levofloxacin (C18H20FN3O4) in 1 g
Assay Accurately weigh the mass of not less than 20
Levofloxacin Tablets, and powder them. Weigh accurately a
portion of the powder, equivalent to about 1 g of levofloxacin (C18H20FN3O4), add 150 mL of diluted 3 mol/L
Supplement I, JP XVI
hydrochloric acid TS (1 in 100), agitate with the aid of ultrasonic waves for 5 minutes, and add diluted 3 mol/L
hydrochloric acid TS (1 in 100) to make exactly 200 mL, and
stir for 10 minutes. Pipet 2 mL of this solution, add diluted 3
mol/L hydrochloric acid TS (1 in 100) to make exactly 200
mL, and filter through a membrane filter with a pore size
not exceeding 0.45 mm. Discard the first 10 mL of the
filtrate, and use the subsequent filtrate as the sample solution. Separately, weigh accurately about 25 mg of levofloxacin hydrate for assay (separately determine the water <2.48>
in the same manner as Levofloxacin Hydrate), and dissolve
in diluted 3 mol/L hydrochloric acid TS (1 in 100) to make
exactly 50 mL. Pipet 2 mL of this solution, add diluted 3
mol/L hydrochloric acid TS (1 in 100) to make exactly 20
mL, and use this solution as the standard solution. Perform
the test with exactly 10 mL each of the sample solution and
standard solution as directed under Liquid Chromatography
<2.01> according to the following conditions, and determine
the peak areas, AT and AS, of levofloxacin of each solution.
Amount (mg) of levofloxacin (C18H20FN3O4)
MS AT/AS 40
MS: Amount (mg) of levofloxacin hydrate for assay, calculated on the anhydrous basis
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 340 nm).
Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilanized
silica gel for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
459C.
Mobile phase: Dissolve 1.00 g of copper (II) sulfate pentahydrate, 1.41 g of L-valine and 6.17g of ammonium acetate
in 800 mL of water, and add 200 mL of methanol.
Flow rate: Adjust the flow rate so that the retention time
of levofloxacin is about 20 minutes.
System suitability
System performance: Dissolve 10 mg of ofloxacin in 20
mL of diluted 3 mol/L hydrochloric acid TS (1 in 100). To 1
mL of this solution add diluted 3 mol/L hydrochloric acid
TS (1 in 100) to make 20 mL. When the procedure is run
with 10 mL of this solution under the above operating conditions, levofloxacin and an enantiomer are eluted in this order with the resolution between these peaks being not less
than 3.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of levofloxacin is not more than 1.0z.
Containers and storage
ContainersTight containers.
Official Monographs
2447
Lobenzarit Sodium
C14H8ClNNa2O4: 335.65
Disodium 2-[(2-carboxylatophenyl)amino]-4-chlorobenzoate
[64808-48-6]
2448
Official Monographs
of about 10 cm, and air-dry the plate. Examine under ultraviolet light (main wavelength: 254 nm): the spot other than
the principal spot obtained from the sample solution is not
more intense than the spot from the standard solution.
(4) Residual solvent Being specified separately.
Loss on drying <2.41>
hours).
Assay Weigh accurately about 0.1 g of Lobenzarit Sodium, previously dried, dissolve in exactly 40 mL of water,
add exactly 60 mL of a mixture of diethyl ether and tetrahydrofuran (1:1), and titrate <2.50> with 0.1 mol/L
hydrochloric acid VS while well shaking (indicator: 10 drops
of bromophenol blue TS) until the blue color of the water
layer changes to a persistent light blue-green. Perform a
blank determination in the same manner, and make any
necessary correction.
Each mL of 0.1 mol/L hydrochloric acid VS
16.78 mg of C14H8ClNNa2O4
Containers and storage
ContainersTight containers.
Supplement I, JP XVI
mol/L phosphate buffer solution, pH 8.0 (1 in 10) to make
exactly 100 mL, and stir until the tablet is completely disintegrated. Pipet 5 mL of this solution, add diluted 0.1 mol/L
phosphate buffer solution, pH 8.0 (1 in 10) to make exactly
V mL so that each mL contains about 50 mg of losartan
potassium (C22H22ClKN6O), centrifuge, and use the supernatant liquid as the sample solution. Then, proceed as
directed in the Assay.
Amount (mg) of losartan potassium (C22H22ClKN6O)
MS AT/AS V/25
Supplement I, JP XVI
Official Monographs
2449
test with exactly 20 mL each of the sample solution and standard solution as directed under Liquid Chromatography
<2.01> according to the following conditions, and determine
the peak areas, AT and AS, of losartan of these solutions.
bulky powder.
It is smooth to the touch and sticky to the skin. It has no
odor or a faint, characteristic odor.
It is practically insoluble in water and in ethanol (99.5).
ContainersTight containers.
Magnesium Stearate
Change to read:
This monograph is harmonized with the European Pharmacopoeia and the U.S.Pharmacopeia. The parts of the text
that are not harmonized are marked with symbols (
).
Purity (1) Acidity or alkalinityHeat 1.0 g of Magnesium Stearate in 20 mL of freshly boiled and cooled water on a
water bath for 1 minute while shaking, cool, and filter. Add
0.05 mL of bromothymol blue TS to 10 mL of the filtrate:
not more than 0.05 mL of 0.1 mol/L hydrochloric acid VS
or 0.1 mol/L sodium hydroxide VS is required to change the
color of the solution.
(2) Chloride <1.03>Perform the test with 10.0 mL of
the sample solution obtained in Identification. Prepare the
control solution with 1.4 mL of 0.02 mol/L hydrochloric
acid VS (not more than 0.1z).
(3) Sulfate <1.14>Perform the test with 6.0 mL of the
sample solution obtained in Identification. Prepare the control solution with 3.0 mL of 0.02 mol/L sulfuric acid VS
(not more than 1.0z).
(4)
Heavy metals <1.07>Heat 1.0 g of Magnesium
Stearate weakly first, then incinerate at about 500 259C.
After cooling, add 2 mL of hydrochloric acid, evaporate on
a water bath to dryness, add 20 mL of water and 2 mL of dilute acetic acid to the residue, and heat for 2 minutes. After
cooling, filter this solution through a filter paper, wash the
filter paper with 15 mL of water, and combine the washing
with the filtrate. To the filtrate add water to make 50 mL,
and perform the test with this solution as the test solution.
Prepare the control solution as follows: evaporate 2 mL of
hydrochloric acid on a water bath to dryness, add 2 mL of
dilute acetic acid, 2.0 mL of Standard Lead Solution and
water to make 50 mL (not more than 20 ppm).
Loss on drying <2.41>
constant mass).
Microbial
Transfer
2450
Official Monographs
Supplement I, JP XVI
System performance: When the procedure is run with 1 mL
of the solution for system suitability test under the above
operating conditions, the relative retention time of methyl
palmitate to methyl stearate is about 0.9, and the resolution
between these peaks is not less than 5.0.
System repeatability: When the test is repeated 6 times
with the solution for system suitability test under the above
operating conditions, the relative standard deviation of the
peak areas of methyl palmitate and methyl stearate are not
more than 3.0z, respectively, and the relative standard
deviation of the ratios of the peak area of methyl palmitate
to methyl stearate is not more than 1.0z.
Assay Transfer about 0.5 g of Magnesium Stearate, accurately weighed, to a 250-mL flask, add 50 mL of a mixture
of ethanol (99.5) and 1-butanol (1:1), 5 mL of ammonia solution (28), 3 mL of ammonium chloride buffer solution,
pH 10, 30.0 mL of 0.1 mol/L disodium dihydrogen
ethylenediamine tetraacetate VS, and 1 to 2 drops of
eriochrome black T TS, and mix. Heat at 45 509C to make
the solution clear, and after cooling, titrate <2.50> the excess
disodium dihydrogen ethylenediamine tetraacetate with 0.1
mol/L zinc sulfate VS until the solution changes from blue
to violet in color. Perform a blank determination in the same
manner, and make any necessary correction.
Each mL of 0.1 mol/L disodium dihydrogen ethylenediamine tetraacetate VS
2.431 mg of Mg
Containers
and storage
ContainersTight containers.
Mefloquine Hydrochloride
Supplement I, JP XVI
Change the Assay as follows:
Assay Weigh accurately about 0.5 g of Mefloquine
Hydrochloride, dissolve in 100 mL of a mixture of acetic anhydride and acetic acid (100) (7:3), and titrate <2.50> with 0.1
mol/L perchloric acid VS (potentiometric titration). Perform a blank determination in the same manner, and make
any necessary correction.
Each mL of 0.1 mol/L perchloric acid VS
41.48 mg of C17H16F6N2O.HCl
10% dl-Methylephedrine
Hydrochloride Powder
dl-10%
Official Monographs
2451
System suitability
System performance: When the procedure is run with 20
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of methylephedrine are not less than 5000
and not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 20 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of methylephedrine is not more than 2.0z.
Methyl Parahydroxybenzoate
125 1289
C
2452
Official Monographs
Assay Weigh accurately about 50 mg each of Methyl Parahydroxybenzoate and Methyl Parahydroxybenzoate RS, dissolve separately in 2.5 mL each of methanol, and add the
mobile phase to make exactly 50 mL. Pipet 10 mL each of
these solutions, add the mobile phase to make exactly 100
mL, and use these solutions as the sample solution and the
standard solution, respectively. Perform the test with exactly
10 mL each of the sample solution and standard solution as
directed under Liquid Chromatography <2.01> according to
the following conditions, and determine the peak areas, AT
and AS, of methyl parahydroxybenzoate of each solution.
Supplement I, JP XVI
Amount (mg) of methyl parahydroxybenzoate (C8H8O3)
M S A T /A S
and storage
ContainersWell-closed con-
tainers.
Mizoribine
Supplement I, JP XVI
Add the following:
(C17H19NO3)2.H2SO4.5H2O: 758.83
(5R,6S)-4,5-Epoxy-17-methyl-7,8-didehydromorphinan-3,6-diol
hemisulfate hemipentahydrate
[6211-15-0]
Official Monographs
2453
(3) ChlorideDissolve 0.10 g of Morphine Sulfate Hydrate in 10 mL of water, add 1 mL of dilute nitric acid, then
add 1 mL of silver nitrate TS: no turbidity is produced.
(4) Meconic acidDissolve 0.20 g of Morphine Sulfate
Hydrate in 5 mL of water, add 5 mL of dilute hydrochloric
acid and 2 drops of iron (III) chloride TS: no red color develops.
(5) Related substancesDissolve 0.20 g of Morphine
Sulfate Hydrate in 10 mL of diluted methanol (4 in 5), and
use this solution as the sample solution. Pipet 1 mL of the
sample solution, add diluted methanol (4 in 5) to make exactly 100 mL, and use this solution as the standard solution
(1). Pipet 5 mL of the standard solution (1), add diluted
methanol (4 in 5) to make exactly 10 mL, and use this solution as the standard solution (2). Perform the test with these
solutions as directed under Thin-layer Chromatography
<2.03>. Spot 10 mL each of the sample solution and the standard solutions (1) and (2) on a plate of silica gel with fluorescent indicator for thin-layer chromatography. Develop the
plate with a mixture of acetone, ethanol (99.5) and ammonia
solution (28) (21:14:3) to a distance of about 12 cm, and airdry the plate. Examine under ultraviolet light (main
wavelength: 254 nm): the spot at Rf value of about 0.17 obtained with the sample solution is not more intense than the
spot with the standard solution (1), and the spot other than
the principle spot, the spot at Rf value of about 0.17 and the
spot at original point is not more intense than the spot with
the standard solution (2).
(6) Residual solvent Being specified separately.
Water <2.48> 11.0 13.0z (0.1 g, volumetric titration,
direct titration).
Residue on ignition <2.44>
2454
Official Monographs
Nartograstim (Genetical
Recombination)
C850H1344N226O245S8: 18905.65
[134088-74-7]
Nartograstim (Genetical Recombination) is an aqueous solution in which a desired product is a recombinant human granulocyte colony-stimulating factor
(G-CSF) analog. It is N-methionylated, and threonine,
leucine, glycine, proline and cysteine residues at the
positions 1, 3, 4, 5 and 17 of G-CSF are substituted by
alanine, threonine, tyrosine, arginine and serine, respectively. It is a glycoprotein consisting of 175 amino
acid residues. It has a stimulating effect on neutrophil
production.
It contains not less than 0.9 mg and not more than
2.1 mg of protein per mL, and not less than 4.0 108
units per mg of protein.
Description Nartograstim (Genetical Recombination) occurs as a clear and colorless liquid.
Identification (1) To a suitable amount of Nartograstim
(Genetical Recombination) add tris-sodium chloride buffer
solution, pH 8.0 so that each mL contains 1 mg of protein,
and use this solution as the sample solution. Put 0.1 mL of
the sample solution in the well of a microplate for antigenantibody reaction test, allow to stand at 59
C for not less
than 10 hours, then remove the liquid, and wash the well.
Then to the well add 0.25 mL of blocking TS for nartograstim test, and allow to stand at room temperature for 1
hour. Remove the blocking TS, add 0.1 mL of rabbit antinartograstim antibody TS to the well, and stir gently at room
temperature for 3 hours. Remove the rabbit antinartograstim antibody TS, and wash the well. Then, add 0.1
mL of peroxidase labeled anti-rabbit antibody TS, stir gently
at room temperature for 2 hours, remove the TS, and wash
the well. Then, add 0.1 mL of 2,2?-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt TS, allow to
stand at room temperature for 10 minutes, add 0.1 mL of a
solution of oxalic acid dihydrate (1 in 50), and name this well
as the sample well. Separately, proceed with 0.1 mL of trissodium chloride buffer solution, pH 8.0 in the same manner
as for the sample solution, and name the well so obtained as
the control well. When compere the sample well and the control well, the sample well reveals a green color, while the
control well reveals no color.
Washing procedure of well: To the well add 0.25 mL of
washing fluid for nartograstim test, allow to stand for 3
Supplement I, JP XVI
minutes, and remove the washing fluid. Repeat this procedure 2 times more.
(2) To a suitable amount of Nartograstim (Genetical
Recombination) add water so that each mL contains 1 mg of
protein. Replace the solvent of 2 mL of this solution with
tris-calcium chloride buffer solution, pH 6.5. To 0.5 mL of
the solution so obtained add 0.5 mL of tris-calcium chloride
buffer solution, pH 6.5 and 5 mL of thermolysin solution (1
in 1000), allow to stand at 379
C for 21 hours, and use this
solution as the sample solution. Separately, proceed with 2
mL of Nartograstim RS in the same manner as for the sample solution, and use the solution so obtained as the standard
solution. Perform the test with 20 mL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions,
and compare these chromatograms: the similar peaks appear
at the same retention times.
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 220 nm).
Column: A stainless steel column 6 mm in inside diameter
and 15 cm in length, packed with octadecylsilanized silica gel
for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
359C.
Mobile phase A: A mixture of water and trifluoroacetic
acid (1000:1).
Mobile phase B: A mixture of acetonitrile, water and
trifluoroacetic acid (900:100:1).
Flowing of the mobile phase: Control the gradient by
mixing the mobile phases A and B as directed in the following table.
Time after injection
of sample (min)
Mobile phase
A (volz)
Mobile phase
B (volz)
0 5
5 90
100
100 40
0
0 60
7.0 7.5
Supplement I, JP XVI
Official Monographs
trophoresis, immerse the gel in a solution of coomassie brilliant blue R-250 in a mixture of water, ethanol (95) and acetic
acid (100) (5:4:1) (1 in 1000), and stir gently at room temperature for not less than 12 hours. Then, remove the color
from the gel in a mixture of water, ethanol (95) and acetic
acid (100) (13:5:2), and dry the gel under reduced pressure.
Determine the areas of the colored bands obtained from the
sample solution and standard solution by a densitometer at
the measure wavelength 560 nm and the control wavelength
400 nm: the total area of the band other than the principal
band obtained from the sample solution is not larger than
the band area obtained from the standard solution.
(2) Host-derived protein Being specified separately.
(3) DNA Being specified separately.
Bacterial endotoxins <4.01>
Being specified
Assay (1) Protein contentTo exactly V1 mL of Nartograstim (Genetical Recombination) add exactly V2 mL of
water so that each mL contains about 0.5 mg of protein, and
centrifuge. Determine the absorbance, A, of the supernatant
liquid at the absorption maximum at about 280 nm as directed under Ultraviolet-visible Spectrophotometry <2.24>.
Amount (mg) of protein in 1 mL of Nartograstim (Genetical
Recombination)
A/8.71 (V1 V2)/V1 10
8.71: Specific absorbance
(2) Specific activityTo a suitable exact amount of Nartograstim (Genetical Recombination) add potency measur-
2455
2456
Official Monographs
Supplement I, JP XVI
2a
1
S 2b
3
Nartograstim for Injection (Genetical Recombination) is a preparation for injection which is dissolved
before use.
It contains not less than 90.0z and not more than
110.0z of the labeled amount of nartograstim (genetical recombination) (C850H1344N226O245S8: 18905.65).
Method of preparation Prepare as directed under Injections, with Nartograstim (Genetical Recombination).
Description Nartograstim for Injection (Genetical Recombination) occurs as white, masses or powder.
Identification Dissolve the content of 1 container of Nartograstim for Injection (Genetical Recombination) in 1 mL
of tris-sodium chloride buffer solution, pH 8.0. To a suitable amount of this solution add tris-sodium chloride buffer
solution, pH 8.0 so that each mL contains 1 mg of Nartograstim (Genetical Recombination), and use this solution
as the sample solution. Then, proceed with the sample solution as directed in the Identification (1) under Nartograstim
(Genetical Recombination).
pH <2.54> The pH of a solution of Nartograstim for Injection (Genetical Recombination) in water, containing 100 mg
Sterility <4.06> Perform the test according to the Membrane filtration method, using the sample solution prepared
by dissolving the sample in water in a concentration to be
used for the injection: it meets the requirement.
Specific activity Nartograstim for Injection (Genetical
Recombination), when perform the assay and the following
test, contains not less than 4.0 108 units of nartograstim
(genetical recombination) per mg nartograstim (genetical
recombination).
Wash out each content of 10 Nartograstim for Injection
(Genetical Recombination) with a suitable amount of potency measuring medium for nartograstim test, wash the empty
containers with the same medium, combine all washings,
and add the same medium to make exactly 50 mL. To an exact amount of this solution add the same medium so that the
concentration of nartograstim (genetical recombination) is
equivalent to 50z to 150z of that of the standard solution,
and use this solution as the sample solution. Separately,
weigh accurately a suitable amount of Nartograstim RS, dissolve in the potency measuring medium for nartograstim test
so that each mL contains exactly 1.2 104 units of nartograstim according to the labeled unit, and use this solution
as the standard solution. Then, determine the nartograstim
potency (unit) in 1 Nartograstim for Injection (Genetical
Recombination) by proceeding as directed in the Assay (2)
under Nartograstim (Genetical Recombination), and calculate the ratio against the amount of nartograstim obtained in
the Assay.
Nartograstim (genetical recombination) potency (unit) in 1
Nartograstim for Injection (Genetical Recombination)
S mean relative potency of the sample solution
d5
Supplement I, JP XVI
Official Monographs
sample
Relative activity of sample solution
2457
System suitability
Proceed as directed in the system suitability in the Assay
(2) under Nartograstim (Genetical Recombination).
Assay Weigh accurately the mass of each content of not
less than 10 Nartograstim for Injection (Genetical Recombination). Weigh accurately an amount of the content, equivalent to about 0.25 mg of Nartograstim (Genetical Recombination) according to the labeled amount, dissolve in exactly
5 mL of the mobile phase, and use this solution as the sample solution. Separately, dissolve a suitable amount of Nartograstim RS in the mobile phase so that each mL contains
about 50 mg of nartograstim, and use this solution as the
standard solution. Perform the test with exactly 100 mL each
of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions, and determine the peak areas, AT and AS, of
nartograstim of these solutions.
Amount (mg) of nartograstim (genetical recombination) in 1
Nartograstim for Injection (Genetical Recombination)
M S A T /A S M /M T 5
Nateglinide
Nifedipine Extended-release
Capsules
2458
Official Monographs
Supplement I, JP XVI
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of nifedipine is not more than 1.0z.
Containers and storage ContainersTight containers.
StorageLight-resistant.
Supplement I, JP XVI
the 1st fluid for dissolution test in 60 minutes is not more
than 15z, and that in the test using the 2nd fluid for dissolution test in 30 minutes is not less than 75z.
Conduct this procedure without exposure to light, using
light-resistant vessels. Start the test with an accurately
weighed amount of Nifedipine Enteric Fine Granules,
equivalent to about 20 mg of nifedipine (C17H18N2O6),
withdraw not less than 20 mL of the medium at the specified
minute after starting the test, and filter through a membrane
filter with a pore size not exceeding 0.45 mm. Discard the
first 10 mL of the filtrate, pipet 5 mL of the subsequent
filtrate, add the dissolution medium to make exactly 10 mL,
and use this solution as the sample solution. Separately,
weigh accurately about 28 mg of nifedipine for assay, previously dried at 1059
C for 2 hours, dissolve in 50 mL of
methanol, and add the dissolution medium to make exactly
100 mL. Pipet 2 mL of this solution, add the dissolution
medium to make exactly 50 mL, and use this solution as the
standard solution. Perform the test with exactly 50 mL each
of the sample solution and standard solution as directed under Liquid Chromatography <2.01>, and determine the peak
areas, AT and AS, of nifedipine of each solution.
Dissolution rate (z) with respect to the labeled amount of
nifedipine (C17H18N2O6)
MS/MT AT/AS 1/C 72
Official Monographs
2459
2460
Official Monographs
Uniformity of dosage units <6.02> Perform the test according to the following method: the Granules in single-unit containers meet the requirement of the Content uniformity test.
Conduct this procedure without exposure to light, using
light-resistant vessels. To the total content of 1 container of
Nifedipine Fine Granules add 50 mL of a mixture of
methanol and water (9:1), agitate for 15 minutes with the
aide of ultrasonic waves with occasional shaking, and shake
for further 15 minutes. Then, add methanol to make exactly
V mL so that each mL contains about 0.1 mg of of nifedipine (C17H18N2O6). Filter this solution through a membrane
filter with a pore size not exceeding 0.45 mm. Discard the
first 10 mL of the filtrate, pipet 5 mL of the subsequent
filtrate, add methanol to make exactly 10 mL, and use this
solution as the sample solution. Separately, weigh accurately
about 50 mg of nifedipine for assay, previously dried at
1059
C for 2 hours, and dissolve in methanol to make exactly
50 mL. Pipet 5 mL of this solution, add methanol to make
exactly 100 mL, and use this solution as the standard solution. Then, proceed as directed in the Assay.
Amount (mg) of nifedipine (C17H18N2O6)
MS AT/AS V/500
Supplement I, JP XVI
System suitability
System performance: When the procedure is run with 50
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of nifedipine are not less than 4000 and
not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 50 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of nifedipine is not more than 1.0z.
Assay Conduct this procedure without exposure to light,
using light-resistant vessels. Weigh accurately a protein of
powdered Nifedipine Fine Granules, equivalent to about 10
mg of nifedipine (C17H18N2O6), add 50 mL of a mixture of
methanol and water (9:1), shake vigorously for 15 minutes,
and add methanol to make exactly 100 mL. Filter this solution through a membrane filter with a pore size not exceeding 0.45 mm. Discard the first 10 mL of the filtrate, pipet 5
mL of the subsequent filtrate, add methanol to make exactly
10 mL, and use this solution as the sample solution.
Separately, weigh accurately about 50 mg of nifedipine for
assay, previously dried at 1059
C for 2 hours, and dissolve in
methanol to make exactly 50 mL. Pipet 5 mL of this solution, add methanol to make exactly 100 mL, and use this solution as the standard solution. Perform the test with exactly
10 mL each of the sample solution and standard solution as
directed under Liquid Chromatography <2.01> according to
the following conditions, and determine the peak areas, AT
and AS, of nifedipine of these solutions.
Amount (mg) of nifedipine (C17H18N2O6)
MS AT/AS 1/5
Supplement I, JP XVI
Containers and storage ContainersTight containers.
StorageLight-resistant.
Norethisterone
Official Monographs
2461
2462
Official Monographs
ContainersTight containers.
Parnaparin Sodium
Supplement I, JP XVI
Add the following:
Supplement I, JP XVI
Official Monographs
Mobile phase
A (volz)
Mobile phase
B (volz)
0 60
100 0
0 100
2463
MS: Amount (mg) of Pemirolast Potassium RS, calculated on the anhydrous basis.
Flow rate: Adjust the flow rate so that the retention time
of pemirolast is about 19 minute.
Time span of measurement: About 3 times as long as the
retention time of pemirolast, beginning after the solvent
peak.
System suitability
Test for required detectability: Pipet 2 mL of the standard
solution, and add diluted 0.1 mol/L phosphate buffer solution for antibiotics, pH 8.0 (1 in 10) to make exactly 20 mL.
Confirm that the peak area of pemirolast obtained with 10
mL of this solution is equivalent to 7 to 13z of that with 10
mL of the standard solution.
System performance: Dissolve 10 mg of pemirolast potassium in 10 mL of diluted 0.1 mol/L phosphate buffer solution for antibiotics, pH 8.0 (1 in 10), transfer this solution to
a colorless test tube, and illuminate with a D65 fluorescent
lamp (3000 lx) for 72 hours. To 2 mL of this solution add 1
mL of methanol and diluted 0.1 mol/L phosphate buffer solution for antibiotics, pH 8.0 (1 in 10) to make 5 mL. When
the procedure is run with 10 mL of this solution under the
above operating conditions, the resolution between the
peak, having the relative retention time about 0.9 to
pemirolast, and the peak of pemirolast is not less than 3.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of pemirolast is not more than 2.0z.
ContainerTight containers.
Sterility <4.06> Perform the test according to the Membrane filtration method: it meets the requirement.
Assay Pipet a volume of Pemirolast Potassium
Ophthalmic Solution, equivalent to 2 mg of pemirolast
potassium (C10H7KN6O), add exactly 2 mL of the internal
standard solution, then add a mixture of diluted 0.1 mol/L
phosphate buffer solution for antibiotics, pH 8.0 (1 in 10)
and methanol (3:2) to make 20 mL, and use this solution as
the sample solution. Separately, weigh accurately about 50
mg of Pemirolast Potassium RS (separately determine the
water <2.48> in the same manner as Pemirolast Potassium),
and dissolve in water to make exactly 50 mL. Pipet 2 mL of
this solution, add exactly 2 mL of the internal standard solution, then add a mixture of diluted 0.1 mol/L phosphate
2464
Official Monographs
cording to the following conditions: the principal peaks obtained from the sample solution and standard solution show
the same retention time, and both spectra of these peaks exhibit similar intensities of absorption at the same wavelengths.
Operating conditions
Column, column temperature, mobile phase, and flow
rate: Proceed as directed in the operating conditions in the
Assay.
Detector: Photodiode array detector (wavelength: 215
nm; spectrum range of measurement: 200 370 nm).
System suitability
System performance: Proceed as directed in the system
suitability in the Assay.
Purity Related substancesUse the sample solution obtained in the Assay as the sample solution. Pipet 1 mL of the
sample solution, add phosphate buffer solution, pH 4.0 to
make exactly 100 mL, and use this solution as the standard
solution. Perform the test with exactly 10 mL each of the
sample solution and standard solution as directed under
Liquid Chromatography <2.01> according to the following
conditions, and determine each peak area by the automatic
integration method: the area of the two peaks, having the
relative retention time of about 0.78 and about 0.92 to
pilocarpine, obtained from the sample solution is not larger
than the peak area of pilocarpine from the standard solution, the area of the peak other than pilocarpine and the
peaks mentioned above is not larger than 1/5 times the peak
area of pilocarpine from the standard solution, and the total
area of the peaks other than pilocarpine is not larger than 2
times the peak area of pilocarpine from the standard solution.
Operating conditions
Detector, column, column temperature, mobile phase,
and flow rate: Proceed as directed in the operating conditions in the Assay.
Time span of measurement: About 1.3 times as long as the
retention time of pilocarpine, beginning after the solvent
peak.
System suitability
Test for required detectability: To exactly 2 mL of the
standard solution add phosphate buffer solution, pH 4.0 to
make exactly 20 mL. Confirm that the peak area of pilocarpine obtained with 10 mL of this solution is equivalent to 7
13z of that with 10 mL of the standard solution.
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of pilocarpine are not less than 3000 and
not more than 2.0, respectively.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of pilocarpine is not more than 2.0z.
Uniformity of dosage units <6.02> Perform the test according to the following method: it meets the requirement of the
Content uniformity test.
Supplement I, JP XVI
To 1 tablet of Pilocarpine Hydrochloride Tablets add a
suitable amount of phosphate buffer solution, pH 4.0,
shake until the tablet is completely disintegrated, then add
phosphate buffer solution, pH 4.0 to make exactly V mL so
that each mL contains about 0.2 mg of pilocarpine
hydrochloride (C11H16N2O2.HCl), and filter through a membrane filter with a pore size not exceeding 0.45 mm. Discard
the first 3 mL of the filtrate, and use the subsequent filtrate
as the sample solution. Separately, weigh accurately about
40 mg of pilocarpine hydrochloride for assay, previously
dried at 1059C for 2 hours, and dissolve in phosphate buffer
solution, pH 4.0 to make exactly 100 mL. Pipet 5 mL of this
solution, add phosphate buffer solution, pH 4.0 to make exactly 10 mL, and use this solution as the standard solution.
Perform the test with exactly 20 mL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions,
and determine the peak areas, AT and AS, of pilocarpine of
each solution.
Amount (mg) of pilocarpine hydrochloride
(C11H16N2O2.HCl)
MS AT/AS V/200
Supplement I, JP XVI
the following conditions, and determine the peak areas, AT
and AS, of pilocarpine of both solutions.
Dissolution rate (z) with respect to the labeled amount of
pilocarpine hydrochloride (C11H16N2O2.HCl)
MS AT/AS V?/V 1/C 9
Official Monographs
2465
Flow rate: Adjust the flow rate so that the retention time
of pilocarpine is about 12 minutes.
System suitability
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of pilocarpine are not less than 3000 and
not more than 2.0, respectively.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of pilocarpine is not more than 1.0z.
Containers and storage
ContainersTight containers.
Piperacillin Sodium
2466
Official Monographs
Supplement I, JP XVI
Mobile phase
A (volz)
Mobile phase
B (volz)
07
7 13
13 41
41 56
56 60
100
100 83
83
83 20
20
0
0 17
17
17 80
80
Flow rate: 1.0 mL per minute. (the retention time of piperacillin is about 33 minutes).
Time span of measurement: About 1.8 times as long as the
retention time of piperacillin beginning after the solvent
peak.
System suitability
Test for required detectability: To exactly 2 mL of the
standard solution add the mobile phase A to make exactly 20
mL. Confirm that the peak area of piperacillin obtained
from 20 mL of this solution is equivalent to 7 to 13z of that
of piperacillin obtained from 20 mL of the standard solution.
System performance: When the procedure is run with 20
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of piperacillin are not less than 15,000 and
not more than 1.5, respectively.
System repeatability:When the test is repeated 3 times
with 20 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of piperacillin is not more than 2.0z.
Potato Starch
Mobile phase
A (volz)
Mobile phase
B (volz)
0 50
50 75
50
50 0
50
50 100
Supplement I, JP XVI
System performance: When the procedure is run with 20
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of pravastatin are not less than 3500 and
not more than 1.6, respectively.
System repeatability: When the test is repeated 6 times
with 20 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of pravastatin is not more than 1.5z.
Official Monographs
2467
Mobile phase
A (volz)
Mobile phase
B (volz)
0 50
50 75
50
50 0
50
50 100
Propyl Parahydroxybenzoate
96 999C
2468
Official Monographs
Supplement I, JP XVI
ing conditions, the relative standard deviation of the peak
area of propyl parahydroxybenzoate is not more than
2.0z.
Residue on ignition <2.44>
Assay Weigh accurately about 50 mg each of Propyl Parahydroxybenzoate and Propyl Parahydroxybenzoate RS, dissolve separately in 2.5 mL each of methanol, and add the
mobile phase to make exactly 50 mL. Pipet 10 mL each of
these solutions, add the mobile phase to make exactly 100
mL, and use these solutions as the sample solution and the
standard solution, respectively. Perform the test with exactly
10 mL each of the sample solution and standard solution as
directed under Liquid Chromatography <2.01> according to
the following conditions, and determine the peak areas, AT
and AS, of propyl parahydroxybenzoate of each solution.
Amount (mg) of propyl parahydroxybenzoate (C10H12O3)
M S A T/ A S
tainers.
and storage
ContainersWell-closed con-
Supplement I, JP XVI
Add the following:
Quetiapine Fumarate
(C21H25N3O2S)2.C4H4O4: 883.09
2-[2-(4-Dibenzo[b,f ][1,4]thiazepin-11-ylpiperazin1-yl)ethoxy]ethanol hemifumarate
[111974-72-2]
Official Monographs
2469
2470
Official Monographs
Supplement I, JP XVI
Fumarate and Quetiapine Fumarate RS (separately determine the water <2.48> in the same manner as Quetiapine
Fumarate), add 60 mL of the mobile phase to them, dissolve
with the aid of ultrasonic waves, and add the mobile phase
to make exactly 100 mL. Pipet 10 mL each of these solutions, add the mobile phase to make exactly 25 mL, and use
these solutions as the sample solution and the standard solution, respectively. Perform the test with exactly 50 mL each
of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions, and determine the peak areas, AT and AS, of
quetiapine.
Amount (mg) of quetiapine fumarate
[(C21H25N3O2S)2.C4H4O4]
M S A T/ A S
ContainersTight containers.
Supplement I, JP XVI
Identification Powder Quetiapine Fumarate Fine Granules. To a portion of the powder, equivalent to 12.5 mg of
quetiapine (C21H25N3O2S), add 60 mL of a mixture of water
and acetonitrile (1:1), shake, then add the same mixture to
make 100 mL, and filter. To 3 mL of the filtrate add the
same mixture to make 25 mL. Determine the absorption
spectrum of this solution as directed under Ultraviolet-visible Spectrophotometry <2.24>: it exhibits a maximum between 290 nm and 296 nm.
Dissolution <6.10> When the test is performed at 50 revolutions per minute according to the Paddle method, using 900
mL of water as the dissolution medium, the dissolution rate
in 30 minutes of Quetiapine Fumarate Fine Granules is not
less than 80z.
Start the test with an accurately weighed amount of
Quetiapine Fumarate Fine Granules, equivalent to about 0.1
g of quetiapine (C21H25N3O2S), withdraw not less than 10
mL of the medium at the specified minute after starting the
test, and filter through a membrane filter with a pore size
not exceeding 1.0 mm. Discard the first 5 mL of the filtrate,
pipet 4 mL of the subsequent filtrate, add water to make exactly 20 mL, and use this solution as the sample solution.
Separately, weigh accurately about 32 mg of Quetiapine
Fumarate RS (separately determine the water <2.48> in the
same manner as Quetiapine Fumarate), and dissolve in water
to make exactly 50 mL. Pipet 4 mL of this solution, add
water to make exactly 100 mL, and use this solution as the
standard solution. Determine the absorbances, AT and AS,
at 289 nm of the sample solution and standard solution as
directed under Ultraviolet-visible Spectrophotometry <2.24>.
Dissolution rate (z) with respect to the labeled amount of
quetiapine (C21H25N3O2S)
MS/MT AT/AS 1/C 360 0.869
Official Monographs
2471
ContainersTight containers.
2472
Official Monographs
Supplement I, JP XVI
membrane filter with a pore size not exceeding 0.45 mm. Discard the first 5 mL of the filtrate, and use the subsequent
filtrate as the sample solution. Separately, weigh accurately
about 18 mg of Quetiapine Fumarate RS (separately determine the water <2.48> in the same manner as Quetiapine
Fumarate), add 60 mL of the mobile phase, dissolve with the
aid of ultrasonic waves, then add the mobile phase to make
exactly 100 mL, and use this solution as the standard solution. Then, proceed as directed in the Assay.
Amount (mg) of quetiapine (C21H25N3O2S)
MS AT/AS V/16 0.869
Supplement I, JP XVI
(54:39:7).
Flow rate: Adjust the flow rate so that the retention time
of quetiapine is about 4 minutes.
System suitability
System performance: When the procedure is run with 50
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of quetiapine are not less than 1400 and
not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 50 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of quetiapine is not more than 2.0z.
Assay To 20 Quetiapine Fumarate Tablets add 20 mL of
water, allow to stand for 15 minutes, shake for 25 minutes,
and add a mixture of water and acetonitrile (1:1) to make exactly 500 mL. Stir the solution for 4 hours. After standing
for 15 minutes, pipet 4 mL of this solution, and add the mobile phase to make exactly V mL so that each mL contains
about 0.16 mg of quetiapine (C21H25N3O2S). Filter this solution through a membrane filter with a pore size not exceeding 0.45 mm. Discard the first 5 mL of the filtrate, and use
the subsequent filtrate as the sample solution. Separately,
weigh accurately about 18 mg of Quetiapine Fumarate RS
(separately determine the water <2.48> in the same manner as
Quetiapine Fumarate), add 60 mL of the mobile phase, dissolve with the aid of ultrasonic waves, then add the mobile
phase to make exactly 100 mL, and use this solution as the
standard solution. Perform the test with exactly 50 mL each
of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions, and determine the peak areas, AT and AS, of
quetiapine.
Amount (mg) of quetiapine (C21H25N3O2S) in 1 tablet of
Quetiapine Fumarate Tablets
MS AT/AS V/16 0.869
Official Monographs
2473
ContainersTight containers.
Rabeprazole Sodium
Riboflavin Powder
2474
Official Monographs
Supplement I, JP XVI
trophotometry <2.24>.
Simvastatin Tablets
Ribostamycin Sulfate
Method of preparation
with Simvastatin.
Rice Starch
Sarpogrelate Hydrochloride
Purity Related substancesPowder not less than 20 Simvastatin Tablets. To a portion of the powder, equivalent to
about 50 mg of Simvastatin, add 200 mL of a mixture of
acetonitrile and 0.05 mol/L acetate buffer solution, pH 4.0
(4:1), and agitate with the aid of ultrasonic waves for 15
minutes. After cooling, add the same mixture to make 250
mL, and centrifuge. To 5 mL of the supernatant liquid add
the same mixture to make 10 mL, and use this solution as the
sample solution. Pipet 1 mL of the sample solution, add a
mixture of acetonitrile and 0.05 mol/L acetate buffer solution, pH 4.0 (4:1) to make exactly 200 mL, and use this solution as the standard solution. Perform the test with exactly
10 mL each of the sample solution and standard solution as
directed under Liquid Chromatography <2.01> according to
the following conditions. Determine each peak area by the
automatic integration method: the area of the peak with the
relative retention time of about 0.5 to simvastatin obtained
from the sample solution is not larger than 1.6 times the
peak area of simvastatin from the standard solution, the
area of the peak with the relative retention time of about 2.0
from the sample solution is not larger than the peak area of
simvastatin from the standard solution, and the total area of
the peaks other than simvastatin is not larger than 4 times
the peak area of simvastatin from the standard solution.
Operating conditions
Detector, column, column temperature, mobile phase,
and flow rate: Proceed as directed in the operating conditions in the Assay.
Time span of measurement: About 2.5 times as long as the
retention time of simvastatin, beginning after the solvent
peak.
System suitability
Test for required detectability: Pipet 2 mL of the standard
solution, and add the mobile phase to make exactly 10 mL.
Confirm that the peak area of simvastatin obtained with 10
mL of this solution is equivalent to 14 to 26z of that with 10
Supplement I, JP XVI
mL of the standard solution.
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of simvastatin are not less than 6000 and
0.9 1.1, respectively.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of simvastatin is not more than 2.0z.
Uniformity of dosage units <6.02> Perform the test according to the following method: it meets the requirement of the
Content uniformity test.
To 1 tablet of Simvastatin Tablets add V/20 mL of water,
and disintegrate the tablet with the aid of ultrasonic waves.
Add a mixture of acetonitrile and 0.05 mol/L acetate buffer
solution, pH 4.0 (4:1) to make 3V/4 mL, and agitate with
the aid of ultrasonic waves for 15 minutes. After cooling,
add the same mixture to make exactly V mL so that each mL
contains about 0.1 mg of simvastatin (C25H38O5), centrifuge,
and use the supernatant liquid as the sample solution. Then,
proceed as directed in the Assay.
Amount (mg) of simvastatin (C25H38O5)
MS AT/AS V/200
Official Monographs
2475
2476
Official Monographs
459C.
Mobile phase: Dissolve 3.90 g of sodium dihydrogen
phosphate dihydrate in 900 mL of water, adjust to pH 4.5
with sodium hydroxide TS or phosphoric acid, and add
water to make 1000 mL. To 700 mL of this solution add
1300 mL of acetonitrile.
Flow rate: Adjust the flow rate so that the retention time
of simvastatin is about 9 minutes.
System suitability
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of simvastatin are not less than 6000 and
0.9 1.1, respectively.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of simvastatin is not more than 1.0z.
Containers and storage
ContainersTight containers.
Streptomycin Sulfate
Supplement I, JP XVI
Sucrose
Change to read:
C12H22O11: 342.30
b-D-Fructofuranosyl a-D-glucopyranoside
[57501]
This monograph is harmonized with the European Pharmacopoeia and the U.S.Pharmacopeia. The parts of the text
that are not harmonized are marked with symbols (
).
Identification Determine the infrared absorption spectrum of Sucrose as directed in the potassium bromide disk
method under Infrared Spectrophotometry <2.25>, and compare the spectrum with the Reference Spectrum: both spectra exhibit similar intensities of absorption at the same wave
numbers.
Optical rotation <2.49>
100 mL, 100 mm).
[a]20
D : 66.3 67.09(26 g, water,
Supplement I, JP XVI
Official Monographs
n20
D
c (g/mL)
1.4138
1.4159
1.4179
1.4200
1.4221
1.4243
1.4264
0.570
0.585
0.600
0.615
0.630
0.645
0.661
System suitability
System repeatability: When the test is repeated 2 times
with the sample solution, the difference between 2 results is
not larger than 3.
(2) Clarity of solutionDissolve 50.0 g of Sucrose in
water to make 100 mL, and use this solution as the sample
solution: the sample solution is clear, and its clarity is not
different from water, or its opalescence is not more than that
of reference suspension 1.
(3) Sulfite
(i) Enzyme reaction: Sulfite is oxidized by sulfite oxidase
to sulfuric acid and hydrogen peroxide which in turn is
reduced by nicotinamide adenine dinucleotide peroxidase in
the presence of nicotinamide adenine dinucleotide reduced
form (NADH). The amount of NADH oxidized is proportional to the amount of sulfite. Calculate the amount of oxidized NADH from the degree of reduction of the absorbance at 340 nm. A suitable kit may be used.
(ii) Procedure: Dissolve 4.0 g of Sucrose in freshly prepared distilled water to make exactly 10 mL, and use this solution as the sample solution. Separately, dissolve 4.0 g of
Sucrose in freshly prepared distilled water, add exactly 0.5
mL of Standard Sulfite Solution, then add freshly prepared
distilled water to make exactly 10 mL, and use this solution
as the standard solution. Use freshly prepared distilled water
as a blank. Separately, introduce 2.0 mL each of the sample
solution, the standard solution and the blank in 10-mm cells,
add 1.00 mL of b-nicotinamide adenine dinucleotide reduced form TS and 10 mL of NADH peroxidase TS, stir with
a plastic stirring rod, and allow to stand at 20 259
C for 5
minutes. Measure the absorbance of these solutions at 340
nm, AT1, AS1 and AB1, as directed under Ultraviolet-visible
Spectrophotometry <2.24>, using water as the blank. Then,
to these solutions add 50 mL each of sulfite oxidase TS, stir,
allow to stand at 20 259C for 30 minutes, then measure the
absorbance of these solutions in the same manner as above,
AT2, AS2 and AB2: the result of (AT1 AT2) (AB1 AB2) is
not larger than half the result of (AS1 AS2) (AB1 AB2)
(not more than 10 ppm expressed as SO2).
(4) Reducing sugarsTransfer 5 mL of the sample solution obtained in (2) to a test-tube about 150 mm long and
about 16 mm in diameter, add 5 mL of water, 1.0 mL of 1
mol/L sodium hydroxide VS and 1.0 mL of methylene blue
TS, mix, and heat in a water bath. After exactly 2 minutes,
take the tube out of the bath, and examine the solution immediately: the blue color does not disappear completely. Ignore any blue color at the air and solution interface.
2477
kC (mScm1) k1 0.35k2
Loss on drying <2.41>
hours).
ContainersWell-closed con-
Tacalcitol Hydrate
C27H44O3.H2O: 434.65
(1S,3R,5Z,7E,24R)-9,10-Secocholesta-5,7,10(19)-triene-1,3,24-triol
monohydrate
[93129-94-3]
2478
Official Monographs
Supplement I, JP XVI
responding to pre-tacalcitol having the relative retention
time of about 0.85 to tacalcitol and tacalcitol is not less than
4.
System repeatability: When the test is repeated 6 times
with 30 mL of the solution for system suitability test under
the above operating conditions, the relative standard deviation of the peak area of tacalcitol is not more than 2.0z.
(2) Related substancesDissolve 1 mg of Tacalcitol Hydrate in 0.2 mL of ethanol (99.5), and use this solution as the
sample solution. Pipet 50 mL of the sample solution, add
ethanol (99.5) to make exactly 5 mL, and use this solution as
the standard solution. Perform the test with these solutions
as directed under Thin-layer Chromatography <2.03>. Spot
20 mL each of the sample solution and standard solution on
a plate of silica gel for thin-layer chromatography. Develop
the plate with a mixture of toluene and acetone (4:3) to a distance of about 15 cm, and air-dry the plate. Spray evenly a
mixture of sulfuric acid and methanol (1:1) on the plate, and
heat at 1059
C for 5 minutes: the spot other than the principal spot obtained from the sample solution is not more
than one, and not more intense than the spot from the standard solution.
(3) Residual solvent Being specified separately.
Water <2.48>
Supplement I, JP XVI
ditions, the number of theoretical plates and the symmetry
factor of the peak of tacalcitol are not less than 1500 and not
more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 40 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of tacalcitol is not more than 1.0z.
Containers and storage ContainersTight containers.
StorageLight-resistant, and at a temperature of 2 89C.
Tacalcitol Lotion
Official Monographs
2479
tion and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions,
and calculate the ratios, QT and QS, of the peak area of
tacalcitol to that of the internal standard.
Amount (mg) of tacalcitol (C27H44O3)
M S Q T/ Q S 2
2480
Official Monographs
Taltirelin Hydrate
C17H23N7O5.4H2O: 477.47
N-[(4S)-1-Methyl-2,6-dioxohexahydropyrimidine-4-carbonyl]L-histidyl-L-prolinamide tetrahydrate
[201677-75-0]
Supplement I, JP XVI
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 210 nm).
Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilanized
silica gel for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
409C.
Mobile phase: Dissolve 3.4 g of potassium dihydrogen
phosphate in 1000 mL of water, adjust to pH 2.5 with phosphoric acid, and add 1.7 g of sodium 1-octanesulfonate. To
900 mL of this solution add 100 mL of acetonitrile.
Flow rate: Adjust the flow rate so that the retention time
of taltirelin is about 15 minutes.
Time span of measurement: About 1.5 times as long as the
retention time of taltirelin, beginning after the solvent peak.
System suitability
Test for required detectability: To 1 mL of the sample solution add the mobile phase to make 100 mL, and use this
solution as the solution for system suitability test. Pipet 1
mL of the solution for system suitability test, and add the
mobile phase to make exactly 20 mL. Confirm that the peak
area of taltirelin obtained with 20 mL of this solution is equivalent to 3.5 to 6.5z of that with 20 mL of the solution
for system suitability test.
System performance: When the procedure is run with 20
mL of the solution for system suitability test under the above
operating conditions, the number of theoretical plates and
the symmetry factor of the peak of taltirelin are not less than
7000 and not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 20 mL of the solution for system suitability test under
the above operating conditions, the relative standard deviation of the peak area of taltirelin is not more than 2.0z.
(3) Residual solvent Being specified separately.
Water <2.48> 14.0 15.5z (0.2 g, volumetric titration,
direct titration).
Residue on ignition <2.44>
ContainersWell-closed contain-
Supplement I, JP XVI
Add the following:
Official Monographs
2481
MS: Amount (mg) of taltirelin hydrate for assay, calculated on the anhydrous basis
Internal standard solutionA solution of o-acetanisidide (1
in 2500).
Disintegration
Dissolution <6.10> When the test is performed at 50 revolutions per minute according to the Paddle method, using 900
mL of water as the dissolution medium, the dissolution rate
in 15 minutes of Taltirelin Orally Disintegrating Tablets is
not less than 85z.
Start the test with 1 tablet of Taltirelin Orally Disintegrating Tablets, withdraw not less than 20 mL of the medium at
the specified minute after starting the test, and filter through
a membrane filter with a pore size not exceeding 0.45 mm.
Discard the first 10 mL of the filtrate, pipet V mL of the subsequent filtrate, add water to make exactly V? mL so that
each mL contains about 5.6 mg of taltirelin hydrate
(C17H23N7O5.4H2O), and use this solution as the sample solution. Separately, weigh accurately about 28 mg of taltirelin
hydrate for assay (separately determine the water <2.48> in
the same manner as Taltirelin Hydrate), and dissolve in
water to make exactly 100 mL. Pipet 2 mL of this solution,
add water to make exactly 100 mL, and use this solution as
the standard solution. Perform the test with exactly 20 mL
each of the sample solution and standard solution as directed under Liquid Chromatography <2.01>, according to the
following conditions, and determine the peak areas, AT and
AS, of taltirelin.
2482
Official Monographs
MS: Amount (mg) of taltirelin hydrate for assay, calculated on the anhydrous basis
C: Labeled amount (mg) of taltirelin hydrate
(C17H23N7O5.4H2O) in 1 tablet
Operating conditions
Proceed as directed in the operating conditions in the Assay.
System suitability
System performance: When the procedure is run with 20
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of taltirelin are not less than 3000 and not
more than 2.0, respectively.
System repeatability: When the test is repeated 6 times
with 20 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of taltirelin is not more than 2.0z.
Assay Weigh accurately, and powder not less than 20 Taltirelin Orally Disintegrating Tablets. Weigh accurately a
portion of the powder, equivalent to about 5 mg of taltirelin
hydrate (C17H23N7O5.4H2O), add 25 mL of the mobile phase
and exactly 5 mL of the internal standard solution, shake for
5 minutes, add the mobile phase to make 50 mL, and filter
through a membrane filter with a pore size not exceeding
0.45 mm. Discard the first 2 mL of the filtrate, and use the
subsequent filtrate as the sample solution. Separately, weigh
accurately about 50 mg of taltirelin hydrate for assay
(separately determine the water <2.48> in the same manner as
Taltirelin Hydrate), and dissolve in the mobile phase to
make exactly 50 mL. Pipet 5 mL of this solution, add exactly
5 mL of the internal standard solution, add the mobile phase
to make 50 mL, and use this solution as the standard solution. Perform the test with 20 mL each of the sample solution
and standard solution as directed under Liquid Chromatography <2.01>, according to the following conditions,
and calculate the ratios, QT and QS, of the peak area of taltirelin to that of the internal standard.
Amount (mg) of taltirelin hydrate (C17H23N7O5.4H2O)
MS QT/QS 1/10 1.178
MS: Amount (mg) of taltirelin hydrate for assay, calculated on the anhydrous basis
Internal standard solutionA solution of o-acetanisidide (1
in 2500).
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 210 nm).
Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilanized
silica gel for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
409C.
Supplement I, JP XVI
Mobile phase: Dissolve 3.4 g of potassium dihydrogen
phosphate in 1000 mL of water, adjust to pH 2.5 with phosphoric acid, and add 1.7 g of sodium 1-octanesulfonate. To
850 mL of this solution add 150 mL of acetonitrile.
Flow rate: Adjust the flow rate so that the retention time
of taltirelin is about 5 minutes.
System suitability
System performance: When the procedure is run with 20
mL of the standard solution under the above operating conditions, taltirelin and the internal standard are eluted in this
order with the resolution between these peaks being not less
than 10.
System repeatability: When the test is repeated 6 times
with 20 mL of the standard solution under the above operating conditions, the relative standard deviation of the ratio of
the peak area of taltirelin to that of the internal standard is
not more than 1.0z.
Containers and storage
ContainersTight containers.
Taltirelin Tablets
Supplement I, JP XVI
Operating conditions
Detector, column, and column temperature: Proceed as
directed in the operating conditions in the Assay.
Mobile phase: Dissolve 3.4 g of potassium dihydrogen
phosphate in 1000 mL of water, adjust to pH 2.5 with phosphoric acid, and add 1.7 g of sodium 1-octanesulfonate. To
900 mL of this solution add 100 mL of acetonitrile.
Flow rate: Adjust the flow rate so that the retention time
of taltirelin is about 15 minutes.
Time span of measurement: About1.5 times as long as the
retention time of taltirelin, beginning from 1/3 times the
retention time of taltirelin.
System suitability
Test for required detectability: To 1 mL of the sample solution add the mobile phase to make 100 mL, and use this
solution as the solution for system suitability test. Pipet 1
mL of the solution for system suitability test, and add the
mobile phase to make exactly 20 mL. Confirm that the peak
area of taltirelin obtained with 20 mL of this solution is
equivalent to 3.5 to 6.5z of that with 20 mL of the solution
for system suitability test.
System performance: When the procedure is run with 20
mL of the solution for system suitability test under the above
operating conditions, the number of theoretical plates and
the symmetry factor of the peak of taltirelin are not less than
7000 and not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 20 mL of the solution for system suitability test under
the above operating conditions, the relative standard deviation of the peak area of taltirelin is not more than 2.0z.
Uniformity of dosage units <6.02> Perform the test according to the following method: it meets the requirement of the
Content uniformity test.
To 1 tablet of Taltirelin Tablets add V/2 mL of the mobile
phase and exactly V/10 mL of the internal standard solution, and agitate with the aid of ultrasonic waves for 10
minutes while occasional shaking. Then, add the mobile
phase to make V mL so that each mL contains about 0.1 mg
of taltirelin hydrate (C17H23N7O5.4H2O), and filter through
a membrane filter with a pore size not exceeding 0.45 mm.
Discard the first 2 mL of the filtrate, and use the subsequent
filtrate as the sample solution. Then, proceed as directed in
the Assay.
Amount (mg) of taltirelin hydrate (C17H23N7O5.4H2O)
MS QT/QS V/500 1.178
MS: Amount (mg) of taltirelin hydrate for assay, calculated on the anhydrous basis
Internal standard solutionA solution of o-acetanisidide (1
in 2500).
Dissolution <6.10> When the test is performed at 50 revolutions per minute according to the Paddle method, using 900
mL of water as the dissolution medium, the dissolution rate
in 30 minutes of Taltirelin Tablets is not less than 85z.
Start the test with 1 tablet of Taltirelin Tablets, withdraw
not less than 20 mL of the medium at the specified minute
Official Monographs
2483
MS: Amount (mg) of taltirelin hydrate for assay, calculated on the anhydrous basis
C: Labeled amount (mg) of taltirelin hydrate
(C17H23N7O5.4H2O) in 1 tablet
Operating conditions
Proceed as directed in the operating conditions in the Assay.
System suitability
System performance: When the procedure is run with 20
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of taltirelin are not less than 3000 and not
more than 2.0, respectively.
System repeatability: When the test is repeated 6 times
with 20 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of taltirelin is not more than 2.0z.
Assay Weigh accurately, and powder not less than 20 Taltirelin Tablets. Weigh accurately a portion of the powder,
equivalent to about 5 mg of taltirelin hydrate (C17H23N7O5.
4H2O), add 25 mL of the mobile phase and exactly 5 mL of
the internal standard solution, shake for 20 minutes, add the
mobile phase to make 50 mL, and filter through a membrane filter with a pore size not exceeding 0.45 mm. Discard
the first 2 mL of the filtrate, and use the subsequent filtrate
as the sample solution. Separately, weigh accurately about
50 mg of taltirelin hydrate for assay (separately determine
the water <2.48> in the same manner as Taltirelin Hydrate),
and dissolve in the mobile phase to make exactly 50 mL.
Pipet 5 mL of this solution, add exactly 5 mL of the internal
standard solution, add the mobile phase to make 50 mL, and
use this solution as the standard solution. Perform the test
with 20 mL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01>, according to the following conditions, and calculate the ratios,
QT and QS, of the peak area of taltirelin to that of the internal standard.
2484
Official Monographs
MS: Amount (mg) of taltirelin hydrate for assay, calculated on the anhydrous basis
Internal standard solutionA solution of o-acetanisidide (1
in 2500).
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 210 nm).
Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilanized
silica gel for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
409C.
Mobile phase: Dissolve 3.4 g of potassium dihydrogen
phosphate in 1000 mL of water, adjust to pH 2.5 with phosphoric acid, and add 1.7 g of sodium 1-octanesulfonate. To
850 mL of this solution add 150 mL of acetonitrile.
Flow rate: Adjust the flow rate so that the retention time
of taltirelin is about 5 minutes.
System suitability
System performance: When the procedure is run with 20
mL of the standard solution under the above operating conditions, taltirelin and the internal standard are eluted in this
order with the resolution between these peaks being not less
than 10.
System repeatability: When the test is repeated 6 times
with 20 mL of the standard solution under the above operating conditions, the relative standard deviation of the ratio of
the peak area of taltirelin to that of the internal standard is
not more than 1.0z.
Supplement I, JP XVI
Add the following:
Tranilast
C18H17NO5: 327.33
2-s[(2E)-3-(3,4-Dimethoxyphenyl)prop-2-enoyl]aminotbenzoic acid
[53902-12-8]
Titanium Oxide
ContainersTight containers.
207 2109
C
Supplement I, JP XVI
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 255 nm).
Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilanized
silica gel for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
259C.
Mobile phase: A mixture of diluted acetic acid (100) (1 in
100) and acetonitrile (3:2).
Flow rate: Adjust the flow rate so that the retention time
of tranilast is about 7 minutes.
Time span of measurement: About 4 times as long as the
retention time of tranilast, beginning after the solvent peak.
System suitability
System performance: When the procedure is run with 5 mL
of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of tranilast are not less than 5000 and not
more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 5 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of tranilast is not more than 3.0z.
(3) ChloroformWeigh accurately about 1 g of
Tranilast, dissolve in exactly 5 mL of a solution, prepared by
adding N,N-dimethylformamide to exactly 1 mL of the internal standard solution to make exactly 100 mL, and use
this solution as the sample solution. Separately, weigh accurately about 3 g of chloroform, and add N,N-dimethylformamide to make exactly 100 mL. Pipet 1 mL of this solution, add exactly 1 mL of the internal standard solution, add
N,N-dimethylformamide to make 100 mL, and use this solution as the standard solution. Perform the test with 1 mL
each of the sample solution and standard solution as directed under Gas Chromatography <2.02> according to the following conditions, and calculate the ratios, QT and QS, of
the peak area of chloroform to that of the internal standard:
the amount of chloroform is not more than 0.006z.
Amount (z) of chloroform
MS/MT QT/QS 1/20
Official Monographs
2485
Flow rate: Adjust the flow rate so that the retention time
of chloroform is about 2 minutes.
System suitability
System performance: When the procedure is run with 1 mL
of the standard solution under the above operating conditions, chloroform and the internal standard are eluted in this
order with the resolution between these peaks being not less
than 3.
System repeatability: When the test is repeated 6 times
with 1 mL of the standard solution under the above operating conditions, the relative standard deviation of the ratio of
the peak area of chloroform to that of the internal standard
is not more than 1.0z.
(4) Residual solvent Being specified separately.
Loss on drying <2.41>
hours).
Assay Weigh accurately about 0.4 g of Tranilast, previously dried, dissolve in 25 mL of N,N-dimethylformamide, add
25 mL of water, and titrate <2.50> with 0.1 mol/L sodium
hydroxide VS, until a 30-seconds persistent light-red color is
obtained (indicator: 3 drops of phenolphthalein TS). Perform a blank determination in the same manner, and make
any necessary correction.
Each mL of 0.1 mol/L sodium hydroxide VS
32.73 mg of C18H17NO5
Containers and storage ContainersWell-closed containers.
StorageLight-resistant.
Tranilast Capsules
2486
Official Monographs
Supplement I, JP XVI
trile (7:3), then add the same mixture to make exactly 200
mL, and filter through a membrane filter with a pore size
not exceeding 0.45 mm. Discard the first 10 mL of the
filtrate, pipet 10 mL of the subsequent filtrate, add exactly
10 mL of the internal standard solution, then add a mixture
of 0.05 mol/L phosphate buffer solution, pH 7.0 and
acetonitrile (7:3) to make 50 mL, and use this solution as the
sample solution. Separately, weigh accurately about 25 mg
of tranilast for assay, previously dried at 1059
C for 3 hours,
and dissolve in a mixture of 0.05 mol/L phosphate buffer
solution, pH 7.0 and acetonitrile (7:3) to make exactly 50
mL. Pipet 10 mL of this solution, add exactly 10 mL of the
internal standard solution, then add a mixture of 0.05
mol/L phosphate buffer solution, pH 7.0 and acetonitrile
(7:3) to make 50 mL, and use this solution as the standard
solution. Perform the test with 5 mL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions,
and calculate the ratios, QT and QS, of the peak area of
tranilast to that of the internal standard.
Amount (mg) of tranilast (C18H17NO5)
M S Q T/ Q S 4
Supplement I, JP XVI
Add the following:
Official Monographs
2487
for dissolution test to make exactly 100 mL, and use this solution as the sample solution. Separately, weigh accurately
about 28 mg of tranilast for assay, previously dried at 1059C
for 3 hours, and dissolve in 2nd fluid for dissolution test to
make exactly 100 mL. Pipet 5 mL of this solution, and add
2nd fluid for dissolution test to make exactly 50 mL. Then,
pipet 5 mL of this solution, add 2nd fluid for dissolution test
to make exactly 25 mL, and use this solution as the standard
solution. Determine the absorbances, AT and AS, at 332 nm
of the sample solution and standard solution as directed under Ultraviolet-visible Spectrophotometry <2.24>.
Dissolution rate (z) with respect to the labeled amount of
tranilast (C18H17NO5)
MS/MT AT/AS 1/C 360
2488
Official Monographs
Supplement I, JP XVI
solution as the sample solution. Then, proceed as directed in
the Assay.
Amount (mg) of tranilast (C18H17NO5)
MS QT/QS V/50
Supplement I, JP XVI
Official Monographs
2489
Sterility <4.06> Perform the test according to the Membrane filtration method: it meets the requirement.
Assay Conduct this procedure using light-resistant vessels.
To exactly a volume of Tranilast Ophthalmic Solution,
equivalent to about 5 mg of tranilast (C18H17NO5), add exactly 10 mL of the internal standard solution, then add
ethanol (99.5) to make 50 mL, and use this solution as the
sample solution. Separately, weigh accurately about 25 mg
of tranilast for assay, previously dried at 1059
C for 3 hours,
and dissolve in ethanol (99.5) to make exactly 50 mL. Pipet
10 mL of this solution, add exactly 10 mL of the internal
standard solution, then add ethanol (99.5) to make 50 mL,
and use this solution as the standard solution. Perform the
test with 5 mL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions, and calculate the ratios,
QT and QS, of the peak area of tranilast to that of the internal standard.
Amount (mg) of tranilast (C18H17NO5)
MS QT/QS 1/5
of
preparation
Prepare
as
directed
under
2490
Official Monographs
Flow rate: Adjust the flow rate so that the retention time
of tranilast is about 7 minutes.
System suitability
System performance: When the procedure is run with 5 mL
of the standard solution under the above operating conditions, the internal standard and tranilast are eluted in this
order with the resolution between these peaks being not less
than 8.
System repeatability: When the test is repeated 6 times
with 5 mL of the standard solution under the above operating conditions, the relative standard deviation of the ratio of
the peak area of tranilast to that of the internal standard is
not more than 1.0z.
Supplement I, JP XVI
cording to the following conditions, and determine the peak
areas, AT and AS, of trichlormethiazide.
Amount (mg) of trichlormethiazide (C8H8Cl3N3O4S2)
in 1 tablet
MS AT/AS V/1000
Operating conditions
Proceed as directed in the operating conditions in the Assay under Trichlormethiazide.
System suitability
System performance: When the procedure is run with 20
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of trichlormethiazide are not less than
5000 and not more than 1.2, respectively.
System repeatability: When the test is repeated 6 times
with 20 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of trichlormethiazide is not more than 1.0z.
Trichlormethiazide Tablets
Uniformity of dosage units <6.02> Perform the test according to the following method: it meets the requirement of the
Content uniformity test.
To 1 tablet of Trichlormethiazide Tablets add V/5 mL of
diluted phosphoric acid (1 in 50), and disintegrate the tablet.
Add 2V/5 mL of acetonitrile, shake vigorously for 15
minutes, add the mobile phase to make exactly V mL so that
each mL contains about 40 mg of trichlormethiazide (C8H8Cl
3N3O4S2). Filter this solution through a membrane filter with
a pore size not exceeding 0.45 mm, discard the first 4 mL of
the filtrate, and use the subsequent filtrate as the sample solution. Then, proceed as directed in the Assay.
Trimethadione Tablets
Valsartan
C24H29N5O3: 435.52
(2S)-3-Methyl-2-(N-s[2?-(1H-tetrazol-5-yl)biphenyl4-yl]methylt
pentanamido)butanoic acid
[137862-53-4]
Supplement I, JP XVI
Identification (1) Determine the absorption spectrum of
a solution of Valsartan in methanol (1 in 62,500) as directed
under Ultraviolet-visible Spectrophotometry <2.24>, and
compare the spectrum with the Reference Spectrum or the
spectrum of a solution of Valsartan RS prepared in the same
manner as the sample solution: both spectra exhibit similar
intensities of absorption at the same wavelengths.
(2) Determine the infrared absorption spectrum of Valsartan as directed in the potassium bromide disk method under Infrared Spectrophotometry <2.25>, and compare the
spectrum with the Reference Spectrum or the spectrum of
Valsartan RS: both spectra exhibit similar intensities of absorption at the same wave numbers.
Optical rotation <2.49> [a]20
D : 64 699(0.5 g calculated
on the anhydrous and corrected on the amount of the residual solvent, methanol, 50 mL, 100 mm).
Purity (1) Heavy metals <1.07>Proceed with 2.0 g of
Valsartan according to Method 4, and perform the test. Prepare the control solution with 2.0 mL of Standard Lead Solution (not more than 10 ppm).
(2) Related substancesDissolve 50 mg of Valsartan in
100 mL of the mobile phase, and use this solution as the
sample solution. Pipet 1 mL of the sample solution, add the
mobile phase to make exactly 100 mL, and use this solution
as the standard solution. Perform the test with exactly 10 mL
each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the
following conditions, and determine each peak area by the
automatic integration method: the area of the peak, having
the relative retention time of about 0.8 to valsartan, obtained from the sample solution is not larger than 1/5 times
the peak area of valsartan from the standard solution, the
area of the peak other than valsartan and the peak mentioned above is not larger than 1/10 times the peak area of
valsartan from the standard solution, and the total area of
the peaks other than valsartan is not larger than 3/10 times
the peak area of valsartan from the standard solution.
Operating conditions
Detector, column, column temperature, mobile phase and
flow rate: Proceed as directed in the operating conditions in
the Assay.
Time span of measurement: About 6 times as long as the
retention time of valsartan, beginning after the solvent peak.
System suitability
Test for required detectability: To exactly 1 mL of the
standard solution add the mobile phase to make exactly 20
mL. Confirm that the peak area of valsartan obtained with
10 mL of this solution is equivalent to 3.5 to 6.5z of that
with 10 mL of the standard solution.
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of valsartan are not less than 1500 and not
more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
Official Monographs
2491
2492
Official Monographs
Supplement I, JP XVI
according to the following conditions, and calculate the ratios, QT and QS, of the peak area of valsartan to that of the
internal standard.
Amount (mg) of valsartan (C24H29N5O3) MS QT/QS
MS: Amount (mg) of Valsartan RS, calculated on the anhydrous basis and corrected on the amount of the
residual solvent
Internal standard solutionA solution of diclofenac sodium
in the mobile phase (1 in 1000).
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 225 nm).
Column: A stainless steel column 3 mm in inside diameter
and 12.5 cm in length, packed with octadecylsilanized silica
gel for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
259C.
Mobile phase: A mixture of water, acetonitrile, and acetic
acid (100) (500:500:1).
Flow rate: Adjust the flow rate so that the retention time
of valsartan is about 5 minutes.
System suitability
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, valsartan and the internal standard are eluted in this
order with the resolution between these peaks being not less
than 5.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the ratio of
the peak area of valsartan to that of the internal standard is
not more than 1.0z.
Containers and storage
ContainersTight containers.
Valsartan Tablets
MS: Amount (mg) of Valsartan RS, calculated on the anhydrous basis and corrected on the amount of the
residual solvent
Dissolution <6.10> When the test is performed at 50 revolutions per minute according to the Paddle method, using 900
mL of water as the dissolution medium, the dissolution rate
of a 20-mg tablet, 40-mg tablet and 80-mg tablet in 30
minutes are not less than 75z, 75z and 80z, respectively,
and of a 160-mg tablet in 45 minutes is not less than 75z.
Start the test with 1 tablet of Valsartan Tablets, withdraw
not less than 20 mL of the medium at the specified minute
after starting the test, and filter through a membrane filter
with a pore size not exceeding 0.5 mm. Discard the first 10
mL of the filtrate, pipet V mL of the subsequent filtrate, add
water to make exactly V? mL so that each mL contains about
22 mg of valsartan (C24H29N5O3), and use this solution as the
sample solution. Separately, weigh accurately about 22 mg
of Valsartan RS (separately determine the water <2.48> and
the residual solvent in the same manners as Valsartan), and
dissolve in methanol to make exactly 50 mL. Pipet 5 mL of
this solution, add water to make exactly 100 mL, and use
this solution as the standard solution. Determine the absorbances, AT and AS, at 250 nm of the sample solution and
standard solution as directed under Ultraviolet-visible Spectrophotometry <2.24>, using water as the control.
Dissolution rate (z) with respect to the labeled amount of
valsartan (C24H29N5O3)
MS AT/AS V?/V 1/C 90
MS: Amount (mg) of Valsartan RS, calculated on the anhydrous basis and corrected on the amount of the
residual solvent
C: Labeled amount (mg) of valsartan (C24H29N5O3) in 1
tablet
Supplement I, JP XVI
Assay Weigh accurately the mass of not less than 20 Valsartan Tablets, and powder. Weigh accurately a portion of
the powder, equivalent to about 50 mg of valsartan
(C24H29N5O3), add 60 mL of the mobile phase, shake thoroughly, add the mobile phase to make exactly 100 mL, and
centrifuge. Pipet 5 mL of the supernatant liquid, add exactly
3 mL of the internal standard solution, add the mobile phase
to make 50 mL, and use this solution as the sample solution.
Separately, weigh accurately about 50 mg of Valsartan RS
(separately, determine the water <2.48> and the residual solvent in the same manner as Valsartan), and dissolve in the
mobile phase to make exactly 100 mL. Pipet 5 mL of this solution, add exactly 3 mL of the internal standard solution,
add the mobile phase to make 50 mL, and use this solution
as the standard solution. Perform the test with 10 mL each of
the sample solution and standard solution as directed under
Liquid Chromatography <2.01> according to the following
conditions, and calculate the ratios, QT and QS, of the peak
area of valsartan to that of the internal standard.
Amount (mg) of valsartan (C24H29N5O3)
M S Q T /Q S
MS: Amount (mg) of Valsartan RS, calculated on the anhydrous basis and corrected on the amount of the
residual solvent
Internal standard solutionA solution of diclofenac sodium
in the mobile phase (1 in 1000).
Operating conditions
Detector: An ultraviolet absorption photometer (wavelength: 225 nm).
Column: A stainless steel column 3 mm in inside diameter
and 12.5 cm in length, packed with octadecylsilanized silica
gel for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
259C.
Mobile phase: A mixture of water, acetonitrile, and acetic
acid (100) (500:500:1).
Flow rate: Adjust the flow rate so that the retention time
of valsartan is about 5 minutes.
System suitability
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, valsartan and the internal standard are eluted in this
order with the resolution between these peaks being not less
than 5.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the ratio of
the peak area of valsartan to that of the internal standard is
not more than 1.0z.
Containers and storage
ContainersTight containers.
Official Monographs
2493
Vasopressin Injection
Voglibose Tablets
2494
Official Monographs
Supplement I, JP XVI
Wheat Starch
Zolpidem Tartrate
Crude Drugs
Akebia Stem
Alisma Rhizome
Alisma Tuber
Alismatis Tuber
2495
2496
Crude Drugs
Apricot Kernel
Supplement I, JP XVI
Aralia Rhizome
Artemisia Leaf
Artemisiae Folium
Artemisia leaf is the leaf and twig of Artemisia princeps Pampanini or Artemisia montana Pampanini
(Compositae).
Description Wrinkled leaves and their fragments, frequently with thin stems. The upper surface of leaf dark
green, the lower surface covered densely with grayish white
cotton-like hairs. When smoothed by immersion in water,
unfolded laminas 4 15 cm long, 4 12 cm wide, 1- to 2pinnately cleft or pinnately parted. Segments in 2 to 4 pairs,
oblong-lanceolate to oblong, apex acuminate sometimes obtuse, margins irregularly lobed or entire. Small sized leaves
tri-cleft or entire, lanceolate.
Order, characteristic; taste, slightly bitter.
Under a microscope <5.01>, a transverse section of leaf
reveals several-cells-layered collenchyma beneath epidermis
of midvein; vascular bundles at the central portion of midvein, occasionally fiber bundles adjacent to phloem and xylem; laminas composed of upper epidermis, pallisad tissue,
spongy tissue and lower epidermis, long soft hairs, T-shaped
hairs and glandular hairs on epidermis of laminas; epidermal
cells contain tannin-like substances, parenchyma cells contain oil-like substances and tannin-like substances.
Identification To 0.5 g of pulverized Artemisia Leaf (the
parts like a floccose substance which are not easily pulverized may be removed) add 5 mL of a mixture of methanol
and water (3:2), shake for 10 minutes, centrifuge, and use
the supernatant liquid as the sample solution. Separately,
dissolve 1 mg each of umbelliferone for thin-layer chromatography and scopoletin for thin-layer chromatography
in 10 mL each of methanol, and use these solutions as the
Supplement I, JP XVI
Crude Drugs
standard solution (1) and the standard solution (2), respectively. Perform the test with these solutions as directed under Thin-layer Chromatography <2.03>. Spot 10 mL of the
sample solution and 5 mL each of the standard solutions (1)
and (2) on a plate of silica gel for thin-layer chromatography. Develop the plate with a mixture of ethyl
acetate, hexane and acetic acid (100) (20:10:1) to a distance
of about 7 cm, and air-dry the plate. Examine under ultraviolet light (main wavelength: 365 nm): two of the spots
among the several spots obtained from the sample solution
have the same color tone and Rf value with the corresponding bluish white fluorescent spot obtained respectively
from the standard solutions (1) and (2).
System suitability(Ultraviolet light (main wavelength: 365
nm)) To 1 mL of the standard solution (1) add methanol to
make 10 mL. Confirm that when perform the test with 1 mL
of this solution under the above conditions, a bluish white
fluorescent spot is detectable.
Purity Artemisia argyiTo 0.5 g of powdered Artemisia
Leaf (the parts like a floccose substance which are not easily
pulverized may be removed) add 5 mL of a mixture of
methanol and water (3:2), shake for 10 minutes, centrifuge,
and use the supernatant liquid as the sample solution.
Separately, to 0.5 g of artemisiaargyi for purity test add 5
mL of a mixture of methanol and water (3:2), shake for 10
minutes, centrifuge, and use the supernatant liquid as the
standard solution. Perform the test with these solutions as
directed under Thin-layer Chromatography <2.03>. Spot 10
mL each of the sample solution and standard solution on a
plate of silica gel for thin-layer chromatography. Develop
the plate with a mixture of ethyl acetate, hexane and acetic
acid (100) (20:10:1) to a distance of about 7 cm, and air-dry
the plate. Spray evenly dilute sulfuric acid on the plate, heat
at 1059
C for 5 minutes, and examine under ultraviolet light
(main wavelength: 365 nm): no spot appears from the sample solution at the position of the green fluorescent spot (Rf
value of about 0.5) obtained from the standard solution.
Loss on drying <5.01>
Total ash <5.01>
2497
Asparagus Tuber
2498
Crude Drugs
Supplement I, JP XVI
Atractylodes Rhizome
Bearberry Leaf
Belladonna Root
Supplement I, JP XVI
acetate layer, add 3 g of anhydrous sodium sulfate to the
ethyl acetate, shake, and filter after the ethyl acetate
becomes clear. Evaporate the filtrate to dryness under
reduced pressure, dissolve the residue in 1 mL of ethanol
(95), and use this solution as the sample solution. Separately, dissolve 2 mg of Atropine Sulfate RS in 1 mL of ethanol
(95), and use this solution as the standard solution. Perform
the test with these solutions as directed under Thin-layer
Chromatography <2.03>. Spot 5 mL each of the sample solution and standard solutions on a plate of silica gel for thinlayer chromatography. Develop the plate with a mixture of
acetone, water and ammonia water (28) (90:7:3) to a distance of about 7 cm, and air-dry the plate. Spray evenly
Dragendorff's TS on the plate: the principal spot from the
sample solution is the same in color tone and Rf value with a
yellow-red spot from the standard solution.
Benincasa Seed
Crude Drugs
2499
Bupleurum Root
Powdered Capsicum
2500
Crude Drugs
Supplement I, JP XVI
Chrysanthemum Flower
Cherry Bark
Pruni Cortex
Cinnamon Bark
Supplement I, JP XVI
Crude Drugs
Cnidium Rhizome
Powdered Clove
2501
2502
Crude Drugs
Supplement I, JP XVI
hairs, and no large starch grains, more than 10 mm in diameter, appearing blue-purple upon addition of iodine TS.
[Note: This item has been revised in the Japanese edition, but
the revision does not require any change to the English text stated in the English edition.]
Identification
(2) To 0.5 g of pulverized Coptis Rhizome add 20 mL of
methanol, shake for 2 minutes, filter, and use the filtrate as
the sample solution. Separately, dissolve 1 mg of Berberine
Chloride RS in 1 mL of methanol, and use this solution as
the standard solution. Perform the test with these solutions
as directed under Thin-layer Chromatography <2.03>. Spot 5
mL each of the sample solution and standard solution on a
plate of silica gel for thin-layer chromatography. Develop
the plate with a mixture of 1-butanol, water and acetic acid
(100) (7:2:1) to a distance of about 7 cm, and air-dry the
plate. Examine under ultraviolet light (main wavelength: 365
nm): one of the spot among the several spots from the sample solution and a yellow to yellow-green fluorescence spot
from the standard solution show the same color tone and the
same Rf value.
Condurango
Coptis Rhizome
Supplement I, JP XVI
Corydalis Tuber
Crude Drugs
2503
Crataegus Fruit
Digenea
2504
Crude Drugs
as the standard solution. Perform the test with these solutions as directed under Thin-layer Chromatography <2.03>.
Spot 5 mL each of the sample solution and standard solution
on a plate of silica gel for thin-layer chromatography. Develop the plate with a mixture of ethyl formate, water and
formic acid (5:1:1) to a distance of about 7 cm, and air-dry
the plate. Spray evenly ninhydrin-ethanol TS for spraying on
the plate, and heat at 1059C for 5 minutes: one of the spot
among the several spots obtained from the sample solution
has the same color tone and Rf value with the yellow-red
spot from the standard solution.
Ephedra Herb
Supplement I, JP XVI
Powdered Fennel
Epimedium Herb
Fritillaria Bulb
Powdered Gambir
Supplement I, JP XVI
Crude Drugs
2505
Description Powdered Gardenia Fruit occurs as a yellowbrown powder, and has a slight odor and a bitter taste.
Under a microscope <5.01>, Powdered Gardenia Fruit reveals fragments of yellow-brown epidermis consisting of
polygonal epidermal cells in surface view; unicellular hairs,
spiral and ring vessels, stone cells often containing crystals
of calcium oxalate; fragments of thin-walled parenchyma
containing yellow pigments, oil drops and rosette aggregates
of calcium oxalate (the above elements from fruit receptacle
and pericarp); fragments of large and thick-walled epidermis
of seed coat, containing a red-brown substance; fragments
of endosperm filled with aleuron grains (the above elements
from seed).
[Note: This item has been revised in the Japanese edition, but
the revision does not require any change to the English text stated in the English edition.]
Gentian
[Note: This item has been revised in the Japanese edition, but
the revision does not require any change to the English text stated in the English edition.]
Ginger
2506
Crude Drugs
Supplement I, JP XVI
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of [6]-gingerol are not less than 5000 and
not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of [6]-gingerol is not more than 1.5z.
Powdered Ginger
Supplement I, JP XVI
add 30 mL of a mixture of methanol and water (3:1), and
repeat the extraction twice more. To the combined all extracts add a mixture of methanol and water (3:1) to make exactly 100 mL, use this solution as the sample solution.
Separately, weigh accurately about 5 mg of [6]-gingerol for
assay, dissolve in a mixture of methanol and water (3:1) to
make exactly 100 mL, and use this solution as the standard
solution. Perform the test with exactly 10 mL each of the
sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions, and determine the peak areas, AT and AS, of [6]-gingerol.
Amount (mg) of [6]-gingerol MS AT/AS
Ginseng
Crude Drugs
2507
cm, and air-dry the plate. Spray evenly vanillin-sulfuric acidC for
ethanol TS for spraying on the plate, and heat at 1059
10 minutes: one of the spot among the several spots from the
sample solution has the same color tone and Rf value with
the spot from the standard solution.
Powdered Ginseng
Glycyrrhiza
2508
Crude Drugs
Powdered Glycyrrhiza
Supplement I, JP XVI
mm in a diameter.
Identification To 2 g of Powdered Glycyrrhiza add 10 mL
of a mixture of ethanol (95) and water (7:3), heat by shaking
on a water bath for 5 minutes, cool, filter, and use the
filtrate as the sample solution. Separately, dissolve 5 mg of
Glycyrrhizinic Acid RS in 1 mL of a mixture of ethanol (95)
and water (7:3), and use this solution as the standard solution. Perform the test with these solutions as directed under
Thin-layer Chromatography <2.03>. Spot 2 mL each of the
sample solution and standard solution on a plate of silica gel
with fluorescent indicator for thin-layer chromatography.
Develop the plate with a mixture of 1-butanol, water and
acetic acid (100) (7:2:1) to a distance of about 7 cm, and airdry the plate. Examine under ultraviolet light (main
wavelength: 254 nm): one of the spot among the several
spots from the sample solution and a spot from the standard
solution show the same color tone and the same Rf value.
Hangeshashinto Extract
Pinellia Tuber
Scutellaria Root
Processed Ginger
Ginger
Ginseng
Glycyrrhiza
Jujube
Coptis Rhizome
1)
2)
3)
5g
2.5 g
2.5 g
2.5 g
2.5 g
2.5 g
1g
6g
3g
3g
3g
3g
3g
1g
5g
2.5 g
2.5 g
2.5 g
2.5 g
2.5 g
1g
Supplement I, JP XVI
odor and a hotter, bitter and slightly sweet taste.
Identification (1) Shake 1.0 g of the dry extract (or 3.0 g
of the viscous extract) with 10 mL of water, add 25 mL of
diethyl ether, and shake. Take the diethyl ether layer,
evaporate the layer under reduced pressure, add 2 mL of
diethyl ether to the residue. Separately, dissolve 1 mg of
wogonin for thin-layer chromatography in 1 mL of
methanol, and use this solution as the standard solution.
Perform the test with these solutions as directed under Thinlayer Chromatography <2.03>. Spot 10 mL of the sample solution and 5 mL of the standard solution on a plate of silica
gel for thin-layer chromatography. Develop the plate with a
mixture of ethyl acetate, hexane and acetic acid (100)
(10:10:1) to a distance of about 7 cm, and air-dry the plate.
Spray evenly iron (III) chloride-methanol TS on the plate:
one of the spot among the several spots obtained from the
sample solution has the same color tone and Rf value with
the yellow-brown spot from the standard solution (Scutellaria Root).
(2) For preparation prescribed Processed Ginger
Shake 1.0 g of dry extract (or 3.0 g of the viscous extract)
with 10 mL of water, add 25 mL of diethyl ether, and shake.
Take the diethyl ether layer, evaporate the layer under
reduced pressure, add 2 mL of diethyl ether to the residue,
and use this solution as the sample solution. Separately, dissolve 1 mg of [6]-shogaol for thin-layer chromatography in 1
mL of methanol, and use this solution as the standard solution. Perform the test with these solutions as directed under
Thin-layer Chromatography <2.03>. Spot 20 mL of the sample solution and 1 mL of the standard solution on a plate of
silica gel for thin-layer chromatography. Develop the plate
with a mixture of cyclohexane and ethyl acetate (2:1) to a
distance of about 7 cm, and air-dry the plate. Spray evenly 4dimethylaminobenzaldehyde TS for spraying on the plate,
heat at 1059
C for 5 minutes, and allow to cool: one of the
spot among the several spots obtained from the sample solution has the same color tone and Rf value with the bluegreen spot from the standard solution (Processed Ginger).
(3) For preparation prescribed GingerShake 1.0 g of
the dry extract (or 3.0 g of the viscous extract) with 10 mL of
water, add 25 mL of diethyl ether, and shake. Take the
diethyl ether layer, evaporate the layer under reduced pressure, add 2 mL of diethyl ether to the residue, and use this
solution as the sample solution. Separately, dissolve 1 mg of
[6]-gingerol for thin-layer chromatography in 1 mL of
methanol, and use this solution as the standard solution.
Perform the test with these solutions as directed under Thinlayer Chromatography <2.03>. Spot 10 mL of the sample solution and 5 mL of the standard solution on a plate of silica
gel for thin-layer chromatography. Develop the plate with a
mixture of ethyl acetate and hexane (1:1) to a distance of
about 7 cm, and air-dry the plate. Spray evenly 4dimethylaminobenzaldehyde TS for spraying on the plate,
heat at 1059
C for 5 minutes, and allow to cool: one of the
spot among the several spots obtained from the sample solution has the same color tone and Rf value with the bluegreen spot from the standard solution (Ginger).
Crude Drugs
2509
(4) Shake 2.0 g of the dry extract (or 6.0 g of the viscous
extract) with 10 mL of sodium hydroxide TS, add 5 mL of 1buthanol, shake, centrifuge, and use the supernatant liquid
as the sample solution. Separately, dissolve 1 mg of Ginsenoside Rg1 RS in 1 mL of methanol, and use this solution
as the standard solution. Perform the test with these solutions as directed under Thin-layer Chromatography <2.03>.
Spot 10 mL of the sample solution and 2 mL of the standard
solution on a plate of silica gel for thin-layer chromatography. Develop the plate with a mixture of ethyl
acetate, 1-propanol, water and acetic acid (100) (7:5:4:1) to a
distance of about 7 cm, and air-dry the plate. Spray evenly
vanillin-sulfuric acid-ethanol TS for spraying on the plate,
heat at 1059
C for 5 minutes, and allow to cool: one of the
spot among the several spots obtained from the sample solution has the same color tone and Rf value with the purple
spot from the standard solution (Ginseng).
(5) Shake 1.0 g of the dry extract (or 3.0 g of the viscous
extract) with 10 mL of water, add 5 mL of 1-buthanol,
shake, centrifuge, and use the supernatant liquid as the sample solution. Separately, dissolve 1 mg of liquiritin for thinlayer chromatography in 1 mL of methanol, and use this solution as the standard solution. Perform the test with these
solutions as directed under Thin-layer Chromatography
<2.03>. Spot 10 mL of the sample solution and 2 mL of the
standard solution on a plate of silica gel for thin-layer chromatography. Develop the plate with a mixture of ethyl
acetate, methanol and water (20:3:2) to a distance of about 7
cm, and air-dry the plate. Spray evenly dilute sulfuric acid
on the plate, and heat at 1059
C for 5 minutes: one of the
spot among the several spots obtained from the sample solution has the same color tone and Rf value with the yellowbrown spot from the standard solution (Glycyrrhiza).
(6) Shake 0.5 g of the dry extract (or 1.5 g of the viscous
extract) with 10 mL of methanol, centrifuge, and use the supernatant liquid as the sample solution. Separately, dissolve
1 mg of coptisine chloride for thin-layer chromatography in
5 mL of methanol, and use this solution as the standard solution. Perform the test with these solutions as directed under Thin-layer Chromatography <2.03>. Spot 5 mL each of
the sample solution and standard solution on a plate of silica
gel for thin-layer chromatography. Develop the plate with a
mixture of ethyl acetate, ammonia solution (28) and
methanol (15:1:1) to a distance of about 7 cm, and air-dry
the plate. Examine under ultraviolet light (main wavelength:
365 nm): one of the spot among the several spots obtained
from the sample solution has the same color tone and Rf
value with the yellow fluorescent spot from the standard solution (Coptis Rhizome).
Purity (1) Heavy metals <1.07>Prepare the test solution
with 1.0 g of the dry extract (or an amount of the viscous extract, equivalent to 1.0 g of the dried substance) as directed
under Extracts (4), and perform the test (not more than 30
ppm).
(2) Arsenic <1.11>Prepare the test solution with 0.67 g
of the dry extract (or an amount of the viscous extract,
equivalent to 0.67 g of the dried substance) according to
2510
Crude Drugs
Supplement I, JP XVI
make exactly 100 mL, and use this solution as the standard
solution. Perform the test with exactly 10 mL each of the
sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions, and determine the peak areas, AT and AS, of glycyrrhizic acid in each solution.
Amount (mg) of glycyrrhizic acid (C42H62O16)
MS AT/AS 1/2
Supplement I, JP XVI
silica gel for liquid chromatography (5 mm in particle diameter).
Column temperature: A constant temperature of about
309C.
Mobile phase: Dissolve 3.4 g of potassium dihydrogen
phosphate and 1.7 g of sodium lauryl sulfate in 1000 mL of a
mixture of water and acetonitrile (1:1).
Flow rate: 1.0 mL per minute (the retention time of berberine is about 8 minutes).
System suitability
System performance: Dissolve 1 mg each of Berberine
Chloride RS and palmatine chloride in the mobile phase to
make 10 mL. When the procedure is run with 10 mL of this
solution under the above operating conditions, palmatine
and berberine are eluted in this order with the resolution between these peaks being not less than 1.5.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of berberine is not more than 1.5z.
Containers and storage
ContainersTight containers.
Crude Drugs
2511
Powdered Ipecac
Hemp Fruit
Ipecac
2512
Crude Drugs
Supplement I, JP XVI
grayish white, not fibrous.
Odor, weak and characteristic; taste, slightly sweet at
first.
Under a microscope <5.01>, a transverse section reveals
periderm composed of a cork layer of several layers of thin
walled cork cells; in cortex parenchyma cells containing
sandy crystals of calcium oxalate sparsely distributed, occasionally a few fibers observed; parenchyma cells contain
starch grains, 1 10 mm in diameter; stone cells very rare.
Identification To 1.0 g of pulverized Lycium Bark add 10
mL of methanol, shake for 15 minutes, filter, and use the
filtrate as the sample solution. Perform the test with the
sample solution as directed under Thin-layer Chromatography <2.03>. Spot 10 mL of the sample solution on a
plate of silica gel for thin-layer chromatography. Develop
the plate with a mixture of 1-butanol, ammonium acetate solution (1 in 20) and acetic acid (100) (2:1:1) to a distance of
about 7 cm, and air-dry the plate. Spray evenly Dragendorff's TS for spraying on the plate, heat at 1059C for 2
minutes, then spray evenly sodium nitrite TS, and allow to
stand for 5 minutes: a dark brown principal spot appears at
an Rf value of about 0.4.
Magnolia Bark
Leonurus Herb
Lycium Bark
Supplement I, JP XVI
spot appears at an Rf value of about 0.3.
Crude Drugs
Total ash <5.01>
Malt
Fructus Hordei Germinatus
2513
ContainersWell-closed contain-
Purity
(3) Foreign matterUnder a microscope <5.01>, usually
vessels and other sclerenchymatous cells are not observable.
Orengedokuto Extract
2514
Crude Drugs
Supplement I, JP XVI
Peach Kernel
Supplement I, JP XVI
and rarely branching from chalaza through the seed coat,
and, appearing as dented longitudinal wrinkles; when
soaked in boiling water and softened, the seed coat and thin,
translucent, white albumen easily separated from the cotyledone; cotyledone white in color.
Almost odorless; taste, slightly bitter and oily.
Under a microscope <5.01>, the outer surface of seed coat
reveals polygonal, long polygonal, or obtuse triangular
stone cells on the protrusion from vascular bundles, shape of
which considerably different according to the position, and
their cell walls almost equally thickened; in lateral view, appearing as a square, rectangle or obtuse triangle.
Peucedanum Root
Crude Drugs
2515
the outermost layer composed of a cork layer, inner tangential walls of some cork cells thickened; collenchyma just inside of the cork layer; in cortex numerous oil canals scattered and intercellular air spaces observed; occasionally
phloem fibers observed at the terminal portion of phloem;
vessels and scattered oil canals in xylem; starch grains in
parenchyma, 2 to 10 several-compound grains.
2) Angelica decursiva Franchet et SavatierApproximate to 1), but without hair-like remains of petioles at the
crown.
Under a microscope <5.01>, a transverse section reveals,
approximate to 1), but cell wall of cork cells not thickened,
phloem fibers not observed at the terminal portion of
phloem, nor oil canals observed in xylem.
Identification 1) Peucedanum praeruptorum DunnTo
1 g of pulverized Peucedanum Root add 10 mL of methanol,
shake for 10 minutes, centrifuge, and use the supernatant
liquid as the sample solution. Separately, dissolve 1 mg of
()-praeruptorin A for thin-layer chromatography in 1 mL
of methanol, and use this solution as the standard solution.
Perform the test with these solutions as directed under Thinlayer Chromatography <2.03>. Spot 10 mL each of the sample solution and standard solution on a plate of silica gel for
thin-layer chromatography. Develop the plate with a mixture of diethyl ether and hexane (3:1) to a distance of about
10 cm, and air-dry the plate. Examine under ultraviolet light
(main wavelength: 365 nm): one of the spot among the several spots from the sample solution has the same color tone
and Rf value with the blue-purple fluorescent spot from the
standard solution.
2) Angelica decursiva Franchet et SavatierTo 1 g of
pulverized Peucedanum Root add 10 mL of methanol, shake
for 10 minutes, centrifuge, and use the supernatant liquid as
the sample solution. Separately, dissolve 1 mg of nodakenin
for thin-layer chromatography in 1 mL of methanol, and use
this solution as the standard solution. Perform the test with
these solutions as directed under Thin-layer Chromatography <2.03>. Spot 10 mL each of the sample solution
and standard solution on a plate of silica gel for thin-layer
chromatography. Develop the plate with a mixture of ethyl
acetate, methanol and water (12:2:1) to a distance of about
10 cm, and air-dry the plate. Examine under ultraviolet light
(main wavelength: 365 nm): one of the spot among the several spots from the sample solution has the same color tone
and Rf value with the purple fluorescent spot from the standard solution.
Pharbitis Seed
2516
Crude Drugs
Phellodendron Bark
Supplement I, JP XVI
Identification
(2) Use the filtrate obtained in (1) as the sample solution.
Separately, dissolve 1 mg of Berberine Chloride RS in 1 mL
of methanol, and use this solution as the standard solution.
Perform the test with these solutions as directed under Thinlayer Chromatography <2.03>. Spot 5 mL each of the sample
solution and standard solution on a plate of silica gel for
thin-layer chromatography. Develop the plate with a mixture of 1-butanol, water and acetic acid (100) (7:2:1) to a distance of about 7 cm, and air-dry the plate. Examine under
ultraviolet light (main wavelength: 365 nm): one of the spot
among the several spots from the sample solution and a spot
with yellow to yellow-green fluorescence from the standard
solution show the same color tone and the same Rf value.
Picrasma Wood
Supplement I, JP XVI
tain rosette aggregates of calcium oxalate and starch grains.
Vivid yellow or red-brown, resinous substance often present
in the vessels.
Crude Drugs
2517
Polygonum Root
Plantago Herb
Processed Ginger
Polygala Root
2518
Crude Drugs
Supplement I, JP XVI
not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of [6]-shogaol is not more than 1.5z.
Pueraria Root
Red Ginseng
Supplement I, JP XVI
Rehmannia Root
Crude Drugs
2519
color tone and Rf value with the spot from the standard solution. When further heat for more than 5 minutes, a blue
spot is not observed at just lower than the spot mentioned
above, or even appears it is only few.
2) Juku-jioSake 0.5 g of the fine cutting of Rehmannia Root with 5 mL of water, add 20 mL of methanol, shake
for 10 minutes, centrifuge, and use the supernatant liquid as
the sample solution. Separately, dissolve 2 mg of fructose
for thin-layer chromatography in 1 mL of a mixture of water
and methanol (1:1), and use this solution as the standard solution (1). Separately, dissolve 3 mg of manninotriose for
thin-layer chromatography in 1 mL of a mixture of water
and methanol (1:1), and use this solution as the standard solution (2). Perform the test with these solutions as directed
under Thin-layer Chromatography <2.03>. Spot 2 mL each of
the sample solution and the standard solutions (1) and (2) on
a plate of silica gel for thin-layer chromatography. Develop
the plate with a mixture of 2-propanol, water and methanol
(3:2:2) to a distance of about 7 cm, and air-dry the plate.
Spray evenly 1,3-naphthalenediol TS on the plate, heat at
1059
C for 10 minutes: the principal spot obtained from the
sample solution has the same color tone and Rf value with
the spot from the standard solution (1). Furthermore, one of
the spot from the several spots obtained from the sample solution has the same color tone and Rf value with the blue
spot from the standard solution (2).
2520
Crude Drugs
Saireito Extract
Supplement I, JP XVI
the filtrate as the sample solution. Perform the test with the
sample solution as directed under Thin-layer Chromatography <2.03>. Spot 5 mL of the sample solution on a
plate of silica gel for thin-layer chromatography. Develop
the plate with a mixture of hexane and ethyl acetate (3:1) to a
distance of about 7 cm, and air-dry the plate. Spray evenly 4methoxybenzaldehyde-sulfuric acid TS on the plate, and
heat at 1059
C for 5 minutes. After cooling for more than 10
minutes under an adequate humidity, examine under ultraviolet light (main wavelength: 365 nm): two spots, one is a
bluish fluorescent spot with an Rf value of about 0.5 and the
another is a yellowish fluorescent spot with an Rf value of
about 0.1, are observed.
Scutellaria Root
Identification
(2) To 1 g of pulverized Scutellaria Root add 25 mL of
methanol, shake for 15 minutes, filter, and use the filtrate as
the sample solution. Separately, dissolve 1 mg of Baicalin
RS in 1 mL of methanol, and use this solution as the standard solution. Perform the test with these solutions as
directed under Thin-layer Chromatography <2.03>. Spot 5
mL each of the sample solution and standard solution on a
plate of silica gel for thin-layer chromatography. Develop
the plate with a mixture of 1-butanol, water and acetic acid
(100) (4:2:1) to a distance of about 7 cm, and air-dry the
plate. Spray evenly iron (III) chloride-methanol TS on the
plate: one of the spot among the several spots from the sample solution has the same color tone and Rf value with the
dark green spot from the standard solution.
Assay Weigh accurately about 0.5 g of pulverized Scutellaria Root, add 30 mL of diluted methanol (7 in 10), heat un-
Schizonepeta Spike
Supplement I, JP XVI
der a reflux condenser on a water bath for 30 minutes, and
cool. Transfer the mixture to a glass-stoppered centrifuge
tube, centrifuge, and separate the supernatant liquid. Wash
the vessel for the reflux extraction with 30 mL of diluted
methanol (7 in 10), transfer the washings to the glass-stoppered centrifuge tube, centrifuge after shaking for 5
minutes, and separate the supernatant liquid. To the residue
add 30 mL of diluted methanol (7 in 10), shake for 5
minutes, centrifuge, and separate the supernatant liquid.
Combine all the extracts, add diluted methanol (7 in 10) to
make exactly 100 mL, then pipet 2 mL of the extract, add
diluted methanol (7 in 10) to make exactly 20 mL, and use
this solution as the sample solution. Separately, weigh accurately about 10 mg of Baicalin RS (separately determine
the water), and dissolve in methanol to make exactly100 mL.
Pipet 5 mL of this solution, add diluted methanol (7 in 10) to
make exactly 10 mL, and use this solution as the standard
solution. Perform the test with exactly 10 mL each of the
sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions. Determine the peak areas, AT and AS, of baicalin in
each solution.
Amount (mg) of baicalin (C21H18O11)
M S A T/ A S 5
Crude Drugs
2521
2522
Crude Drugs
Amount (mg) of baicalin (C21H18O11)
M S A T/ A S 5
Powdered Senega
Supplement I, JP XVI
Senna Leaf
Shosaikoto Extract
Supplement I, JP XVI
about 0.1 g of dried substance), add exactly 50 mL of diluted
methanol (7 in 10), shake for 15 minutes, filter, and use the
filtrate as the sample solution. Separately, weigh accurately
about 10 mg of Baicalin RS (separately determine the water),
and dissolve in methanol to make exactly 100 mL. Pipet 5
mL of this solution, add diluted methanol (7 in 10) to make
exactly 10 mL, and use this solution as the standard solution. Perform the test with exactly 10 mL each of the sample
solution and standard solution as directed under Liquid
Chromatography <2.01> according to the following conditions, and determine the peak areas, AT and AS, of baicalin
in each solution.
Amount (mg) of baicalin (C21H18O11)
MS AT/AS 1/4
Crude Drugs
2523
portion; cells of medullary ray mostly not lignified, and extremely thick-walled and large stone cells scattered here and
there; primary cortex containing needle crystals of calcium
oxalate; medullary rays containing starch gains, mainly simple grain, 3 20 mm in diameter, and small needle crystals of
calcium oxalate.
Smilax Rhizome
2524
Crude Drugs
Supplement I, JP XVI
Toad Venom
Bufonis Venenum
Toad Cake
Bufonis Crustum
Tokishakuyakusan Extract
Swertia Herb
Method of preparation
1)
2)
3)
4)
3g
3g
6g
4g
4g
4g
3g
3g
6g
4g
4g
5g
3g
3g
4g
4g
4g
4g
3g
3g
4g
4g
4g
4g
Supplement I, JP XVI
Description Tokishakuyakusan Extract is a light brown to
blackish brown, powder or viscous extract. It has a characteristic odor, and a slight sweet taste at first and a bitter taste
later.
Identification (1) Shake 1.0 g of the dry extract (or 3.0 g
of the viscous extract) with 15 mL of water and 5 mL of 0.1
mol/L hydrochloric acid TS, then add 25 mL of diethyl
ether, and shake. Take the diethyl ether layer, evaporate the
layer under reduced pressure, add 2 mL of diethyl ether to
the residue, and use this solution as the sample solution.
Separately, dissolve 1 mg of (Z)-ligustilide for thin-layer
chromatography in 10 mL of methanol, and use this solution as the standard solution. Perform the test with these solutions as directed under Thin-layer Chromatography
<2.03>. Spot 10 mL each of the sample solution and standard
solution on a plate of silica gel for thin-layer chromatography, develop the plate with a mixture of ethyl
acetate and hexane (1:1) to a distance of about 10 cm, and
air-dry the plate. Examine under ultraviolet light (main
wavelength: 365 nm): one of the spot among the several
spots from the sample solution has the same color tone and
Rf value with the bluish white fluorescent spot from the
standard solution (Japanese Angelica Root; Cnidium Rhizome).
(2) Shake 1.0 g of the dry extract (or 3.0 g of the viscous
extract) with 10 mL of water, add 10 mL of 1-buthanol,
shake, centrifuge, and use the supernatant liquid as the sample solution. Separately, dissolve 1 mg of Paeoniflorin RS in
1 mL of methanol, and use this solution as the standard solution. Perform the test with these solutions as directed under Thin-layer Chromatography <2.03>. Spot 5 mL each of
the sample solution and standard solution on a plate of silica
gel for thin-layer chromatography, develop the plate with a
mixture of ethyl acetate, methanol and water (20:3:2) to a
distance of about 10 cm, and air-dry the plate. Spray evenly
4-methoxybenzaldehyde-sulfuric acid TS on the plate, and
heat at 1059
C for 5 minutes: one of the spot among the
several spots from the sample solution has the same color
tone and Rf value with the purple spot from the standard solution (Peony Root).
(3) (For preparation prescribed Atractylodes Rhizome)
Shake 1.0 g of the dry extract (or 3.0 g of the viscous extract)
with 10 mL of water, add 25 mL of diethyl ether, shake, and
take the diethyl ether layer. Evaporate the layer under
reduced pressure, add 2 mL of diethyl ether to the residue,
and use this solution as the sample solution. Separately, dissolve 1 mg of atractylenolide III for thin-layer chromatography in 2 mL of methanol, and use this solution as
the standard solution. Perform the test with these solutions
as directed under Thin-layer Chromatography <2.03>. Spot 5
mL each of the sample solution and standard solution on a
plate of silica gel for thin-layer chromatography. Develop
the plate with a mixture of ethyl acetate and hexane (1:1) to a
distance of about 10 cm, and air-dry the plate. Spray evenly
dilute sulfuric acid on the plate, heat at 1059C for 5 minutes,
and examine under ultraviolet light (main wavelength: 365
nm): one of the spot among the several spots from the sam-
Crude Drugs
2525
ple solution has the same color tone and Rf value with the
bluish white fluorescent spot from the standard solution
(Atractylodes Rhizome).
(4) (For preparation prescribed Atractylodes Lancea
Rhizome) Shake 2.0 g of the dry extract (or 6.0 g of the viscous extract) with 10 mL of water, add 25 mL of hexane,
and shake. Take the hexane layer, add anhydrous sodium
sulfate to dry, and filter. Evaporate the filtrate under
reduced pressure, add 0.5 mL of hexane to the residue, and
use this solution as the sample solution. Perform the test
with the sample solution as directed under Thin-layer Chromatography <2.03>. Spot 20 mL of the sample solution on a
plate of silica gel with fluorescent indicator for thin-layer
chromatography, develop the plate with a mixture of hexane
and acetone (7:1) to a distance of about 10 cm, and air-dry
the plate. Examine under ultraviolet light (main wavelength:
254 nm): a dark purple spot observed at an Rf value of about
0.4. The spot shows greenish brown color after splaying
evenly 4-dimethylaminobenzaldehyde TS for splaying, heating at 1059C for 5 minutes and allowing to cool (Atractylodes Lancea Rhizome).
(5) Shake 2.0 g of the dry extract (or 6.0 g of the viscous
extract) with 10 mL of sodium carbonate TS, add 25 mL of
diethyl ether, and shake. Take the diethyl ether layer,
evaporate the layer under reduced pressure, add 1 mL of
diethyl ether to the residue, and use this solution as the sample solution. Separately, dissolve 1 mg of alisol A for thinlayer chromatography in 1 mL of methanol, and use this solution as the standard solution. Perform the test with these
solutions as directed under Thin-layer Chromatography
<2.03>. Spot 10 mL each of the sample solution and standard
solution on a plate of silica gel for thin-layer chromatography. Develop the plate with a mixture of ethyl
acetate, hexane and acetic acid (100) (10:10:3) to a distance
of about 10 cm, and air-dry the plate. Spray evenly 4methoxybenzaldehyde-sulfuric acid-acetic acid TS on the
plate, heat at 1059
C for 5 minutes, and examine under
ultraviolet light (main wavelength: 365 nm): one of the spot
among the several spots from the sample solution has the
same color tone and Rf value with the yellowish fluorescent
spot from the standard solution (Alisma Rhizome).
Purity (1) Heavy metals <1.07>Prepare the test solution
with 1.0 g of the dry extract (or an amount of the viscous extract, equivalent to 1.0 g of the dried substance) as directed
under Extracts (4), and perform the test (not more than 30
ppm).
(2) Arsenic <1.11>Prepare the test solution with 0.67 g
of the dry extract (or an amount of the viscous extract,
equivalent to 0.67 g of the dried substance) according to
Method 3, and perform the test (not more than 3 ppm).
Loss on drying <2.41> The dry extractNot more than
9.5z (1 g, 1059C, 5 hours).
The viscous extractNot more than 66.7z (1 g, 1059
C, 5
hours).
Total ash <5.01>
dried basis.
2526
Crude Drugs
Supplement I, JP XVI
paeoniflorin in each solution.
Amount (mg) of paeoniflorin (C23H28O11)
MS AT/AS 1/2
Supplement I, JP XVI
Mobile phase: A mixture of water, acetonitrile and phosphoric acid (550:450:1).
Flow rate: 1.0 mL per minute (the retention time of atractylenolide III is about 10 minutes).
System suitability
System performance: When the procedure is run with 10
mL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry
factor of the peak of atractylenolide III are not less than
5000 and not more than 1.5, respectively.
System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operating conditions, the relative standard deviation of the peak
area of atractylenolide III is not more than 1.5z.
(4) AtractylodinConduct this procedure without exposure to light using light-resistant vessels. Weigh accurately
about 0.5 g of the dry extract (or an amount of the viscous
extract, equivalent to about 0.5 g of the dried substance),
add exactly 50 mL of methanol, shake for 15 minutes, filter,
and use the filtrate as the sample solution. Perform the test
with exactly 10 mL each of the sample solution and atractylodin TS for assay as directed under Liquid Chromatography <2.01> according to the following conditions,
and determine the peak areas, AT and AS, of atractylodin in
each solution.
Amount (mg) of atractylodin CS AT/AS 50
ContainersTight containers.
Crude Drugs
2527
Turmeric
Powdered Turmeric
Uncaria Hook
2528
Crude Drugs
Zanthoxylum Fruit
Supplement I, JP XVI
Supplement I, JP XVI
Add the following 29 spectra:
Aldioxa
Auranofin
Azelnidipine
2529
2530
Brotizolam
Calcium Pantothenate
Supplement I, JP XVI
Supplement I, JP XVI
Carboplatin
Cefteram Pivoxil
2531
2532
Colestimide
L-Cystine
Daunorubicin Hydrochloride
Supplement I, JP XVI
Supplement I, JP XVI
Dorzolamide Hydrochloride
Edaravone
Emedastine Fumarate
2533
2534
Epalrestat
Ibuprofen Piconol
Iohexol
Supplement I, JP XVI
Supplement I, JP XVI
Isosorbide Mononitrate
Lafutidine
Lobenzarit Sodium
2535
2536
Norethisterone
Quetiapine Fumarate
Supplement I, JP XVI
Supplement I, JP XVI
Sucrose
Tacalcitol Hydrate
Taltirelin Hydrate
2537
2538
Tranilast
Valsartan
Supplement I, JP XVI
Supplement I, JP XVI
2539
2540
Azelnidipine
Brotizolam
Supplement I, JP XVI
Supplement I, JP XVI
Dorzolamide Hydrochloride
Edaravone
2541
2542
Emedastine Fumarate
Epalrestat
Ibuprofen Piconol
Supplement I, JP XVI
Supplement I, JP XVI
Iohexol
Lafutidine
Lobenzarit Sodium
2543
2544
Quetiapine Fumarate
Supplement I, JP XVI
Supplement I, JP XVI
Tacalcitol Hydrate
Tranilast
Valsartan
2545
GENERAL INFORMATION
G1
Equipment
Near-infrared spectrophotometers can either be a distributed near-infrared spectrophotometer or a Fourier transform near-infrared spectrophotometer1). Interference filtertype near-infrared spectrophotometers that use interference
filter in the spectrometry section are also available, however,
this type of equipment is hardly used in the field of pharmaceutical quality control.
1.1. Distributed near-infrared spectrophotometer
This equipment is comprised of light source section, sample section, spectrometry section, photometry section, signal
processing section, data processing section, display-recordoutput section. Halogen lamps, tungsten lamps, light emitting diodes and other such devices that can emit high intensity near-infrared light in a stable manner and used in the
light source section. The sample section is comprised of a
sample cell and a sample holder. Equipment that have an optical fiber section that is comprised of optical fibers and a
collimator are equipped with a function for transmitting
light to sample section, which is remotely located away from
the spectrophotometer main unit. Quartz is ordinarily used
as material for optical fibers
The spectrometry section is intended to extract light of required wavelength, using dispersive devices and is comprised
of slits, mirrors and dispersive devices. Potential dispersive
devices include prisms, diffraction grating, acousto-optical
tunable filters (AOTF), or liquid crystal tunable filters
(LCTF).
The photometry section is comprised of detectors and amplifiers. Sensors include semiconductor detectors (silicon,
lead sulfide, indium-gallium-arsenic, indium-antimony), as
well as photomultiplier tubes. Detecting methods that use
semiconductor detectors generally perform detections with
2547
2548
General Information
Determination
There are three types of measurement methods that are
used with near-infrared spectrometry: transmittance
method, diffuse reflectance method and transmittance
reflectance method. The section of measurement methods
relies on the shape of samples and applications. The transmittance method or diffuse reflectance method is used for
solid samples, including fine particles. The transmittance
method or transmittance reflectance method is used for liquid samples.
2.1. Transmittance method
The degree of decay for incident light intensity as the light
from a light source passes through a sample, is represented
as transmittance rate T (z) or absorbance A with the transmittance method. A sample is placed in the light path between a light source and a detector, the arrangement of
which is ordinarily same as that of the spectroscopic
method.
T 100t
t I/I0 10acl
I0: Incident light intensity
I: Transmitted light intensity
a: Absorptivity
c: Solution concentration
l: Layer length (sample thickness)
A log t log (1/t ) log (I0/I ) acl
This method is applied for taking measurements of samples that are liquids and solutions. Quartz glass cells and
flow cells are used, with the layer length of 1 5 mm along.
Furthermore, this method can also be applied for taking
measurements of samples that are solids, including fine par-
Supplement I, JP XVI
ticles. It is also known as diffuse transmittance method.
Selecting appropriate layer length is critical for this method,
since the transmitted light intensity varies depending on
grain sizes and surface condition of samples.
2.2. Diffuse reflectance method
The ratio of the reflection light intensity I, emitted from
the sample in a wide reflectance range and a control reflection light intensity Ir emitted from surface of a substance, is
expressed as reflectance R (z) with the diffuse reflectance
method. The near-infrared light penetrates to a depth of
several mm into solid samples, including fine particles. In
that process, transmission, refraction, reflection and dispersion are repeated, and diffusion takes place, but a portion of
the diffused light is emitted again from the surface of the
sample and captured by a detector. The spectrum for the
diffuse reflectance absorbance (Ar) can ordinarily be obtained by plotting logarithm of inverse numbers for reflectance (1/r) against wavelengths (wave numbers).
R 100r
r I/Ir
I: Reflection light intensity of light, diffuse reflected off
the sample
Ir: Control reflection light intensity of light emitted from
surface of reference substance
Ar log (1/r) log (Ir/I )
The intensity of diffuse reflectance spectrum can also be
expressed with the Kubelka-Munk (K-M) function. The K-M
function is derived, based on the existence of a sample with
sufficient thickness, and expressed in terms of light scattering coefficient, which is determined by absorptivity, grain
size, shape and fill condition (compression).
This method is applied to solid samples, including fine
particles, and requires a diffuse reflector.
2.3. Transmittance reflectance method
The transmittance reflectance method is a combination of
the transmittance method and reflectance method. A mirror
is used to re-reflect a light that has passed through a sample
in order to take a measurement of transmittance reflectance
rate, T * (z). Light path must be twice the thickness of the
sample. On the other hand, the light reflected off a mirror
and enters into a detector is used as the control light. When
this method is applied to suspended samples, however, a
metal plate or a ceramic reflector with rough surface that
causes diffuse reflectance is used instead of a mirror.
Transmittance reflectance absorbance (A*) is obtained by
the following formula with this method:
T * 100t*
t * I/IT
I: Intensity of transmitted and reflected light, in cases
where a sample is placed
IT: Intensity of reflected light, in cases where is no sample
A* log (1/t *)
This is a method that is applied to solid samples, including
fine particles, as well as liquids and suspended samples. The
Supplement I, JP XVI
thickness of a sample must be adjusted when applying this
method to a solid sample. Ordinarily adjustment is made by
setting absorbance to 0.1 2 (transmittance of 79 1z),
which provides the best linearity and S/N ratio of detector.
A cell with appropriate layer length, according to the grain
size of the fine particle, must be selected when applying the
method to a fine particle sample.
3.
General Information
2549
2550
General Information
Supplement I, JP XVI
der given conditions.
(ii) Whether or not the method is adequately robust to
deal with variables such as handling of samples (for instance
fill condition for fine particle samples, etc.) and configuration matrix.
(iii) Whether or not about the same level of accuracy or
precision can be obtained, in comparison with the existing
and established analysis methods, which are available as
standards.
(iv) Sustaining and managing performance of an analysis method, once established, are critical. Continuous and
systematic maintenance and inspection work must therefore
be implemented. Furthermore, it must be determined
whether or not appropriate evaluation procedures are available to deal with change controls or implementation of revalidation on changes made in manufacturing processes or
raw materials, as well as changes arising from replacement
of major components in equipment.
(v) Whether or not there are appropriate evaluation
procedures in place to verify validity of transferring implementation of an analysis, which presupposed the use of a
specific equipment, from such originally intended equipment to another equipment (model transfer) for the purpose
of sharing the analysis method.
5.1. Qualitative analysis
Qualitative analysis, such as verification of substances, is
performed after preparing a reference library that includes
inter-lot variations within tolerance range and chemometrics
methodologies, such as multivariate analysis, have been established. Minute quality characteristic variations between
lots can also be established by using this method.
Furthermore, multivariate analysis includes direct analysis
methods that consider wavelengths (wave numbers) and absorption as variables, such as wavelength correlation
method, residual sum of squares, range sum of squares,
along with factor analysis method, cluster analysis method,
discriminant analysis method, as well as SIMCA (Soft independent modeling of class analogy).
It is also possible to consider the overall near-infrared absorption spectrum as a single pattern and to identify
parameters obtained by applying multivariate analysis
methods or characteristic wavelength (wave number) peaks
of the sample substance as indices for monitoring, for the
purpose of manufacturing process control for active substances or preparations.
5.2. Quantitative analysis
Quantitative analysis uses spectrums of sample groups
and analysis values obtained through the existing and established analysis methods, to obtain quantitative models with
methodologies of chemometorics. These are used to calculate concentrations of individual ingredients and material
values of samples being measured, using conversion formulas. Chemometrics methodologies for obtaining quantitative
models include multiple regression analysis method, main
ingredient regression analysis method and PLS (Partial least
squares) regression analysis method.
In cases where the composition of a sample is simple, concentrations of ingredients in the sample that are subject to
Supplement I, JP XVI
analysis can be calculated, by plotting a calibration curve using the absorbance of a specific wavelength (wave number)
or the correlating relationship between the parameters and
concentration, using samples for preparation of calibration
curves with known concentrations (calibration curve
method).
References
1) General Rules for Near-infrared Spectrophotometric
Analysis, JIS K 0134 (2002), Japanese Industrial Standards
2) Near-Infrared Spectrophotometry, 2.2.40, European
Pharmacopoeia 5.0 (2005)
3) Near-Infrared Spectrophotometry, <1119>, US Pharmacopoeia 30 (2007)
G2
Solid-state Properties
General Information
2551
Principle
When particles in Brownian motion in solution or in suspension are irradiated with laser light, scattered light from
the particles fluctuates depending on their diffusion coefficients. The intensity of the scattered light from larger particles fluctuates more slowly, because the larger particles
move more slowly. On the other hand, the intensity of the
scattered light from smaller particles fluctuates more rapidly, because they move faster.
In dynamic light scattering measurements, the particle diameter is determined by applying the Stokes-Einstein equation to analysis of the detected fluctuations of scattered light
intensity, which reflect the diffusion coefficient of the particles.
kT
1012
3phD
Fig. 1
2552
General Information
Supplement I, JP XVI
standard deviation must be less than 2z. In addition, the
measured polydispersity index must be less than 0.1.
Fig. 2
(i) Laser: a monochromatic laser polarized with its electric field component perpendicular to the plane formed by
the incident light and light-receiving optical axes (vertical
polarization).
(ii) Sample holder: a holder whose temperature can be
measured and controlled within an accuracy of 0.39C.
(iii) Measuring cell: a rectangular or cylindrical cell
made of optical glass or optical plastic, which can be placed
in the sample holder. The cell is integrated with the sample
holder in some apparatus.
(iv) Light-receiving optics and detector: light optics and
detector which capture the scattered light from the sample at
a single scattering angle between 909to 1809and convert the
captured light to a photon pulse (digitized signal). In the case
that a polarization analyzer is included, it shall be positioned
so that the transmittance of the vertically polarized light is
maximized.
(v) Correlator: a device which calculates the autocorrelation function from the number of photon pulses in a certain
time.
(vi) Spectrum analyzer: a device which calculates the frequency power spectrum by performing Fourier transformation of the frequency components present in the scattered
light fluctuation signals.
(vii) Computation unit: data processor for determining
the particle diameter distribution from the autocorrelation
function obtained by the correlator or from the frequency
power spectrum. Some computation units also function as a
correlator or spectrum analyzer.
2.2. Validation and reproducibility of the instrument
Because the particle diameter obtained by dynamic light
scattering is not a relative value calculated using standard
particles but an absolute value based on a fundamental principle, calibration of the value is unnecessary.
However, it is necessary to confirm the performance of
the instrument by using particles with certified diameter,
when the instrument is first installed or if abnormal performance is suspected. In addition, it is desirable to confirm the
proper performance of the instrument at least every year
thereafter.
As standard particles of known diameter, polystyrene latex particles with a narrow distribution of diameter shall be
used, whose average particle size is certified to be approximately 100 nm as determined by dynamic light scattering.
The measured average diameter of these particles must be
within 2z of the stated diameter range, and the relative
3. Measurement
3.1. Choice of the dispersion liquid
The dispersion liquid shall fulfill all of the following requirements.
(i) It shall be non-absorbing at the wavelength of the
laser.
(ii) It shall not cause damage such as corrosion to the
materials of the instrument.
(iii) It shall not dissolve, swell or coagulate the particles.
(iv) It shall have a refractive index different from that of
the particulate material.
(v) Its refractive index and viscosity shall be known within an accuracy of 0.5z.
(vi) It shall be clean enough not to interfere with the
measurements.
3.2. Cleaning the measuring cell
The degree of cell washing required depends on the conditions of the measurement.
When an individually packaged clean disposable cell is
used, cleaning by blowing off dust with compressed clean air
is sufficient. When a cell is intended to be washed rigorously, the cell is fully rinsed beforehand with water to remove
water-rinsable adhesion substances and is washed with a
nonabrasive detergent.
3.3. Sample preparation
It is necessary to prepare a sample whose concentration is
within an appropriate range to eliminate the influence of the
multiple scattering of light. In addition, it is important to remove dust, which may affect the measurement, and to prevent their re-introduction during the preparation.
When the sample is shaken, dust-laden air is entrapped in
the sample and air is dissolved in the solvent. The invisible
small air bubbles scatter light more strongly than do the
sample particles to be measured. It is necessary not to shake
the sample violently after preparation, but to swirl it gently.
A homogeneous sample solution can be prepared quickly by
adding diluent to the concentrated sample droplet rather
than dropping the sample droplet into the diluent.
3.4. Measurement procedure
1) Switch the instrument on and allow it to warm up.
A period of approximately 30 minutes is typically required for stabilizing the laser intensity and bringing
the sample holder to the desired temperature.
2) Choose the appropriate dispersion liquid, and record
the count rate or the amplitude of the signals of scattered light fluctuation from the dispersion liquid.
3) Place the sample containing the dispersed particles in
the instrument, and wait until temperature equilibrium is established between the sample and the sample
holder. It is desirable to control and measure the temperature within an accuracy of 0.39
C.
4) Perform a preliminary measurement of the sample,
and set the particle concentration within the appropriate range based on 5.2.
5) Perform the measurement with the appropriate meas-
Supplement I, JP XVI
uring time and number of integrations.
Record the average particle diameter and the polydispersity index for each measurement.
7) If the measured values are dependent on the particle
concentration, adopt the extrapolated infinite dilution values of the average particle diameter and the
polydispersity index (or the measured values at the
lowest particle concentration).
8) Confirm that no significant sedimentation has occurred in the sample at the end of the measurement.
The presence of sediment indicates that the sample
may have aggregated or precipitated, or that the sample may be unsuitable for measurement by dynamic
light scattering.
9) Perform the measurement for each sample at least
three times.
3.5. Repeatability
The repeatability of the determination of the average particle diameter, evaluated in terms of relative standard deviation, must be less than 5z.
6)
4.
Data analysis
The dispersion that is the target for the measurement is irradiated with the laser light. Phases of the light scattered by
each particle fluctuate because the dispersed particles are in
Brownian motion. The observed scattered intensity, which is
the sum of the scattered light (result of interference), fluctuates along the time axis. Analyzing the fluctuation of the
scattered light intensity as a function of time provides information on the motion of the dispersed particles.
Analysis by photon correlation spectroscopy is performed
using the autocorrelation function of the scattered light intensity. This autocorrelation function depend only on the
time difference (correlation time) and is independent of the
time at which the measurement is started. For a large number of monodisperse particles in Brownian motion in a scattering volume, the autocorrelation function of the scattered
light intensity is basically an exponential decay function of
the correlation time. Polydispersity index is a parameter indicating the distribution of the decay constant, and is also a
scale indicating the broadness of the distribution of particle
diameter.
Frequency analysis is performed using the frequency power spectrum calculated from the scattered light intensity. The
amplitude of the frequency power spectrum is proportional
to the scattered light intensity and the concentration of the
sample, and the characteristic frequency is inversely proportional to the particle diameter. The decay constant and the
characteristic frequency are related to the translational
diffusion coefficient of homogeneous spherical particles in
Brownian motion. The diffusion constant of the spherical
particles dispersed in the dispersion liquid is related to the
particle diameter according to the Stokes-Einstein equation
in the absence of inter-particle interaction. The polydispersity index determined by frequency analysis is a measure of
the broadness of the particle diameter distribution calculated
from the particle diameter distribution based on the scattered light intensity, and might differ from the polydispersi-
General Information
2553
2554
General Information
Water-Solid Interactions:
Determination of
Sorption-Desorption Isotherms
and of Water Activity
This text is harmonized with the European Pharmacopoeia and the U.S. Pharmacopeia. The parts of the text that
are not harmonized are marked with symbols ( ).
The
RH (Pc/P0) 100
Pc: pressure of water vapour in the system
P0: saturation pressure of water vapour under the same
conditions
A.
B.
C.
D.
E.
F.
G.
H.
I.
Humidity controller
Temperature controlled chamber
Balance module
Humidity regulated module
Reference
Sample
Vapour humidifier
Flow control module
Dry gas
Supplement I, JP XVI
The ratio Pc/P0 is referred to as the relative pressure.
Sorption or water uptake is best assessed starting with dried
samples and subjecting them to a known relative humidity.
Desorption is studied by beginning with a system already
containing sorbed water and reducing the relative humidity.
As the name indicates, the sorption-desorption isotherm is
valid only for the reference temperature, hence a special
isotherm exists for each temperature. Ordinarily, at
equilibrium, moisture content at a particular relative humidity must be the same, whether determined from sorption or
desorption measurements. However, it is common to see
sorption-desorption hysteresis.
1.2. Methods
Samples may be stored in chambers at various relative humidities. The mass gained or lost for each sample is then
measured. The major advantage of this method is convenience, while the major disadvantages are the slow rate of
reaching constant mass, particularly at high relative humidities, and the error introduced in opening and closing the
chamber for weighing. Dynamic gravimetric water sorption
systems allow the on-line weighing of a sample in a controlled system to assess the interaction of the material with
moisture at various programmable levels of relative humidity at a constant temperature. The major benefit of a controlled system is that isothermal conditions can be more reliably established and that the dynamic response of the sample
to changing conditions can be monitored. Data points for
the determination of the sorption isotherm (e.g. from 0 per
cent to approximately 95 per cent RH, non condensing) are
only taken after a sufficiently constant signal indicates that
the sample has reached equilibrium at a given level of humidity. In some cases (e.g. deliquescence), the maximum
time may be restricted although the equilibrium level is not
reached. The apparatus must adequately control the temperature to ensure a good baseline stability as well as accurate
control of the relative humidity generation. The required relative humidities can be generated, e.g. by accurately mixing
dry and saturated vapour gas with flow controllers. The electrostatic behaviour of the powder must also be considered.
The verification of the temperature and the relative humidity
(controlled with, for example, a certified hygrometer, certified salt solutions or deliquescence points of certified salts
over an adequate range), must be consistent with the instrument specification. The balance must provide a sufficient
mass resolution and long term stability.
It is also possible to measure amounts of water uptake not
detectable gravimetrically using volumetric techniques. In
the case of adsorption, to improve sensitivity, one can increase the specific surface area of the sample by reducing
particle size or by using larger samples to increase the total
area. It is important, however, that such comminution of the
solid does not alter the surface structure of the solid or render it more amorphous or otherwise less ordered in crystallinity. For absorption, where water uptake is independent of
specific surface area, only increasing sample size will help.
Increasing sample size, however, will increase the time to establish some type of equilibrium. To establish accurate
values, it is important to get desolvation of the sample as
Supplement I, JP XVI
thoroughly as possible. Higher temperatures and lower pressures (vacuum) facilitate this process; however, one must be
aware of any adverse effects this might have on the solid
such as dehydration, chemical degradation or sublimation.
Using higher temperatures to induce desorption, as in a thermogravimetric apparatus, likewise must be carefully carried
out because of these possible pitfalls.
1.3. Report and interpretation of the data
Sorption data are usually reported as a graph of the apparent mass change in per cent of the mass of the dry sample
as a function of relative humidity or time. Sorption isotherms are reported both in tabular form and as a graph.
The measurement method must be traceable with the data.
Adsorption-desorption hysteresis can be interpreted, for
example, in terms of the porosity of the sample, its state of
agglomeration (capillary condensation), the formation of
hydrates, polymorphic change, or liquefying of the sample.
Certain types of systems, particularly those with microporous solids and amorphous solids, are capable of sorbing
large amounts of water vapour. Here, the amount of water
associated with the solid as relative humidity is decreased, is
greater than the amount that originally sorbed as the relative
humidity was increased. For microporous solids, vapour adsorption-desorption hysteresis is an equilibrium phenomenon associated with the process of capillary condensation.
This takes place because of the high degree of irregular curvature of the micropores and the fact that they ``fill''
(adsorption) and ``empty'' (desorption) under different
equilibrium conditions. For non-porous solids capable of
absorbing water, hysteresis occurs because of a change in the
degree of vapour-solid interaction due to a change in the
equilibrium state of the solid, e.g. conformation of polymer
chains, or because the time scale for structural equilibrium is
longer than the time scale for water desorption. In measuring sorption-desorption isotherms, it is therefore important
to establish that something close to an equilibrium state has
been reached. Particularly with hydrophilic polymers at high
relative humidities, the establishment of water sorption or
desorption values independent of time is quite difficult,
since one is usually dealing with a polymer plasticised into its
``fluid'' state, where the solid is undergoing significant
change.
In the case of crystal hydrate formation, the plot of water
uptake versus pressure or relative humidity will in these cases
exhibit a sharp increase in uptake at a particular pressure
and the amount of water taken up will usually exhibit a
stoichiometric mole:mole ratio of water to solid. In some
cases, however, crystal hydrates will not appear to undergo a
phase change or the anhydrous form will appear amorphous. Consequently, water sorption or desorption may appear more like that seen with adsorption processes. X-ray
crystallographic analysis and thermal analysis are particularly useful for the study of such systems.
For situations where water vapour adsorption occurs
predominantly, it is very helpful to measure the specific surface area of the solid by an independent method and to express adsorption as mass of water sorbed per unit area of
solid surface. This can be very useful in assessing the possi-
General Information
2555
ble importance of water sorption in affecting solid properties. For example, 0.5 per cent m/m uptake of water could
hardly cover the bare surface of 100 m2/g, while for 1.0
m2/g this amounts to 100 times more surface coverage. In
the case of pharmaceutical solids which have a specific surface area in the range of 0.01 m2/g to 10 m2/g, what appears
to be low water content could represent a significant amount
of water for the available surface. Since the ``dry surface
area'' is not a factor in absorption, sorption of water with
amorphous or partially amorphous solids can be expressed
on the basis of unit mass corrected for crystallinity, when the
crystal form does not sorb significant amounts of water relative to the amorphous regions.
2. Determination of The Water Activity
2.1. Principle
Water activity, Aw, is the ratio of vapour pressure of water
in the product (P) to saturation pressure of water vapour
(P0) at the same temperature. It is numerically equal to
1/100 of the relative humidity (RH) generated by the
product in a closed system. RH can be calculated from direct
measurements of partial vapour pressure or dew point, or
from indirect measurement by sensors whose physical or
electric characteristics are altered by the RH to which they
are exposed. Ignoring activity coefficients, the relationship
between Aw and equilibrium relative humidity (ERH) are
represented by the following equations:
Aw P/P0
ERH (per cent) Aw 100
2.2. Method
The water activity is determined by placing the sample in a
small airtight cup inside which the equilibrium between the
water in the solid and the headspace can be established. The
volume of the headspace must be small in relation to the
sample volume in order not to change the sorption state of
sample during the test. The equilibration as a thermodynamic process takes time but may be accelerated by forced circulation within the cell. The acquired water activity value is
only valid for the simultaneously determined temperature.
This requires a precise temperature-measuring device as part
of the equipment. Furthermore, the probe must be thermally
insulated to guarantee a constant temperature during the
test. The sensor measuring the humidity of the headspace air
above the sample is a key component. Theoretically, all
types of hygrometers can be used, but for analytical purposes miniaturisation and robustness are a precondition.
The Aw measurement may be conducted using the dew
point/chilled mirror method1. A polished, chilled mirror is
used as a condensing surface. The cooling system is electronically linked to a photoelectric cell into which light is reflected from the condensing mirror. An air stream, in equilibrium with the test sample, is directed at the mirror which cools
until condensation occurs on the mirror. The temperature at
which this condensation begins is the dew point from which
the ERH is determined. Commercially available instruments
using the dew point/chilled mirror method or other technologies need to be evaluated for suitability, validated, and
2556
General Information
Table 1
Supplement I, JP XVI
Aw
97.3
90.2
75.3
52.9
32.8
11.2
0.973
0.902
0.753
0.529
0.328
0.112
G3
Biotechnological/Biological
Products
Instrument
A mass spectrometer is composed of an ion source, an
analyzer, an ion detector, and a data system (Fig. 1). A peptide and protein sample introduced into the ion source is
ionized by soft-ionization methods, such as matrix-assisted
laser desorption/ionization (MALDI) and electrospray ioni-
zation (ESI). The charged and gas phased ions are sorted according to the m/z ratio under a vacuum in the analyzer,
which may be a quadrupole, time-of-flight, ion trap or
Fourier transform ion cyclotron resonance analyzer. The ion
flux collected in the detector is converted to an electric signal. Then the signal is recorded as a mass spectrum. MS/MS
is carried out by using two mass spectrometers connected in
series, an ion-trap mass spectrometer and Fourier transform
ion cyclotron resonance mass spectrometer. The precursor
ions are generally fragmented by collision-induced dissociation, post-source decay, electron capture dissociation, etc.
2. Analytical mode
2.1. MS
There are two useful modes for MS:
(1) Total ion monitoring
The signals of the entire ion are acquired over the chosen
range of m/z value. This mode provides information on the
masses of the molecule of interest and different species.
(2) Selected ion monitoring
The signals of the ion at chosen m/z value are acquired.
This mode is useful for the sensitive measurement of the
chosen molecule.
2.2. MS/MS
There are four essential modes for MS/MS:
(1) Product ion analysis
The signals of all the product ions produced from the
precursor at chosen m/z value are acquired. This mode provides structural information on the substrates and various
co-existing species.
(2) Precursor ion scan mode
The signals of the precursor that yields the product ion at
chosen m/z value are monitored. This mode is used for sorting the molecules containing a component of interest.
(3) Constant neutral loss scan mode
The signals of the precursor that loses the fragment at
chosen m/z value are monitored. This mode is useful to sort
the molecules containing a component of interest.
(4) Selected reaction monitoring
The signals of product ions at chosen m/z value that are
produced from the precursor at chosen m/z value are monitored. This mode allows for sensitive and selective measure-
Supplement I, JP XVI
ment and is used for quantification of a molecule in a complex mixture.
3. Analytical procedure
3.1. MS
In advance, it should be conformed if the detectability and
the difference between the calculated mass and observed
mass meet the criteria stated in the monograph by mass
measuring using a test solution specified in the system
suitability in the monograph. If they do not meet the criteria, the system should be optimized by adjustment of the voltage of the ion source, analyzer and detector, as well as by
calibration using appropriate mass calibrator. MS is performed according to the sample preparation and operating
conditions indicated in the monograph. The general procedure is described as follows.
(1) Matrix-assisted laser desorption/ionization (MALDI)
A desalted peptide and protein sample is dissolved in an
appropriate solvent, e.g., an aqueous solution of trifluoroacetic acid. A suitable matrix, such as a-ciano-4-hydroxycinnamic acid, 2,5-dihydroxybenzoic acid, or sinapic acid, is
dissolved in an aqueous solution containing acetonitrile and
trifluoroacetic acid. A mixture of sample solution and
matrix solution is deposited on a sample plate and dried. The
sample on the plate is set in the ion source, and ionized by a
laser beam at suitable intensity.
(2) Electrospray ionization (ESI)
A desalted peptide and protein sample is dissolved in a
suitable solvent, such as an aqueous solution containing
acetic acid and methanol or acetonitrile. The sample solution is sprayed through a needle tip and held at a potential of
several kilovolts. The sample is introduced by using a syringe
or HPLC.
3.2. MS/MS
System suitability is tested by MS/MS of the test sample
specified in the monograph. The detectability and system
performance should be confirmed based on the detection of
the product ions specified in the monograph. The sample is
ionized in the same way as for MS, and the chosen precursor
is fragmented by the suitable conditions specified in the
monograph. The signals are recorded as a mass spectrum. A
peptide containing disulfide bonds is generally reduced by
dithiothreitol, 2-mercaptethanol and tris (2-carboxyethyl)
phosphine. The reduced peptides are derivatized with
monoiodoacetic acid, iodoacetamide, and 4-binylpyridine.
4. Identification test
4.1. Mass of the molecule
The monoisotopic mass of the peptide is preferably acquired. If the monoisotopic mass is not detectable, the
average mass is calculated from the top of the ion peak.
Deconvolution is effective for calculating the average mass
of multiply-charged ions from proteins. The mass should
meet the criteria specified in the monograph.
4.2. Amino acid sequence
After measuring the mass of the sample peptide, the
presence of the specified product ions that arise from the
selected precursor is confirmed according to the conditions
indicated in the monograph. Digestion of sample proteins
General Information
2557
with a suitable enzyme followed by MS/MS is sometimes effective for sequencing of the high-molecular weight proteins
which provide insufficient product ions. Details of the digestion procedure are provided in the section on peptide mapping.
5. Glossary
Ion-trap (IT)
Ion-trap refers to the quadrupole ion trap mass analyzer
in a restricted sense. Ions stored in the analyzer by applying
radio frequency voltage to ring electrodes are separated by
subsequent ejection of the ions from the analyzer by varying
the voltage on the ring electrodes. This allows multiple stage
MS in which a selected ion is repeatedly trapped, fragmented
and ejected.
Electrospray ionization (ESI)
The sample in solution is sprayed through a needle tip and
held at high-voltage at atmospheric pressure. The sample is
ionized by a formation of charged liquid droplets. Highmolecular mass proteins are detected as multiply-charged
ions. The analyzer can be connected with HPLC.
Quadrupole (Q)
The analyzer is composed of four parallel electrodes
which have a hyperboloidal or cylindrical cross-section. The
ions transmitted to the analyzer are separated by varying the
potential of direct and radio frequency components applied
to the rods so that the filter for sorting the m/z values of
ions is changed.
Collision-induced dissociation (CID)
When an ion collides with a neutral atom or molecule (He,
Ar, N2 and so on), some of the translational energy of the
collision is converted into internal energy, thereby causing
dissociation. The terms low-energy CID and high-energy
CID refer to those CIDs for which the translational energy
of the precursor ions is lower than 1000 eV and higher than
1000 eV, respectively.
Electron capture dissociation (ECD)
Multiply-charged positive ions interact with low energy
electrons producing charge-reduced radical ions, which readily dissociate. This method is primarily used for MS/MS in
FT-ICR MS or IT MS.
Time-of-flight (TOF)
The ionized sample is accelerated at high-voltage and
separated based on the time required for an ion to travel to
the detector. There are two types of analyzer, a linear type in
which ions travel linearly from the ion source to the detector, and a reflectron type where ions are inverted by a reflectron. The latter type allows high-resolution measurement by
correction of the variation in the initial energy of ions.
Fourier transform ion cyclotron resonance (FT-ICR)
The analyzer is based on the principle that the cyclotron
frequency of the ions in a magnetic field is inversely proportional to its m/z value. Ions are excited to a larger radius orbit using radio frequency energy and their image current is
detected on receiver plates. The resulting data are devolved
2558
General Information
G4
Microorganisms
Microbiological Evaluation of
Processing Areas for Sterile
Pharmaceutical Products
Change to read as follows:
Microbiological Environmental
Monitoring Methods of
Processing Areas for Sterile
Pharmaceutical Products
This chapter describes the methods for the evaluation of
air-cleanliness and the recommended limits for environmental microorganisms. The main purposes of this chapter are 1)
to confirm that the designed cleanliness levels and microbial
limits are attained and maintained in processing areas for
sterile pharmaceutical products, and 2) to confirm that the
number of particulates and microorganisms are appropriately controlled in the processing environment for sterile pharmaceuticals.
In reference to the evaluation methods and the recommended limits described in this chapter, a risk assessment
should be formed for each manufacturing facility and acceptance criteria should be established based on the identified
risks. Alternative measuring methods can be applied on rational grounds.
1.
Definitions
For the purposes of this chapter, the following definitions
apply:
(i) Action level: An established number of objects to be
monitored (and species of microorganisms, if appropriate)
that requires immediate investigation and corrective action
based on the investigation when exceeded.
(ii) Alert level: An established number of objects to be
monitored (and species of microorganisms, if appropriate)
that gives early warning of potential problems.
Supplement I, JP XVI
(iii) Aseptic processing: Filling of sterile products and
other operations performed under the environmental conditions in which air supply, materials, equipment, and personnel are regulated to control microbial and particulate contamination to acceptable levels.
(iv) Aseptic processing area: The classified part of a facility in which air supply, materials, equipment, and personnel
are highly regulated to control microbial and particulate
contamination to acceptable levels. The area is classified
into two categories: Grade A and Grade B.
(v) Microorganisms: General term for bacteria, fungi, protozoa, viruses, etc. In this chapter, microorganisms indicate
only bacteria and fungi.
(vi) Shift: Scheduled period of work or production during
which operations are conducted by a single or defined group
of workers.
(vii) Risk assessment: A series of processes including identification, analysis, and evaluation of hazards that may
cause harm in accordance with ICH Q9, ``Quality Risk
Management.'' In this chapter, ``harm'' indicates contamination of products or manufacturing areas; ``hazards'' indicates possible causes of the contamination, such as personnel, environment, or operations carried out. Risk is expressed as a combination of the probable incidence and
severity of the harm.
(viii) Calibration: The act of establishing the relationship
between values indicated by a measuring instrument and the
values represented by a material measure, by comparison
with the corresponding known values of a standard instrument or a standard reference material and of adjusting the
accuracy of the measuring instrument for the proper use.
(ix) At rest: The state in which production equipment is installed and operating, with no operating personnel present.
(x) In operation: The state in which the installed equipment is functioning in the defined operating mode with the
specified number of personnel working.
2.
Processing areas
Processing areas refer to areas in which actions such as
cultivation, extraction/purification, washing and drying of
containers and stoppers, weighing of raw materials, preparation of solutions, sterilization, filling, sealing, and packaging are performed, including the gowning area.
The processing areas for sterile pharmaceutical products
are maintained and controlled to prevent containers, raw
materials, and in-process products from microbial and particulate contamination.
Personnel engaged in such activities in the areas should
receive necessary training in hygiene, microbiology,
manufacturing technology, and clothing.
2.1. Classification of processing areas
(i) Grade A: A local area in which operational activities to
prevent contamination risks of products at a high level are
conducted. For pharmaceutical products prepared aseptically, the area is designed to preserve sterility of sterilized pharmaceutical products, containers, and closures that are
exposed within it. In this area, manipulations of sterile
materials prior to filling operation (e.g. aseptic connections,
Supplement I, JP XVI
General Information
Table 2
A
B
C
D
Grade
Air-cleanliness
in operation
Size
0.5 mm
5.0 mm
0.5 mm
5.0 mm
A
B
C
D
3520
3520
352000
3520000
20
29
2900
29000
3520
352000
3520000
*2
20
2900
29000
*2
Grade
2559
air sample
(CFU/m3)
settle plates*2
(CFU/plate)
1
10
100
200
1
5
50
100
Microorganisms on surfaces
contact plates
gloves
(CFU/24 30 cm2)
(CFU/5 fingers)
1
5
25
50
1
5
2560
General Information
Supplement I, JP XVI
1
2
4
6
8
10
24
28
32
36
52
56
64
68
72
76
104
108
116
148
156
192
232
276
352
436
500
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Table 4
Grade
airborne
microorganisms
In operation
C, D*
microorganisms on surfaces
instruments, walls etc.
gloves, gowns
At the completion
of each operation
At the completion
of each operation
In operation
At the completion
of each operation
At the completion
of each operation
Once a month
Twice a week
Twice a week
Other areas
Once a month
Once a week
Once a week
* When a contamination risk is low, for example, where products are not exposed to the surrounding environment, monitoring frequency may be reduced accordingly.
Supplement I, JP XVI
e.g., the near vicinity (e.g. within 30 cm) of a site where
products are exposed to the surrounding environment, a site
that is prone to potential sources of contamination due to
frequent human interventions and traffic or due to susceptibility to lower cleanliness levels, or a site regarded as worstpoint based on the airflow analysis.
3.4. Monitoring methods
Appropriate methods should be selected according to the
items to be monitored. Consideration should be given to
potential contamination risks increased by interventions of
personnel who are involved in sampling and disturbance of
airflow during sampling.
For monitoring of airborne microorganisms, there are two
types of microbial sampling methods: active sampling
methods and passive sampling methods. Various types of
culture medium and culture methods are available for different types of microorganisms to be monitored. For details,
refer to Section 5, ``Measurement of microorganisms'' in
this chapter.
3.5. Environmental control criteria
Establishment of an alert level for each item to be monitored can lead to early detection of performance degradation
of facilities. It is also useful to control risks. In environmental monitoring, it is important to evaluate whether the specified cleanliness level for a monitored object is constantly
maintained. The measured values obtained by environmental monitoring are averaged. The contamination risks are
evaluated based on the averaged values and should not be
underestimated.
In a case where bacteria are detected in a Grade A area,
assessment of potential effect on the products should be carried out. Surfaces and personnel should be monitored after
the completion of critical operations.
Measurement of 5.0 mm airborne particulates in Grade
A and B areas is useful for early detection of abnormalities
in the environment. When 5.0 mm airborne particulates
are continuously or frequently detected, even if the number
is low, further investigation should be encouraged due to
possible abnormalities that may have impact on the environment.
3.6. Evaluation of monitoring data and measures to be
taken when the limit is exceeded
Environmental monitoring data should be evaluated both
in the short-term and the long-term. The following items
should be included in the evaluation:
(i) Changes in numbers of microorganisms and airborne
particulates over a period of time
(ii) Changes in detected species of microorganisms
(iii) Changes of monitoring points
(iv) Review of the validity of alert and action levels
(v) Review of frequency of positive results from each operator
(vi) Changes that may impact the monitoring results during the monitoring periods
Trend analysis of environmental monitoring data will provide information required to predict potential deterioration
of the manufacturing environment before it occurs and to
determine its probable causes. Information that may impact
General Information
2561
Measurement of particulates
For measurement of particulates, particle counters that
can detect particulates of different sizes are used. In general,
a particle counter is composed of an air suction pump, a sensor that discerns particle size from variations in the reflection of a laser beam, and a converter unit. When there is
distance between a counter and a sampling point, sampling
tubing is used. To measure distribution of particulates precisely, the inlet of the sampling probe is positioned parallel
to airflow, and air is aspirated at the same velocity as the airflow.
For measurement of particulates, calibrated devices
should be used. Consideration should be given to length, diameter of the tubing, and radii of any bends in the tubing, as
well as to the device itself. Calibration items include flow
rate, counting efficiency, false counts, and counting loss.
There are three types of methods for particulates monitoring; an independent particle counter is placed at individual
monitoring point; a network of sequentially accessed
monitoring points is connected by manifold to a single particle counter; or a combination of the two. In any method, the
concentration of particulates in the predetermined particulate size range according to the cleanliness level of the area to
be monitored should be indicated or recorded. When
monitoring 5.0 mm particulates, a short length of sample
tubing should be used, because of the relatively higher rate
of precipitation of particulates of large size. For particulate
monitoring, the selection of the monitoring system may take
into account any health risks of operators presented by the
materials used in the manufacturing operation (e.g. pathogens, radiopharmaceuticals, or strong sensitizers).
In general, continuous monitoring is recommended in a
Grade A area. Sampling volumes that can be accurately converted to volume per m3 should be applied.
5.
Measurement of microorganisms
Measurement methods of microorganisms for environmental monitoring include active microbial sampling
methods, measurement methods for microorganisms on surfaces, and settling plates. Various types of sampling devices
and measurement methods are available for the sampling
and measurement of microorganisms in the air and on surfaces. Appropriate samplers and measuring methodology
should be selected according to the purpose of monitoring
and the items to be monitored.
5.1. Measurement by cultivation
5.1.1. Active microbial sampling methods
Methods in which a fixed volume of air is aspirated and
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Supplement I, JP XVI
5.1.2. Measurement methods for microorganisms on surfaces
The area to be surface-sampled should be designated according to the condition and shape of the object to be monitored.
(i) Contact plates: A contact plate is used with an appropriate contact surface and sufficient area. In principle,
the recommended sampling area for equipment or apparatuses is 24 30 cm2.
The culture medium surface should be brought into contact with the sampling site for several seconds by applying
uniform pressure without circular or linear movement. After
contact and removal, the plates are covered, and as soon as
possible, incubated under appropriate culture conditions.
After a contact plate has been used, the site to which the
plate was applied must be wiped aseptically to remove any
adherent culture medium.
(ii) Swabs: A sterilized, lint-free swab that is suitable for
collecting microorganisms is premoistened with an appropriate rinse fluid, and then sampling is conducted by swabbing
the defined sampling area in a slow circular movement or in
closely parallel strokes while changing direction. After sampling, the swab is agitated in a specified amount of an appropriate sterilized rinse fluid, and the rinse fluid is assayed
for viable organisms according to Section 4.05 of the
Microbiological Examination of Non-sterile Products.
(iii) Adhesive sheets: An adhesive sheet for sampling is
evenly applied to the surface of the item to be monitored and
removed. This process should be repeated several times for
one sampling area. Microorganisms captured on the adhesive sheet are counted in an appropriate manner. Ultrasonic
treatment can be applied to recover microorganisms into solution.
5.1.3. Settling plates (passive microbial sampling method)
Petri dishes of a specified diameter (petri dishes 9 cm in diameter are commonly used) containing a suitable culture
medium are placed at the measurement location, and the
cover is removed. The plates are exposed for a specified time
and the microorganisms deposited from the air onto the agar
surface are enumerated after incubation. This method is not
effective for quantitative monitoring of total airborne
microorganisms, because it does not detect microorganisms
that do not settle onto the surface of the culture media, and
the settling velocity of aggregates of microorganisms is
affected by air currents and disturbances in airflow.
Although the results obtained by the settle plate method are
only qualitative or semi-quantitative, this method is suitable
for long-term evaluation of possible contamination of
products or devices by airborne microorganisms.
Before using this method, it should be ensured that the
growth of microorganisms is not inhibited due to dryness of
the agar surface after lengthy exposure. The data obtained
by settling plates can be useful when considered in combination with results from active sampling methods.
5.1.4. Cultivation
Culture conditions under which microorganisms can grow
with high reproducibility should be applied in environmental
monitoring. Growth promotion testing should be performed
Supplement I, JP XVI
General Information
Table 5
2563
Media (examples)
Microorganisms to
be detected
Media
25 309C
More than 5 days
Aerobes
30 359C
More than 5 days
20 259C
More than 5 days
Anaerobes
30 359C
More than 5 days
(under an anaerobic culture condition)
Extraction Liquids
Saline solution
Phosphate buffered saline solution
Phosphate buffered solution, pH 7.2
Buffered sodium chloride-peptone solution, pH 7.0
Peptone saline solution
Peptone solution
15.0 g
5.0 g
5.0 g
1.0 g
15 g
Water
1000 mL
Adjust pH to 7.1 7.5 at 259C after sterilization in an
autoclave using a validated cycle.
(iii) Glucose peptone agar medium
Peptone
5.0 g
Yeast extract
2.0 g
Glucose
20.0 g
Magnesium sulfate heptahydrate
0.5 g
Potassium dihydrogen phosphate
1.0 g
Agar
15.0 g
Water
1000 mL
Adjust pH to 5.6 5.8 at 259C after sterilization in an
autoclave using a validated cycle.
(iv) Reinforced clostridial agar medium
Beef extract
10.0 g
Peptone
10.0 g
Yeast extract
3.0 g
Soluble starch
1.0 g
Dextrose monohydrate
5.0 g
Cystein hydrochloride monohydrate
0.5 g
Sodium chloride
5.0 g
Sodium acetate
3.0 g
Agar
15.0 g
Water
1000 mL
Adjust pH to 6.6 7.0 at 259C after sterilization in an
autoclave using a validated cycle.
(v) Phosphate buffered solution
Potassium dihydrogen phosphate
Sodium chloride
Water
0.0425 g
8.5 g
1000 mL
2564
General Information
Supplement I, JP XVI
10.0 g
5.0 g
1000 mL
5.1.5. Identification
Identification of microorganisms detected in Grade A and
B areas to the species level is recommended. Genotypic
methods are more accurate and precise than traditional
biochemical and phenotypic techniques. These results can be
used for investigations into contaminants found in sterility
tests or process simulations. See ``Rapid Identification
Method of Microorganisms by Gene Analysis'' for additional information on gene analysis.
5.2. Rapid test methods
Rapid test methods can provide results in a shorter time
compared with traditional culture methods.
In general, scientifically validated devices should be used
for the following aspects of the identification process:
(i) Collecting method (filtration, impact, adhesion, or air
aspiration etc.)
(ii) Detection signal (fluorescence, luminescence etc.)
(iii) Detection device
In many cases, the detection thresholds in the rapid test
methods are higher than those in traditional methods.
Sufficient consideration should be given to qualification of
equipment and calibration methods when introducing rapid
test methods. In addition, as the measurement principles are
different from those in cultural methods, acceptance criteria
for each method should be established based on scientific
rationale. The acceptance criteria for rapid test methods
should be equivalent to or more stringent than those for
traditional methods.
6. References
(i) PIC/S GUIDE TO GOOD MANUFACTURING PRCTICE FOR MEDICAL PRODUCTS ANNEXES: Annex
1-Manufacture of sterile medicinal products (September
2009)
(ii) ISO/DIS 14644-1 (2010): Cleanrooms and associated
controlled environmentsPart 1: Classification of air
cleanliness by particle concentration
G5
Crude Drugs
Si 1 Ni
m
1 eTr/T1i
p sin b
M0
1eTr/T1i cos b
VM
(1)
where Ni is the number of resonating 1H which gives the signal, V is the volume of the sample solution, m is the mass of
the sample, M is the molecular mass of the substance measured, p is the purity of the sample, b is the excitation pulse
angle, T1i is the spin-lattice relaxation time of 1H which gives
the signal, Tr is the repetition time, M0 is the equilibrium
magnetization1) and the subscript i indicates the independent
signal. The relaxation time of a 1H is different depending on
the environments of the 1Hs. Since the sensitivity of NMR is
not so good, the signal-to-noise ratio (S/N ratio) of signals
should generally be improved by measuring it repeatedly and
averaging noises. When the NMR measurement is performed under the condition with the repetition time Tr
sufficiently longer than the longest T1 among the T1s of the
signals observed for the analyte compound, the condition of
1eTr/T11 for all of the signals of the analyte compounds
would be satisfied and quantitative analysis utilizing NMR
(quantitative NMR) can be performed. On the other hand,
when NMR is used for the structural determination, priority
is given to improve detection sensitivity, and the condition
for increasing the S/N ratio of signals by using repeated
Supplement I, JP XVI
General Information
Si
Ni
Sj
Nj
(2)
pa
Sa N s M a m s
ps
Ss N a M s m a
(3)
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General Information
Supplement I, JP XVI
ple is evaluated to be 2.8z taking it into consideration of the
absolute purity determined by quantitative NMR with the
assurance of metrological traceability.
5. Supply of Certified Reagents by Using Quantitative
NMR
Currently, in the accreditation system of the International
Accreditation Japan (IA Japan), the National Institute of
Technology and Evaluation (ASNITE), a feasibility study
how the accreditation should be given to the organization
which performs the assay certification of the reagents has
been in progress. In addition, in the IA Japan, addition of
``Quantitative NMR'' to the test method categories is scheduled. Therefore, in the near future, the reagent manufacturers will become able to perform the assay certification of
the reagent after having this accreditation. Under such situation, the user of the reagent would not be required to perform qualitative NMR individually to obtain the purity
value with SI traceability. Furthermore, the inter-institutional errors (including inter-instrumental errors) would become
negligible, and we will be able to carry out more precise and
accurate quantitation assay of the sample by incorporating
the labeled certified value on the reagent into the calculation
of the quantitative value of the sample.
6.
1)
2)
3)
Reference
T. Saito, et al., Accred. Qual. Assur. 14, 79 86 (2009)
J. Hosoe, et al., Pharmaceutical and Medical Device
Regulatory Science, 41, 960 970 (2010)
J. Hosoe, et al., Pharmaceutical and Medical Device
Regulatory Science, 43, 182 193 (2012)
G8
Water
Supplement I, JP XVI
ties using well water or industrial water as source water, it is
necessary for produced water to meet the Quality Standards
for Drinking Water and an additional requirement for ammonium of ``not more than 0.05 mg/L.'' Furthermore,
when Water is to be used after storing for a period of time, it
is necessary to prevent microbial proliferation.
Water is used as source water for Purified Water and
Water for Injection. It is also used for manufacturing intermediates of active pharmaceutical ingredients (APIs), and
for pre-washing of the equipments used in the manufacture
of pharmaceutical products.
1.2. Purified Water
The specifications for ``Purified Water'' and ``Purified
Water in Containers'' are prescribed in the JP monographs.
Purified Water is prepared by distillation, ion-exchange,
reverse osmosis (RO), ultrafiltration (UF) capable of removing microorganisms and substances with molecular masses
of not less than approximately 6000, or a combination of
these processes from Water, after applying some adequate
pretreatments if necessary. For the production of Purified
Water, appropriate control of microorganisms is required.
Particularly, in the case that Purified Water is prepared by
ion-exchange, RO or UF, it is necessary to apply the treatments adequate for preventing microbial proliferation, or to
sanitize the system periodically.
When Purified Water is treated with chemical agents for
sterilizing, preventing microbial proliferation, or maintaining the endotoxin level within an appropriate control range,
a specification suitable for the intended use of treated water
should be established individually, and a process control for
keeping the quality of treated water in compliance with the
specification thus established should be performed.
``Purified Water in Containers'' is prepared from Purified
Water by introducing it in a tight container.
1.3. Sterile Purified Water
The specification for ``Sterile Purified Water in Containers'' (its alternative name is Sterile Purified Water) is
prescribed in the JP monograph.
Sterile Purified Water in Container is prepared from Purified Water by 1) introducing it into a hermetic container,
sealing up the container, then sterilizing the product, or 2)
making it sterile by using a suitable method, introducing the
sterilized water into a sterile hermetic container by applying
aseptic manipulation, then sealing up the container.
Plastic containers for aqueous injections may be used in
place of hermetic containers.
1.4. Water for Injection
The specifications for ``Water for Injection'' and ``Sterile
Water for Injection in Containers'' are prescribed in the JP
monographs. Water for Injection is prepared by distillation
or reverse osmosis and/or ultrafiltration (RO/UF), either
from Water after applying some adequate pretreatments
such as ion exchange, RO, etc., or from Purified Water.
In the case of water processing systems based on distillation, it is necessary to take care for avoiding contamination
of produced water by the impurities accompanied with the
entrain.
In the case of water processing system based on RO/UF, it
General Information
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2568
General Information
tion apparatus, chorine sterilization apparatus, oxidationreduction apparatus, residual chlorine-removing apparatus,
precise filtration apparatus, reverse osmosis apparatus,
ultrafiltration apparatus, ion exchange apparatus, etc., depending on the quality of source water. The facilities for
producing Water for Injection consist of apparatus for supplying pretreated water, sterilization apparatus with ultraviolet rays, heat exchange apparatus, membrane modules, apparatus for cleaning and sterilizing the facilities, etc. The
facilities for supplying Water for Injection consist of a reservoir tank for storing Water for Injection in the facilities temporarily, pipe lines, heat exchange apparatus, a pump for
circulating Water for Injection in the facilities, pressure control apparatus, etc.
In the case that Water for Injection is stored in the water
processing system temporarily, it should usually be circulated in a loop consisting of a reservoir tank and pipe line at a
temperature not lower than 809
C for preventing microbial
proliferation.
When Purified Water is produced by RO/UF, basic composition of water processing system is almost the same as
that for Water for Injection described above.
When RO/UF is utilized for preparing pharmaceutical
water, it is necessary to select the most appropriate combination of membrane modules in consideration of the quality of
source water and the quality of produced water required for
its intended use. When the ultrafiltration membrane is used
to prepare Purified Water or Water for Injection, membrane
modules capable of removing microorganisms and substances with molecular masses not less than approximately
6000 should be used.
3.
Supplement I, JP XVI
lations, Ear Preparations and Nasal Preparations, appropriately controlled Purified Water (or Purified Water in Containers) in vial count level should be used, and for Liquids
and Solutions among Inhalations, strictly controlled Purified Water (or Purified Water in Containers) in vial count
level should be used. For the Liquids and Solutions for Oral
Administration, Syrups, Suppositories for Vaginal Use,
Ointments and Creams, which require care against
microbiological contamination, Purified Water (or Purified
Water in Containers) adequately controlled from microbiological viewpoints should be used in consideration of the
possible impacts of preservatives formulated in the drug
products. For the manufacture of products containing crude
drugs, it is recommended to select adequate type of water
considering viable counts of the crude drugs used for
manufacturing the product and microbial limit required for
the product.
Water used for pre-washing of containers or equipment
surfaces that comes in direct contact with the drug products
should have the quality not lower than that of Water. Water
used for final rinsing should have an equivalent quality to
that of water used for manufacturing drug products.
3.2. Active Pharmaceutical Ingredient (API)
Water used for manufacturing active pharmaceutical ingredient (API) should be selected in consideration of the
characteristics of drug product for which the API is to be
used, and its manufacturing process, so that the quality of
the final drug product is assured.
Water used for manufacturing API or for cleaning containers or equipment surfaces that come in direct contact
with the raw materials or API intermediates, should have the
quality not lower than that of Water adequately controlled
from the chemical and microbiological viewpoints, even if
the water is used at an earlier stage of synthetic or extraction
process in the manufacture of API. Water used in the final
purification process should have the quality equal to or
higher than that of Purified Water (or Purified Water in
Containers). Water used for final rinsing of containers or
equipment surfaces that comes in direct contact with the
APIs should have an equivalent quality to that of water used
for manufacturing the APIs.
For manufacturing sterile API, Sterile Purified Water in
Containers or Water for Injection (or Sterile Water for Injection in Containers) should be used. Similarly, for
manufacturing APIs used for drug products where endotoxin control is required and there are no subsequent processes
capable of removing endotoxins, Water for Injection (or
Sterile Water for Injection in Containers), or Purified Water
(or Purified Water in Containers) for which endotoxins are
controlled at a low level, should be used.
4. Quality Control of Pharmaceutical Water
4.1. Outline
Verification that water with the quality required for its intended use has been produced by the pharmaceutical water
processing system through substantial validation studies at
an earlier stage of its operation, is the prerequisite for conducting quality control on pharmaceutical water in a routine
Supplement I, JP XVI
General Information
2569
Class of
Pharmaceutical
Water
Application
Remarks
Water for Injection or Injections, Dialysis Agents (Peritoneal For Hemodialysis Agents, unless otherSterile Water for In- Dialysis Agents and Hemodialysis wise specified, Water for Injection,
Water for Injection in Containers, or
jection in Containers Agents)
water suitable for the dialysis.
Purified Water or
Purified Water in
Containers
Water
For Liquids and Solutions for Oral Administration, Syrups, Suppositories for
Vaginal Use, Ointments, Creams and so
on for which precautions should be taken
against microbial contamination, Purified Water (or Purified Water in Containers) adequately controlled from
microbiological viewpoints should be
used, taking in mind the affection of containing preservatives.
Among Preparations Related to Crude The viable counts in crude drugs and the
Drugs: Extracts, Pills, Infusions and objective microbial limits of product
Decoctions, Teabags, Fluidextracts
should be considered in selecting water to
be used.
APIs
Water
API Intermediates
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Supplement I, JP XVI
Table 2
tem has deviated from its normal operating range. Exceeding it indicates that corrective action must be taken to bring
the system back within its normal operating range.
Alert and action levels should be established within the
specified acceptance criteria of the water required for its intended use in consideration of available technologies and the
quality required for the water. Consequently, exceeding an
alert or action level does not necessarily indicate that the
quality of produced water has become inadequate for its intended use.
4.4. Microbiological Monitoring
The main purpose of microbiological monitoring program
for pharmaceutical water processing system is to foresee any
microbiological quality deterioration of the produced water,
and to prevent any adverse effects on the quality of pharmaceutical products. Consequently, detecting all of the
microorganisms present in the water to be monitored may
not be necessary. However it is required to adopt a monitoring technique able to detect a wide range of microorganisms,
including slow growing microorganisms.
The following indicate incubation-based microbiological
monitoring techniques for pharmaceutical water processing
systems. To adopt a rapid microorganism detection technique, it is necessary to confirm in advance that the microbial counts obtained by such techniques are equivalent to those
obtained by the incubation-based monitoring techniques.
4.4.1. Media and Incubation Conditions
There are many mesophilic bacteria of heterotrophic type
that are adapted to poor nutrient water environments.
Heterotrophic bacteria may form bio-films in many pharmaceutical water processing systems, and to cause quality
deterioration of the produced water. Therefore, it is useful
to monitor microbiological quality of water by using the
R2A Agar Medium, which is excellent for growing bacteria
of oligotrophic type.
Table 2 shows examples of measurement methods, minimum sample sizes, media, and incubation periods for estimating viable counts.
Method
Water
Incubation
Period
Membrane Filtration
1.0 mL
100 mL
Minimum
1.0 mL
Sample Size
Media
Purified Water
C or
R2A Agar Medium: 20 259
Incubation
C or 30 359C
20 259
30 359C
Temperature
Standard Agar Medium: 30 359C
20 259
C or 30 359
C
Supplement I, JP XVI
The media shown in Table 2 are as follows.
Standard Agar Medium
Casein peptone
5.0 g
Yeast extract
2.5 g
Glucose
1.0 g
Agar
15.0 g
Water
1000 mL
Mix all the ingredients, and sterilize by heating in an
autoclave at 1219
C for 15 20 minutes. pH after sterilization: 6.9 7.1.
(ii) R2A Agar Medium
Peptone (casein and animal tissue)
0.5 g
Casamino acid
0.5 g
Yeast extract
0.5 g
Sodium pyruvate
0.3 g
Glucose
0.5 g
Magnesium sulfate heptahydrate
0.05 g
Soluble starch
0.5 g
Dipotassium hydrogen phosphate
0.3 g
Agar
15.0 g
Water
1000 mL
Mix all the ingredients, and sterilize by heating in an
autoclave at 1219
C for 15 20 minutes. pH after sterilization: 7.1 7.3.
(i)
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Supplement I, JP XVI
Table 3 Stage 1 Allowable Conductivity for Different
Temperatures*
Temperature
(9
C)
Allowable
Conductivity
(mScm1)
0
5
10
15
20
25
30
35
40
45
50
0.6
0.8
0.9
1.0
1.1
1.3
1.4
1.5
1.7
1.8
1.9
Temperature
C)
(9
Allowable
Conductivity
(mScm1)
55
60
65
70
75
80
85
90
95
100
2.1
2.2
2.4
2.5
2.7
2.7
2.7
2.7
2.9
3.1
Supplement I, JP XVI
4.5.2. Monitoring of TOC as the Indicator for Organic
Impurities
The acceptance criterion of TOC is specified as ``not
greater than 0.50 mg/L (500 ppb)'' in the monographs of
Purified Water and Water for Injection. However it is
recommended for each facility preparing pharmaceutical
water to conduct operation control of pharmaceutical water
processing system through TOC monitoring on produced
water based on its own alert and action levels for TOC determined individually. The following are the recommended action levels for TOC.
Action Level: 300 ppb (in-line)
400 ppb (off-line)
The Quality Standards for Drinking Water provided under the Article 4 of the Japanese Water Supply Law require
that TOC should be ``not greater than 3 mg/L (3 ppm)''.
Taking the above recommended action levels into consideration, it is also recommended for each facility to conduct
quality control of source water through TOC monitoring
based on its own alert and action levels for TOC determined
individually.
The JP specifies the Test for Total Organic Carbon
<2.59>, and normally, TOC measurement should be conducted using an apparatus which meets the requirements described in the JP method. However, if a TOC apparatus
conforms to the apparatus suitability test requirements described in ``<643> TOTAL ORGANIC CARBON'' of the
USP, or those described in the ``Methods of Analysis 2.2.44.
TOTAL ORGANIC CARBON IN WATER FOR PHARMACEUTICAL USE'' of the EP, the apparatus can be used
for the monitoring of pharmaceutical water processing system, if sufficiently pure water not contaminated with ionic
organic substances, or organic substances having nitrogen,
sulfur, phosphorus or halogen atoms in their chemical structures, is used as the source water supplied to the system.
A TOC apparatus, characterized by calculating the
amount of organic carbon from the difference in conductivity before and after the decomposition of organic substances
without separating carbon dioxide from the sample solution,
may be influenced negatively or positively, when applied to
the water specimens containing ionic organic substances, or
organic substances having nitrogen, sulfur, phosphorus or
halogen atoms in their chemical structures. Therefore, the
apparatus used for TOC monitoring should be selected appropriately in consideration of the purity of the water to be
monitored and the contamination risk in the case of apparatus failure.
4.6. Storage of Water for Injection
In storing Water for Injection temporarily, adequate
measures able to prevent microbial proliferation stringently,
such as circulating it in a loop at a high temperature must be
taken, and an appropriate storage time should also be established based on the validation studies, in consideration of
the risks of contamination and quality deterioration.
5. Points to Consider for Assuring the Quality of Pharmaceutical Water in Containers
There are some specific points to consider for assuring the
General Information
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General Information
products packed in small scale plastic containers, it is necessary to pay attention to the increase of materials released
from containers during storage.
The test of potassium permanganate-reducing substances
is retained in the specifications of pharmaceutical water in
containers, not as the most suitable method for the test of
organic impurities present in the water in containers, but as a
counter measure for performing the test of the water in containers with the same test method despite of the material
(glass, polyethylene, polypropylene, etc.) and the size (0.5
2000 mL) of the containers, and the duration of storage.
Therefore, it is recommended to adopt the test of TOC as
the alternative for the test of potassium permanganatereducing substances, and to perform quality control of pharmaceutical water in containers based on TOC measurements
under the responsibility of each manufacturer, if possible.
In such cases, it is recommended to adopt the following
values as the levels preferable to attain.
For products containing not more than 10 mL of water:
TOC
not greater than 1500 ppb
For products containing more than 10 mL of water:
TOC
not greater than 1000 ppb
As for the pharmaceutical water packed in the plastic containers made of polyethylene, polypropylene, etc., in addition to the concern for the release of materials such as
monomer, oligomers, plasticizers, etc. from plastics, it is
necessary to pay attention to the storage environment of the
products to avoid the contaminations with low molecular
volatile organics such as ethanol, or low molecular air pollutants such as nitrogen oxides, since these plastics have the
properties of permeating various gases.
5.2.3. Microbial Limit (Total Aerobic Viable Counts)
For Purified Water in Containers, it is not required to assure the sterility, but it is necessary to produce it by using
sanitary or aseptic processes in order to meet the acceptance
criterion of ``102 CFU/mL'' for total aerobic viable counts
throughout the period of their storages. It is also necessary
to take special care against microbial contamination during
its circulation. In addition, it is recommended to use them as
soon as possible after opening their seals.
The acceptance criterion of ``102 CFU/mL'' for total aerobic viable counts of Purified Water in Container is at the
same level as the action level for viable counts in the production of Purified Water (in bulk). However, different from
the case of microbiological monitoring of Purified Water,
Soybean-Casein Digest Agar Medium is used for the test of
total aerobic viable counts of Purified Water in Containers
to detect microorganisms contaminated from the surroundings during its storage and circulation.
5.3. Points to consider in the case that commercially available products of pharmaceutical water in containers are used
for the manufacture of pharmaceutical products
It is allowable to use commercially available products of
pharmaceutical water in containers (Purified Water in Containers, Sterile Purified Water in Containers and Sterile
Water for Injection in Containers) for the manufacture of
pharmaceutical products and products for clinical trial, and
Supplement I, JP XVI
for the tests of pharmaceutical products. In such cases, it is
necessary to consider the following points.
(i) When such products are used for manufacturing
pharmaceutical products, it is recommended to use
them soon after confirming their compliances to the
requirements of JP monograph from the test results
at the time of its receipt or those offered from the
supplier of the products.
(ii) In the case that such products are used for manufacturing pharmaceutical products, it is necessary to
validate the process in which the water was used as a
part of process validation of pharmaceutical products. In the case that they are used for manufacturing products for clinical trial, it is necessary to confirm that the water doesn't give any adverse effects
on the quality of the products.
(iii) The products of sterile pharmaceutical water in containers should be used only once after opening their
seals, and it must be avoided to use them again after
storage.
(iv) It is recommended to prepare a standard operation
practice (SOP) adequate for its intended use, considering that the contamination and quality deterioration of the water due to human and laboratory environmental origins might go on rapidly immediately
after opening the product seal.
Supplement I, JP XVI
General Information
2575
G9
Others
International Harmonization
Implemented in the Japanese
Pharmacopoeia Sixteenth Edition
JP16 (Supplement I)
Remarks
Crospovidone
Definition
limits of content
Identification A
Identification (1)
Identification B
Identification (2)
Identification C
Particle size
Peroxides
Water-soluble substances
Impurity A
Loss on drying
Loss on drying
Sulphated ash
Residue on ignition
Assay
Assay
Storage
JP16 (Supplement I)
Remarks
Magnesium Stearate
Definition
limits of content
Identification A
Identification
Identification B
Acidity or alkalinity
Loss on drying
Loss on drying
Limit of chloride
Limit of sulfate
Limit of cadmium
not specified
Limit of lead
not specified
Limit of nickel
not specified
Assay
Assay
2576
General Information
Supplement I, JP XVI
JP16 (Supplement I)
Remarks
Sucrose
Definition
origin
Appearance of solution
Conductivity
Conductivity
Optical rotation
Colour value
Dextrins
Dextrins
Reducing sugars
Sulphite
Loss on drying
Loss on drying
Bacterial endotoxins
Bacterial endotoxins
Labelling
origin
JP16 (Supplement I)
Remarks
General Information
Water-Solids Interactions
Water-Solids Interactions
: Determinations of the SorptionDesorption Isotherms and the Water
Activity
(Introduction)
Introduction
not specified
not specified
not specified
1. Determination of Sorption-desorption Isotherms
Principle
1.1 Principle
Methods
1.2 Methods
Principle
2.1 Principle
Method
2.2 Method
Supplement I, JP XVI
General Information
Change to read:
Jun. 2011 (Rev.2)
Harmonized items
Bulk Density and Tapped Density of
Powders
JP16 (Supplement I)
3.01 Determination of Bulk and
Tapped Densities
(Introduction)
Bulk density
Method 1: Measurement in a graduated cylinder
Procedure
Method 2: Measurement in a
volumeter
Apparatus
Procedure
Method 3: Measurement in a vessel
Apparatus
Procedure
Tapped density
Method 1
Procedure
2.1.2. Procedure
Procedure
Method 3
Procedure
1. Bulk density
Apparatus
Method 2
Remarks
2.2. Method 2
2.2.1. Procedure
2.3. Method 3
2.3.1. Procedure
Figure 1 Volumeter
Figure 3
Fig. 3.01-3
Change to read:
Jun. 2011 (Rev.2)
Harmonized items
Bacterial Endotoxins Test
JP16 (Supplement I)
4.01 Bacterial Endotoxins Test
(Introduction)
(Introduction)
Apparatus
1. Apparatus
2. Preparation of solutions
Remarks
2577
General Information
2578
Supplement I, JP XVI
Gel-clot technique
4. Gel-clot techniques
(i) Procedure
4.2.1. Procedure
(ii) Interpretation
4.2.2. Interpretation
(i) Procedure
4.3.1. Procedure
(4) Test
(i) Procedure
5.4.1. Procedure
(ii) Calculation
(iii) Interpretation
5.4.3. Interpretation
Amoebocyte lysate
Lysate TS
Water for bacterial endotoxins test
(BET)
Table 1
Table 4.01-1
Table 2
Table 4.01-2
Table 3
Table 4.01-3
Table 4
Table 4.01-4
Change to read:
Jun. 2010 (Rev.3)
Harmonized items
Dissolution
JP16 (Supplement I)
6.10 Dissolution Test
Apparatus
1. Apparatus
Remarks
JP's particular description:
The test also aims at preventing significant bioinequivalence.
Supplement I, JP XVI
Apparatus 2 (Paddle apparatus)
General Information
1.2. Apparatus for Paddle Method
(Apparatus 2)
not specified
Apparatus suitability
2. Apparatus suitability
Procedure
Apparatus 1 or 2
Immediate-release dosage forms
2579
3. Procedure
3.1. Basket Method or Paddle
Method
3.1.1. Immediate-release Dosage
Forms
Procedure
(i) Procedure
Dissolution medium
Time
(iii) Time
Procedure
(i) Procedure
Dissolution medium
Time
(iii) Time
(iii) Time
Method A
Method B
Time
Apparatus 3
not specified
Procedure
(i) Procedure
Dissolution medium
Time
(iii) Time
2580
General Information
Supplement I, JP XVI
3.2.2. Extended-release Dosage
Forms
(i) Procedure
Dissolution medium
Time
(iii) Time
4. Interpretation
4.1.1. Interpretation 1
4.1.2. Interpretation 2
Extended-release dosage forms
4.2.1. Interpretation 1
4.2.2. Interpretation 2
Delayed-release dosage forms
Nonharmonized items:
Different dissolution medium.
Deletion of disharmonized part on the
value Q.
JP's particular description:
Setting of Interpretation 2.
4.3.1. Interpretation 1
4.3.2. Interpretation 2
Acceptance Table 1
Acceptance Table 2
Acceptance Table 3
Acceptance Table 4
Figure 3 Apparatus 3
not specified
Figure 4 Apparatus 4
(top) large cell for tablets and capsules
(bottom) tablet holder for the large
cell
Figure 5 Apparatus 4
(top) small cell for tablets and capsules
(bottom) tablet holder for the small
cell
Supplement I, JP XVI
General Information
Change to read:
Jun. 2010 (Rev.2)
Harmonized items
Citric Acid, Anhydrous
JP16 (Supplement I)
Remarks
Definition
limits of content
Identification
Identification
Appearance of solution
Oxalic acid
Sulphates
Aluminium
not specified
Water
Water
Sulphated ash
Residue on ignition
Assay
Assay
Change to read:
Jun. 2010 (Rev.2)
Harmonized items
Citric Acid Monohydrate
JP16 (Supplement I)
Citric Acid Hydrate
Definition
limits of content
Identification
Identification
Appearance of solution
Oxalic acid
Sulphates
Aluminium
not specified
Water
Water
Sulphated ash
Residue on ignition
Assay
Assay
Remarks
2581
2582
General Information
Supplement I, JP XVI
Change to read:
Jun. 2012 (Rev.1, Corr.1)
Harmonized items
Cellacefate
JP16 (Supplement I)
Remarks
Cellacefate
Definition
Identification
Identification
Viscosity
Viscosity
Water
Water
Residue on ignition
Residue on ignition
Phthalyl content
Content of acetyl
Change to read:
Nov. 2010 (Rev.4)
Harmonized items
Anhydrous Lactose
JP16 (Supplement I)
Anhydrous Lactose
Definition
origin
Identification
Specific rotation
Optical rotation
Acidity or alkalinity
Loss on drying
Loss on drying
Residue on ignition
Residue on ignition
Water
Water
Isomer ratio
Microbial contamination
Microbial limit
Remarks
Supplement I, JP XVI
General Information
2583
Change to read:
Nov. 2011 (Rev.1, Corr.1)
Harmonized items
Ethyl Parahydroxybenzoate
JP16 (Supplement I)
Remarks
Ethyl Parahydroxybenzoate
Definition
limits of content
Identification A
Melting point
Identification B
Identification
Appearance of solution
Acidity
Related substances
Sulphated ash
Residue on ignition
Assay
Assay
Change to read:
Jun. 2010 (Rev.1)
Harmonized items
Butyl Parahydroxybenzoate
JP16 (Supplement I)
Remarks
Butyl Parahydroxybenzoate
Definition
limits of content
Identification A
Melting point
Identification B
Identification
Appearance of solution
Acidity
Related substances
Sulphated ash
Residue on ignition
Assay
Assay
2584
General Information
Supplement I, JP XVI
Change to read:
Nov. 2011 (Rev.1, Corr.1)
Harmonized items
JP16 (Supplement I)
Propyl Parahydroxybenzoate
Propyl Parahydroxybenzoate
Definition
limits of content
Identification A
Melting point
Identification B
Identification
Appearance of solution
Acidity
Related substances
Sulphated ash
Residue on ignition
Assay
Assay
Remarks
Change to read:
Nov. 2011 (Rev.1, Corr.1)
Harmonized items
Methyl Parahydroxybenzoate
JP16 (Supplement I)
Remarks
Methyl Parahydroxybenzoate
Definition
limits of content
Identification A
Melting point
Identification B
Identification
Appearance of solution
Acidity
Related substances
Sulphated ash
Residue on ignition
Assay
Assay
Change to read:
Jun. 2011 (Rev.2, Corr.1)
Harmonized items
Benzyl Alcohol
JP16 (Supplement I)
Benzyl Alcohol
Definition
limits of content
Refractive index
Refractive index
Acidity
Peroxide value
Residue on evaporation
Assay
Assay
Remarks
Supplement I, JP XVI
General Information
Change to read:
Jun. 2011 (Rev.1)
Harmonized items
JP16 (Supplement I)
Definition
limits of content
Identification (1)
Identification (1)
Identification (2)
Identification (2)
Acid-insoluble substances
Chloride
Sulfate
Carbonate
Barium
Loss on ignition
Loss on ignition
Assay
Assay
Remarks
Change to read:
Jun. 2011 (Rev.1)
Harmonized items
Dibasic Calcium Phosphate
JP16 (Supplement I)
Dibasic Calcium Phosphate Hydrate
Definition
limits of content
Identification (1)
Identification (1)
Identification (2)
Identification (2)
Acid-insoluble substances
Chloride
Sulfate
Carbonate
Barium
Loss on ignition
Loss on ignition
Assay
Assay
Remarks
2585
INDEX
A
Absorptive Cream, 313
Acacia, 1593
Powdered, 1593
Acebutolol Hydrochloride, 313
Aceglutamide Aluminum, 314
Acemetacin, 315
Capsules, 316
Tablets, 317
Acetaminophen, 318
Acetazolamide, 319
Acetic Acid, 319
Glacial, 320
Acetohexamide, 320
Acetylcholine Chloride for Injection,
322
Acetylcysteine, 322
Acetylsalicylic Acid, 400
Tablets, 400
Achyranthes Root, 1594
Aciclovir, 323
for Injection, 2359
for Syrup, 325
Injection, 325
Ointment, 2359
Syrup, 326
Aclarubicin Hydrochloride, 327
Acrinol
and Zinc Oxide Oil, 329, 2360
and Zinc Oxide Oil, Compound,
330
and Zinc Oxide Ointment, 330
Hydrate, 328, 2360
Actinomycin D, 331, 2360
Adrenaline, 331
Injection, 332
Solution, 332
Adsorbed
Diphtheria Toxoid for Adult Use,
738
Diphtheria-Purified Pertussis-Tetanus Combined Vaccine, 739
Diphtheria-Tetanus Combined Toxoid, 739
Habu-venom Toxoid, 908
Hepatitis B Vaccine, 909
Purified Pertussis Vaccine, 1230
Tetanus Toxoid, 1479
Afloqualone, 333
Agar, 1594
Powdered, 1595
Ajmaline, 334
Tablets, 334
Akebia Stem, 1595, 2495
Alacepril, 335
Tablets, 336
L-Alanine, 337
Albumin Tannate, 338
Alcohol, 802
Dehydrated, 803
for Disinfection, 804
Aldioxa, 339, 2360
Granules, 2361
Tablets, 2361
Alendronate
Sodium Hydrate, 340
Sodium Injection, 341
Sodium Tablets, 342
Alimemazine Tartrate, 343
Alisma
Rhizome, 1595, 2495
Rhizome, Powdered, 1596, 2495
Tuber, 2495
Tuber, Powdered, 2495
Allopurinol, 344
Tablets, 344
Alminoprofen, 345
Tablets, 346
Aloe, 1596
Powdered, 1597
Alpinia Officinarum Rhizome, 1598,
2495
Alprazolam, 347
Alprenolol Hydrochloride, 348
Alprostadil, 349
Alfadex, 352
Injection, 350
Alum, 357
Solution, 358
Powder, Salicylated, 1371
Aluminum
Acetylsalicylate, 401
Monostearate, 356
Potassium Sulfate Hydrate, 357
Silicate Hydrate with Silicon Dioxide,
1598
Silicate, Natural, 354
Silicate, Synthetic, 356
Sucrose Sulfate Ester, 1429
Amantadine Hydrochloride, 358
Ambenonium Chloride, 359
Amidotrizoic Acid, 360
Amikacin Sulfate, 361
for Injection, 362
Injection, 362
Aminoacetic Acid, 895
Aminobenzylpenicillin
Anhydrous, 383
Hydrate, 384
Sodium, 385
Aminophylline
Hydrate, 363
Injection, 363
Amiodarone Hydrochloride, 364
Tablets, 366, 2362
Amitriptyline Hydrochloride, 367
Tablets, 367
Amlexanox, 368
Tablets, 370
Amlodipine Besilate, 370
Orally Disintegrating Tablets, 2363
Tablets, 372
Ammonia Water, 373
Amobarbital, 373
Sodium for Injection, 374, 2364
Amomum Seed, 1599
Powdered, 1599, 2495
Amosulalol Hydrochloride, 375
Tablets, 376
Amoxapine, 377
Amoxicillin, 378
Capsules, 379
Hydrate, 378
Amphotericin B, 380
for Injection, 381
Syrup, 382
Tablets, 382
Ampicillin
Anhydrous, 383
Ethoxycarbonyloxyethyl Hydrochloride, 415
Hydrate, 384
Sodium, 385
Sodium for Injection, 386
Ampicillinphthalidyl Hydrochloride,
1450
Amyl Nitrite, 387
Anemarrhena Rhizome, 1599
Anesthamine, 809
Anesthetic Ether, 805
Angelica Dahurica Root, 1599
Anhydrous
Aminobenzylpenicillin, 383
Ampicillin, 383
Caffeine, 489
Citric Acid, 645, 2387
Dibasic Calcium Phosphate, 504,
2375
Ethanol, 803, 2413
Lactose, 1018, 2436
Light, Silicic Acid, 1385
Antipyrine, 388
Apricot Kernel, 1600, 2496
Water, 1601
Aprindine Hydrochloride, 388
Capsules, 389
2587
2588
Index
Supplement I, JP XVI
B
Bacampicillin Hydrochloride, 415
Bacitracin, 416
Baclofen, 417
Tablets, 418
Bakumondoto Extract, 1606
Bamethan Sulfate, 419
Barbital, 419
Barium Sulfate, 420
Bear Bile, 1608
Bearberry Leaf, 1608, 2498
Bitter
Cardamon, 1611
Orange Peel, 1612
Tincture, 1613
Bleomycin
Hydrochloride, 465
Sulfate, 467
Boric Acid, 468
Bromazepam, 469
Bromhexine Hydrochloride, 470
Bromocriptine Mesilate, 471
Bromovalerylurea, 471
Brotizolam, 2370
Brown Rice, 1613
Bucillamine, 472
Tablets, 473
Bucumolol Hydrochloride, 474
Bufetolol Hydrochloride, 475
Buformin Hydrochloride, 476
Enteric-coated Tablets, 476
Tablets, 478
Bumetanide, 479
Bunazosin Hydrochloride, 479
Bupivacaine Hydrochloride Hydrate,
2371
Bupleurum Root, 1613, 2499
Bupranolol Hydrochloride, 480
Buprenorphine Hydrochloride, 481
Burdock Fruit, 1614
Burnt Alum, 357
Busulfan, 482
Butenafine Hydrochloride, 483
Cream, 484
Solution, 484
Spray, 485
Butropium Bromide, 485
Butyl Parahydroxybenzoate, 486,
2372
C
Cacao Butter, 487
Cadralazine, 487
Tablets, 488
Caffeine
and Sodium Benzoate, 491
Anhydrous, 489
Hydrate, 490
Calciferol, 787
Calcitonin (Salmon), 492
Calcium
Chloride Hydrate, 497
Chloride Injection, 497
Folinate, 498
Gluconate Hydrate, 499
Hydroxide, 500
Lactate Hydrate, 500
Leucovorin, 498
Oxide, 501
Pantothenate, 501, 2374
Paraaminosalicylate Granules, 503
Paraaminosalicylate Hydrate, 502
Polystyrene Sulfonate, 506
Supplement I, JP XVI
Stearate, 508
Calumba, 1615
Powdered, 1615
Camellia Oil, 508
Camostat Mesilate, 509
Camphor
Synthetic, 510
d-Camphor, 510
dl-Camphor, 510
Candesartan Cilexetil, 511, 2376
Tablets, 512
Capsicum, 1615
and Salicylic Acid Spirit, 1618
Powdered, 1616, 2499
Tincture, 1617
Capsules, 514
Capsules
Acemetacin, 316
Amoxicillin, 379
Aprindine Hydrochloride, 389
Cefaclor, 529
Cefadroxil, 535
Cefalexin, 537
Cefdinir, 553
Cefixime, 561
Cinoxacin, 643
Clindamycin Hydrochloride, 651
Clofibrate, 658
Clorazepate Dipotassium, 665
Doxifluridine, 754
Droxidopa, 760
Emedastine Fumarate Extendedrelease, 2403
Flopropione, 842
Flurazepam, 854, 2420
Indometacin, 961
Methotrexate, 1093
Nifedipine Extended-release, 2457
Nizatidine, 1172
Rifampicin, 1348
Roxatidine Acetate Hydrochloride
Extended-release, 1361
Sodium Iodide (123I), 1404
Sodium Iodide (131I), 1404
Sulpiride, 1442
Tranexamic Acid, 1519
Tranilast, 2485
Ubenimex, 1547
Vitamin A, 1566
Vitamin A Oil, 1566
Captopril, 514
Carbamazepine, 515
Carbazochrome Sodium Sulfonate Hydrate, 516
Carbetapentane Citrate, 1223
Carbetapentene Citrate, 1223
Carbidopa Hydrate, 517
L-Carbocisteine, 518
Carbolic Acid, 1236
for Disinfection, 1236
Liquefied, 1237
Carbon Dioxide, 518
Carboplatin, 2376
Index
Injection, 2378
Carboxymethylcellulose, 519
Calcium, 519
Sodium, 520
Cardamon, 1618
Carmellose, 519
Calcium, 519
Sodium, 520
Carmofur, 521
Carnauba Wax, 522
Carteolol Hydrochloride, 522
Carumonam Sodium, 523
Carvedilol, 525
Tablets, 526
Cassia Seed, 1618
Castor Oil, 527
Aromatic, 528
Catalpa Fruit, 1619
Cefaclor, 528
Capsules, 529
Compound Granules, 532
Fine Granules, 531
Cefadroxil, 534
Capsules, 535
for Syrup, 535
Cefalexin, 536
Capsules, 537
for Syrup, 539
Cefalotin Sodium, 540
Cefatrizine Propylene Glycolate, 541
for Syrup, 542
Cefazolin Sodium, 543, 2379
for Injection, 544
Hydrate, 545
Cefbuperazone Sodium, 546
Cefcapene Pivoxil Hydrochloride
Fine Granules, 550
Hydrate, 548
Tablets, 551
Cefdinir, 552, 2379
Capsules, 553
Fine Granules, 554
Cefditoren Pivoxil, 555
Fine Granules, 556, 2379
Tablets, 556
Cefepime Dihydrochloride
for Injection, 559
Hydrate, 557
Cefixime
Capsules, 561
Hydrate, 560
Cefmenoxime Hydrochloride, 562
Cefmetazole Sodium, 564
for Injection, 565
Cefminox Sodium Hydrate, 565
Cefodizime Sodium, 566
Cefoperazone Sodium, 568, 2380
Cefotaxime Sodium, 569
Cefotetan, 570
Cefotiam
Hexetil Hydrochloride, 572
Hydrochloride, 575
Hydrochloride for Injection, 576
2589
2590
Index
Cholecalciferol, 630
Cholera Vaccine, 630
Cholesterol, 631
Chorionic Gonadotrophin, 897
for Injection, 899
Chotosan Extract, 1619
Chrysanthemum Flower, 1622, 2500
Cibenzoline Succinate, 632
Tablets, 632
Ciclacillin, 634
Ciclosporin, 634
A, 634
Cilastatin Sodium, 636
Cilazapril
Hydrate, 637
Tablets, 638
Cilostazol, 639
Tablets, 640
Cimetidine, 641
Cimicifuga Rhizome, 1622
Cinchocaine Hydrochloride, 709
Cinnamon
Bark, 1623, 2500
Bark, Powdered, 1623
Oil, 1623
Cinoxacin, 642
Capsules, 643
Cisplatin, 644
Citric Acid
Anhydrous, 645, 2387
Hydrate, 645, 2388
Citrus Unshiu Peel, 1624, 2501
Clarithromycin, 646
Tablets, 647
Clebopride Malate, 649
Clemastine Fumarate, 650
Clematis Root, 1625
Clindamycin
Hydrochloride, 650, 2388
Hydrochloride Capsules, 651
Phosphate, 652
Phosphate Injection, 653
Clinofibrate, 654
Clobetasol Propionate, 655
Clocapramine Hydrochloride Hydrate,
656
Clofedanol Hydrochloride, 657
Clofibrate, 657
Capsules, 658
Clomifene Citrate, 659, 2389
Tablets, 660, 2389
Clomipramine Hydrochloride, 661
Clonazepam, 661
Clonidine Hydrochloride, 662
Cloperastine Hydrochloride, 663
Clorazepate Dipotassium, 664
Capsules, 665
Clotiazepam, 666
Clotrimazole, 667
Clove, 1625
Oil, 1626
Powdered, 1625, 2501
Cloxacillin Sodium Hydrate, 668
Supplement I, JP XVI
Cloxazolam, 669
Cnidium
Monnieri Fruit, 1626, 2501
Rhizome, 1626, 2501
Rhizome, Powdered, 1627, 2501
Cocaine Hydrochloride, 670
Coconut Oil, 670
Cod Liver Oil, 674
Codeine Phosphate
Hydrate, 671
Powder, 1z, 671, 2389
Powder, 10z, 672, 2390
Tablets, 672
Coix Seed, 1627
Powdered, 1627, 2501
Colchicine, 674
Colestimide, 2390
Tablets, 2391
Colistin
Sodium Methanesulfonate, 676
Sulfate, 677
Compound
Acrinol and Zinc Oxide Oil, 330
Diastase and Sodium Bicarbonate
Powder, 706
Hycodenone Injection, 1197
Iodine Glycerin, 967
Methyl Salicylate Spirit, 1107
Oxycodone and Atropine Injection,
1197
Oxycodone Injection, 1197
Phellodendron Powder for
Cataplasm, 1709
Rhubarb and Senna Powder, 1725
Salicylic Acid Spirit, 1372
Scopolia Extract and Diastase Powder, 1744
Thianthol and Salicylic Acid Solution, 1488
Vitamin B Powder, 1567
Concentrated
Glycerin, 893
Glycerol, 893
Condurango, 1628, 2502
Fluidextract, 1628
Coptis Rhizome, 1628, 2502
Powdered, 1629, 2502
Corn
Oil, 678
Starch, 678, 2392
Cornus Fruit, 1630
Cortisone Acetate, 679
Corydalis Tuber, 1631, 2503
Powdered, 1632, 2503
Crataegus Fruit, 1632, 2503
Creams
Absorptive, 313
Betamethasone Valerate and Gentamicin Sulfate, 450
Butenafine Hydrochloride, 484
Hydrophilic, 934
Ibuprofen Piconol, 2428
Ketoconazole, 1006
D
Daiokanzoto Extract, 1634
Danazol, 691
Dantrolene Sodium Hydrate, 691
Daunorubicin Hydrochloride, 692,
2394
Deferoxamine Mesilate, 693
Dehydrated Alcohol, 803
Dehydrocholate Sodium Injection,
696
Dehydrocholic Acid, 694
Injection, 696
Purified, 695
Demethylchlortetracycline Hydrochloride, 696
Dental
Antiformin, 387
Iodine Glycerin, 968
Paraformaldehyde Paste, 1215
Phenol with Camphor, 1237
Sodium Hypochlorite Solution, 387
Triozinc Paste, 1540
Dermatol, 461
Deslanoside, 698
Injection, 698
Dexamethasone, 699
Dextran
40, 700
40 Injection, 701
70, 702
Sulfate Sodium Sulfur 5, 703
Sulfate Sodium Sulfur 18, 704
Dextrin, 704
Dextromethorphan Hydrobromide Hydrate, 705
Diagnostic Sodium Citrate Solution,
1399
Diastase, 706
Supplement I, JP XVI
and Sodium Bicarbonate Powder,
706
and Sodium Bicarbonate Powder,
Compound, 706
Diazepam, 706
Tablets, 707
Dibasic
Calcium Phosphate, Anhydrous,
504, 2375
Calcium Phosphate Hydrate, 504,
2375
Sodium Phosphate Hydrate, 1408
Dibekacin Sulfate, 708, 2395
Ophthalmic Solution, 709
Dibucaine Hydrochloride, 709
Dichlorphenamide, 711
Tablets, 712
Diclofenac Sodium, 710
Diclofenamide, 711
Tablets, 712
Dicloxacillin Sodium Hydrate, 713
Diethylcarbamazine Citrate, 713
Tablets, 714, 2396
Difenidol Hydrochloride, 715
Diflucortolone Valerate, 715
Digenea, 1635, 2503
Digitoxin, 717
Tablets, 718
Digoxin, 719
Injection, 720
Tablets, 721
Dihydrocodeine Phosphate, 723
Powder, 1z, 724, 2396
Powder, 10z, 724, 2397
Dihydroergotamine Mesilate, 725
Dihydroergotoxine Mesilate, 726
Dilazep Hydrochloride Hydrate, 728
Diltiazem Hydrochloride, 729
Dilute
Hydrochloric Acid, 925
Iodine Tincture, 967
Diluted Opium Powder, 1184
Dimemorfan Phosphate, 730
Dimenhydrinate, 731
Tablets, 732
Dimercaprol, 732
Injection, 733
Dimorpholamine, 733
Injection, 734
Dinoprost, 735
Dionin, 813
Dioscorea Rhizome, 1635
Powdered, 1636
Diphenhydramine, 735
and Bromovalerylurea Powder, 736
Hydrochloride, 737
Phenol and Zinc Oxide Liniment,
737
Tannate, 738
Diphenylhydantoin, 1242
Powder, 1242
Sodium for Injection, 1244
Tablets, 1243
Index
Diphtheria
Antitoxin, Equine, Freeze-dried,
738
-Purified Pertussis-Tetanus Combined Vaccine, Absorbed, 739
-Tetanus Combined Toxoid, 739
-Tetanus Combined Toxoid, Absorbed, 739
Toxoid, 738
Toxoid for Adult Use, Absorbed,
738
Dipyridamole, 739
Disodium Edetate Hydrate, 1400
Disopyramide, 740
Distigmine Bromide, 741
Tablets, 741
Disulfiram, 742
Dobutamine Hydrochloride, 743
Dolichos Seed, 1636
Domperidone, 744
Donepezil Hydrochloride, 745, 2397
Fine Granules, 746
Tablets, 747
Dopamine Hydrochloride, 749
Injection, 749
Dorzolamide Hydrochloride, 2397
Ophthalmic Solution, 2399
Doxapram Hydrochloride Hydrate,
750
Doxazosin Mesilate, 751
Tablets, 752
Doxifluridine, 753
Capsules, 754
Doxorubicin Hydrochloride, 755
for Injection, 756
Doxycycline Hydrochloride Hydrate,
757
Dried
Aluminum Hydroxide Gel, 353
Aluminum Hydroxide Gel Fine Granules, 354
Aluminum Potassium Sulfate, 357
Sodium Carbonate, 1395
Sodium Sulfite, 1417
Thyroid, 1494
Yeast, 1580
Droperidol, 758
Droxidopa, 759
Capsules, 760
Fine Granules, 761
Dydrogesterone, 762
Tablets, 762
E
Ebastine, 763
Orally Disintegrating Tablets, 764
Tablets, 765
Ecabet Sodium
Granules, 768
Hydrate, 767
Ecarazine Hydrochloride, 1510
Ecothiopate Iodide, 769
2591
Edaravone, 2400
Injection, 2401
Edrophonium Chloride, 770
Injection, 770
EDTA Sodium Hydrate, 1400
Elcatonin, 771
Eleutherococcus Senticosus Rhizome,
1636
Emedastine Fumarate, 2402
Extended-release Capsules, 2403
Emorfazone, 774
Tablets, 774
Enalapril Maleate, 775
Tablets, 777
Enflurane, 778
Enoxacin Hydrate, 779
Enviomycin Sulfate, 780
Epalrestat, 2404
Tablets, 2405
Eperisone Hydrochloride, 781
Ephedra Herb, 1637, 2504
Ephedrine Hydrochloride, 782
Injection, 783
Powder, 783
Powder, 10z, 783, 2406
Tablets, 784
Epimedium Herb, 1638, 2504
Epinephrine, 331
Injection, 332
Solution, 332
Epirizole, 785
Epirubicin Hydrochloride, 786
Epoetin
Alfa (Genetical Recombination),
2407
Beta (Genetical Recombination),
2410
Ergocalciferol, 787
Ergometrine Maleate, 788
Injection, 789
Tablets, 789
Ergotamine Tartrate, 790
Erythromycin, 791
Enteric-Coated Tablets, 792
Ethylsuccinate, 793
Lactobionate, 793
Stearate, 794
Estazolam, 795
Estradiol Benzoate, 796
Injection, 796
Injection (Aqueous Suspension),
797
Estriol, 798
Injection (Aqueous Suspension),
798
Tablets, 799
Etacrynic Acid, 800
Tablets, 801
Ethacridine Lactate, 328
Ethambutol Hydrochloride, 801
Ethanol, 802, 2413
Anhydrous, 803, 2413
for Disinfection, 804, 2413
2592
Index
Ethenzamide, 804
Ether, 805
Anesthetic, 805
Ethinylestradiol, 806
Tablets, 806
Ethionamide, 807
Ethosuximide, 808
Ethoxybenzamide, 804
Ethyl
Aminobenzoate, 809
Cysteine Hydrochloride, 809
L-Cysteine Hydrochloride, 809
Icosapentate, 810
Parahydroxybenzoate, 811, 2413
Ethylenediamine, 812
Ethylmorphine Hydrochloride Hydrate, 813
Etidronate Disodium, 813
Tablets, 814
Etilefrine Hydrochloride, 815
Tablets, 815
Etizolam, 817
Fine Granules, 817
Tablets, 819
Etodolac, 820
Etoposide, 821
Eucalyptus Oil, 822
Eucommia Bark, 1638
Euodia Fruit, 1639
Exsiccated Gypsum, 1655
Extracts
Bakumondoto, 1606
Belladonna, 1610
Chotosan, 1619
Crude Glycyrrhiza, 1651
Daiokanzoto, 1634
Glycyrrhiza, 1651
Goshajinkigan, 1652
Hachimijiogan, 1656
Hangekobokuto, 1659
Hangeshashinto, 2508
Hochuekkito, 1661
Juzentaihoto, 1671
Kakkonto, 1674
Kamishoyosan, 1676
Keishibukuryogan, 1679
Mukoi-Daikenchuto, 1691
Nux Vomica, 1696
Orengedokuto, 1698, 2513
Rikkunshito, 1725
Ryokeijutsukanto, 1729
Saibokuto, 1732
Saikokeishito, 1734
Saireito, 1737, 2520
Scopolia, 1742
Shakuyakukanzoto, 1752
Shimbuto, 1753
Shosaikoto, 1756, 2522
Shoseiryuto, 1758
Tokishakuyakusan, 2524
Supplement I, JP XVI
F
Famotidine, 822
for Injection, 823
Injection, 824
Powder, 825
Tablets, 826
Faropenem Sodium
for Syrup, 828
Hydrate, 827
Tablets, 829
Felbinac, 831
Fenbufen, 831
Fennel, 1639
Oil, 1640
Powdered, 1639, 2504
Fentanyl Citrate, 832
Ferrous Sulfate Hydrate, 832
Fexofenadine Hydrochloride, 833,
2414
Tablets, 2415
Filgrastim (Genetical Recombination),
2416
Injection, 2419
Fine Granules
Cefaclor, 531
Cefcapene Pivoxil Hydrochloride,
550
Cefdinir, 554
Cefditoren Pivoxil, 556, 2379
Cefteram Pivoxil, 590
Donepezil Hydrochloride, 746
Dried Aluminum Hydroxide Gel,
354
Droxidopa, 761
Etizolam, 817
Haloperidol, 910
Irsogladine Maleate, 977
Levofloxacin, 2443
Nifedipine, 2459
Nifedipine Enteric, 2458
Pravastatin Sodium, 1278, 2466
Precipitated Calcium Carbonate,
495
Probucol, 1294
Quetiapine Fumarate, 2470
Risperidone, 1351
Sarpogrelate Hydrochloride, 1375
Tranilast, 2487
Troxipide, 1541
Flavin Adenine Dinucleotide Sodium,
834
Flavoxate Hydrochloride, 836
Flecainide Acetate, 836
Tablets, 838
Flomoxef Sodium, 839
for Injection, 840
Flopropione, 841
Capsules, 842
Fluconazole, 843
Flucytosine, 844
Fludiazepam, 845
Supplement I, JP XVI
G
Gabexate Mesilate, 875
b-Galactosidase
(Aspergillus), 876
(Penicillium), 876
Gallium (67Ga) Citrate Injection, 878
Gambir, 1641
Powdered, 1641, 2504
Gardenia Fruit, 1642
Powdered, 1642, 2505
Gas Gangrene Antitoxin, Equine, 878
Gastrodia Tuber, 1643
Gefarnate, 878
Gelatin, 879
Purified, 880
Gentamicin Sulfate, 881
Ophthalmic Solution, 882
Gentian, 1644, 2505
and Sodium Bicarbonate Powder,
1645
Powdered, 1644
Geranium Herb, 1645
Powdered, 1645, 2505
Ginger, 1645, 2505
Powdered, 1646, 2506
Processed, 1719, 2517
Ginseng, 1646, 2507
Powdered, 1647, 2507
Glacial Acetic Acid, 320
Glehnia Root and Rhizome, 1649
Glibenclamide, 883
Gliclazide, 883
Glimepiride, 884
Tablets, 886, 2420
Glucose, 888
Injection, 888
L-Glutamic Acid, 889
L-Glutamine, 890
Glutathione, 891
Glycerin, 892
and Potash Solution, 894
Concentrated, 893
Glycerol, 892
Concentrated, 893
Monostearate, 894
Glycine, 895
Glycyrrhiza, 1649, 2507
Extract, 1651
Extract, Crude, 1651
Powdered, 1650, 2508
Gonadorelin Acetate, 895
Goshajinkigan Extract, 1652
Gramicidin, 903
Granules
Aldioxa, 2361
Azelastine Hydrochloride, 411
Calcium Paraaminosalicylate, 503
Cefaclor Compound, 532
Ecabet Sodium, 768
L-Isoleucine, L-Leucine and L-Valine,
984
Index
Pas-calcium, 503
Ursodeoxycholic Acid, 1554
Griseofulvin, 904
Tablets, 905
Guaiacol Glyceryl Ether, 906
Guaifenesin, 906
Guanabenz Acetate, 907
Guanethidine Sulfate, 908
Gypsum, 1655
H
Hachimijiogan Extract, 1656
Haloperidol, 909
Fine Granules, 910
Tablets, 911
Halothane, 912
Haloxazolam, 913
Hangekobokuto Extract, 1659
Hangeshashinto Extract, 2508
Hemp Fruit, 1661, 2511
Heparin
Calcium, 914, 2422
Sodium, 916, 2423
Sodium Injection, 919, 2425
L-Histidine, 920
Hydrochloride Hydrate, 920
Hochuekkito Extract, 1661
Homatropine Hydrobromide, 921
Homochlorcyclizine Hydrochloride,
922
Honey, 1664
Houttuynia Herb, 1665
Human
Chorionic Gonadotrophin, 897
Chorionic Gonadotrophin for Injection, 899
Menopausal Gonadotrophin, 899,
2421
Normal Immunoglobulin, 923
Hycoato Injection, 1197
Hydralazine Hydrochloride, 923
for Injection, 923
Powder, 924, 2425
Tablets, 924
Hydrochloric Acid, 925
Dilute, 925
Lemonade, 926
Hydrochlorothiazide, 926
Hydrocortisone, 927
Acetate, 928
and Diphenhydramine Ointment,
929
Butyrate, 929
Sodium Phosphate, 930
Sodium Succinate, 931
Succinate, 932
Hydrocotarnine Hydrochloride Hydrate, 933
Hydrogenated Oil, 934
Hydrophilic
Cream, 934
Petrolatum, 1231
2593
I
Ibudilast, 943
Ibuprofen, 944
Piconol, 2428
Piconol Cream, 2428
Piconol Ointment, 2429
Ichthammol, 944
Idarubicin Hydrochloride, 945
for Injection, 946
Idoxuridine, 947
Ophthalmic Solution, 947
Ifenprodil Tartrate, 948
Imidapril Hydrochloride, 949
Tablets, 950
Imipenem
and Cilastatin Sodium for Injection,
953
Hydrate, 952
Imipramine Hydrochloride, 954
Tablets, 955
Immature Orange, 1665
Imperata Rhizome, 1665
Indapamide, 956
Tablets, 957
Indenolol Hydrochloride, 958
Indigocarmine, 959
Injection, 959
Indium (111In) Chloride Injection, 960
Indometacin, 960
Capsules, 961
Suppositories, 962
Influenza HA Vaccine, 963
Injection
Acetylcholine Chloride for, 322
Aciclovir, 325
Aciclovir for, 2359
Adrenaline, 332
Alendronate Sodium, 341
Alprostadil, 350
Amikacin Sulfate for, 362
Amikacin Sulfate, 362
Aminophylline, 363
Amobarbital Sodium for, 374, 2364
Amphotericin B for, 381
Ampicillin Sodium for, 386
Arbekacin Sulfate, 392
L-Arginine Hydrochloride, 395
Ascorbic Acid, 398
Atropine Sulfate, 407
Aztreonam for, 414
2594
Index
Injection (continued )
Benzylpenicillin Potassium for, 437
Calcium Chloride, 497
Carboplatin, 2378
Cefazolin Sodium for, 544
Cefepime Dihydrochloride for, 559
Cefmetazole Sodium for, 565
Cefotiam Hydrochloride for, 576
Cefozopran Hydrochloride for, 577
Ceftazidime for, 588
Chlorpheniramine Maleate, 623
Chlorpromazine Hydrochloride,
627
Chorionic Gonadotrophin for, 899
Clindamycin Phosphate, 653
Compound Hycodenone, 1197
Compound Oxycodone, 1197
Compound Oxycodone and Atropine, 1197
Cyanocobalamin, 685
Dehydrocholate Sodium, 696
Dehydrocholic Acid, 696
Deslanoside, 698
Dextran 40, 701
Digoxin, 720
Dimercaprol, 733
Dimorpholamine, 734
Diphenylhydantoin Sodium for,
1244
Dopamine Hydrochloride, 749
Doxorubicin Hydrochloride for,
756
Edaravone, 2401
Edrophonium Chloride, 770
Ephedrine Hydrochloride, 783
Epinephrine, 332
Ergometrine Maleate, 789
Estradiol Benzoate, 796
Estradiol Benzoate, (Aqueous Suspension), 797
Estriol, (Aqueous Suspension), 798
Famotidine for, 823
Famotidine, 824
Filgrastim (Genetical Recombination), 2419
Flomoxef Sodium for, 840
Folic Acid, 862
Fosfomycin Sodium for, 868
Fructose, 870
Furosemide, 872
Gallium (67Ga) Citrate, 878
Glucose, 888
Heparin Sodium, 919, 2425
Human Chorionic Gonadotrophin
for, 899
Hycoato, 1197
Hydralazine Hydrochloride for,
923
Idarubicin Hydrochloride for, 946
Imipenem and Cilastatin Sodium for,
953
Indigocarmine, 959
Indium (111In) Chloride, 960
Supplement I, JP XVI
Iodinated (131I) Human Serum Albumin, 966
Iohexol, 2432
Isepamicin Sulfate, 981
Isoniazid, 986
Isotonic Sodium Chloride, 1397
Levallorphan Tartrate, 1029
Lidocaine Hydrochloride, 1035
Lidocaine, 1035
Lincomycin Hydrochloride, 1038
Magnesium Sulfate, 1059
D-Mannite, 1064
D-Mannitol, 1064
Meglumine Iotalamate, 1073
Meglumine Sodium Amidotrizoate,
1074
Meglumine Sodium Iodamide, 1075
Mepivacaine Hydrochloride, 1082
Meropenem for, 1087
Metenolone Enanthate, 1089
Minocycline Hydrochloride for,
1124
Mitomycin C for, 1127
Morphine and Atropine, 1130
Morphine Hydrochloride, 1131
Nartograstim for, (Genetical Recombination), 2456
Neostigmine Methylsulfate, 1151
Nicardipine Hydrochloride, 1153
Nicotinic Acid, 1162
Noradrenaline, 1174
Noradrenaline Hydrochloride, 1174
Norepinephrine Hydrochloride,
1174
Norepinephrine, 1174
Operidine, 1231
Opium Alkaloids and Atropine,
1187
Opium Alkaloids and Scopolamine,
1188
Opium Alkaloids Hydrochlorides,
1186
Oxytocin, 1205
Ozagrel Sodium for, 1207
Papaverine Hydrochloride, 1212
Peplomycin Sulfate for, 1226
Pethidine Hydrochloride, 1231
Phenolsulfonphthalein, 1239
Phenytoin Sodium for, 1244
Piperacillin Sodium for, 1255
Prednisolone Sodium Succinate for,
1290
Procainamide Hydrochloride, 1296
Procaine Hydrochloride, 1299
Progesterone, 1304
Protamine Sulfate, 1317
Pyridoxine Hydrochloride, 1324
Reserpine, 1338
Riboflavin Phosphate, 1345
Riboflavin Sodium Phosphate,
1345
Roxatidine Acetate Hydrochloride
for, 1363
Supplement I, JP XVI
Powdered, 1667, 2511
Syrup, 1667
Ipratropium Bromide Hydrate, 974
Ipriflavone, 975
Tablets, 976
Iproveratril Hydrochloride, 1561
Irsogladine Maleate, 976
Fine Granules, 977
Tablets, 978
Isepamicin Sulfate, 980
Injection, 981
Isoflurane, 982
L-Isoleucine, 983
L-Leucine and L-Valine Granules,
984
Isoniazid, 985
Injection, 986
Tablets, 986
l-Isoprenaline Hydrochloride, 987
Isopropanol, 988
Isopropyl Alcohol, 988
Isopropylantipyrine, 989
Isosorbide, 989
Dinitrate, 990
Dinitrate Tablets, 991
Mononitrate 70z/Lactose 30z,
2433
Mononitrate Tablets, 2435
Isotonic
Salt Solution, 1397
Sodium Chloride Injection, 1397
Sodium Chloride Solution, 1397
Isoxsuprine Hydrochloride, 992
Tablets, 993
Itraconazole, 994
J
Japanese
Angelica Root, 1668, 2511
Angelica Root, Powdered, 1669,
2512
Encephalitis Vaccine, 995
Gentian, 1669
Gentian, Powdered, 1669
Valerian, 1670
Valerian, Powdered, 1670
Josamycin, 995, 2436
Propionate, 997, 2436
Tablets, 996
Jujube, 1670
Seed, 1671
Juzentaihoto Extract, 1671
K
Kainic Acid
and Santonin Powder, 999
Hydrate, 998
Kakkonto Extract, 1674
Kallidinogenase, 1000
Kamishoyosan Extract, 1676
Kanamycin
Index
Monosulfate, 1002
Sulfate, 1003, 2436
Kaolin, 1004
Keishibukuryogan Extract, 1679
Ketamine Hydrochloride, 1005
Ketoconazole, 1005
Cream, 1006
Lotion, 1007
Solution, 1008
Ketoprofen, 1008
Fumarate, 1009
Kitasamycin, 1010
Acetate, 1012
Tartrate, 1013
Koi, 1681
L
Labetalol Hydrochloride, 1014
Tablets, 1015
Lactic Acid, 1016
L-Lactic Acid, 1017
Lactose, 1019
Anhydrous, 1018, 2436
Hydrate, 1019
Lactulose, 1020
Lafutidine, 2438
Tablets, 2439
Lanatoside C, 1021
Tablets, 1021
Lanolin
Hydrous, 1022
Purified, 1023
Lard, 1024
Latamoxef Sodium, 1024
Lauromacrogol, 1026
Lemonades
Hydrochloric Acid, 926
Lenampicillin Hydrochloride, 1026
Lenograstim (Genetical Recombination), 2440
Leonurus Herb, 1682, 2512
L-Leucine, 1028
Leucomycin, 1010
Acetate, 1012
Tartrate, 1013
Levallorphan Tartrate, 1029
Injection, 1029
Levodopa, 1030
Levofloxacin
Fine Granules, 2443
Hydrate, 1031
Ophthalmic Solution, 2445
Tablets, 2446
Levomepromazine Maleate, 1032
Levothyroxine Sodium
Hydrate, 1032
Tablets, 1033
Lidocaine, 1034
Hydrochloride Injection, 1035
Injection, 1035
Light
Anhydrous Silicic Acid, 1385
2595
M
Macrogol
400, 1050
1500, 1051
4000, 1052
6000, 1052
20000, 1053
Ointment, 1053
Magnesium
Carbonate, 1054
Oxide, 1055
Silicate, 1056
Stearate, 1057, 2449
Sulfate Hydrate, 1058
Sulfate Injection, 1059
2596
Index
Supplement I, JP XVI
Capsules, 1093
Methoxsalen, 1095
Methyl
Parahydroxybenzoate, 1103, 2451
Salicylate, 1106
Salicylate Spirit, Compound, 1107
Methylbenactyzium Bromide, 1096
Methylcellulose, 1096
Methyldopa
Hydrate, 1098
Tablets, 1099
dl-Methylephedrine Hydrochloride,
1100
Powder, 1101
Powder, 10z, 1101, 2451
Methylergometrine Maleate, 1101
Tablets, 1102
Methylprednisolone, 1104
Succinate, 1104
Methylrosanilinium Chloride, 1105
Methyltestosterone, 1107
Tablets, 1108
Meticrane, 1109
Metildigoxin, 1110
Metoclopramide, 1111
Tablets, 1112
Metoprolol Tartrate, 1113
Tablets, 1113
Metronidazole, 1114
Tablets, 1115
Metyrapone, 1116
Mexiletine Hydrochloride, 1117
Miconazole, 1118
Nitrate, 1118
Microcrystalline Cellulose, 599
Micronomicin Sulfate, 1119
Midecamycin, 1120
Acetate, 1121
Migrenin, 1122
Minocycline Hydrochloride, 1123
for Injection, 1124
Tablets, 1125
Mitomycin C, 1126
for Injection, 1127
Mizoribine, 1127, 2452
Tablets, 1128
Monobasic Calcium Phosphate Hydrate, 505
Monosodium Trichloroethyl Phosphate, 1531
Syrup, 1532
Morphine
and Atropine Injection, 1130
Hydrochloride Hydrate, 1131
Hydrochloride Injection, 1131
Hydrochloride Tablets, 1132
Sulfate Hydrate, 2453
Mosapride Citrate
Hydrate, 1133
Powder, 1134
Tablets, 1136
Moutan Bark, 1690
Powdered, 1691, 2513
Mukoi-Daikenchuto Extract,
Mulberry Bark, 1693
Mupirocin Calcium
Hydrate, 1137
Ointment, 1139
1691
N
Nabumetone, 1139
Tablets, 1141
Nadolol, 1142
Nafamostat Mesilate, 1143
Nalidixic Acid, 1144
Naloxone Hydrochloride, 1145
Naphazoline
and Chlorpheniramine Solution,
1146
Hydrochloride, 1145
Nitrate, 1146
Naproxen, 1147
Narcotine, 1179
Hydrochloride, 1180
Nartograstim (Genetical Recombination), 2454
for Injection, 2456
Natamycin, 1246
Nateglinide, 1148, 2457
Tablets, 1149
Natural Aluminum Silicate, 354
Nelumbo Seed, 1693
Neomycin Sulfate, 869
Neostigmine Methylsulfate, 1151
Injection, 1151
Nicardipine Hydrochloride, 1152
Injection, 1153
Nicergoline, 1154
Powder, 1155
Tablets, 1156
Niceritrol, 1157
Nicomol, 1158
Tablets, 1159
Nicorandil, 1159
Nicotinamide, 1160
Nicotinic Acid, 1161
Injection, 1162
Nifedipine, 1162
Enteric Fine Granules, 2458
Extended-release Capsules, 2457
Fine Granules, 2459
Nilvadipine, 1163
Tablets, 1164
Nitrazepam, 1166
Nitrendipine, 1166
Tablets, 1167
Nitrogen, 1168
Nitroglycerin Tablets, 1169
Nitrous Oxide, 1170
Nizatidine, 1171
Capsules, 1172
Noradrenaline, 1173
Hydrochloride Injection, 1174
Injection, 1174
Norepinephrine, 1173
Supplement I, JP XVI
Hydrochloride Injection, 1174
Injection, 1174
Norethisterone, 1175, 2461
Norfloxacin, 1175
Norgestrel, 1176
and Ethinylestradiol Tablets, 1177
Nortriptyline Hydrochloride, 1178
Noscapine, 1179
Hydrochloride Hydrate, 1180
Notopterygium, 1694
Nuphar Rhizome, 1694
Nutmeg, 1695
Nux Vomica, 1695
Extract, 1696
Extract Powder, 1696
Tincture, 1697
Nystatin, 1180
O
Ofloxacin, 1181
Ointments
Aciclovir, 2359
Acrinol and Zinc Oxide, 330
Betamethasone Valerate and Gentamicin Sulfate, 452
Hydrocortisone and Diphenhydramine, 929
Ibuprofen Piconol, 2429
Macrogol, 1053
Mupirocin Calcium, 1139
Polyethylene Glycol, 1053
Simple, 1388
Sulfur, Salicylic Acid and Thianthol,
1441
White, 1575
Zinc Oxide, 1586
Olive Oil, 1182
Omeprazole, 1182
Enteric-coated Tablets, 2461
Operidine, 1230
Injection, 1231
Ophiopogon Tuber, 1698
Ophthalmic Solution
Dibekacin Sulfate, 709
Dorzolamide Hydrochloride, 2399
Gentamicin Sulfate, 882
Idoxuridine, 947
Levofloxacin, 2445
Pemirolast Potassium, 2462
Silver Nitrate, 1387
Tranilast, 2489
Zinc Sulfate, 1587
Opium
Ipecac Powder, 1698
Powder, Diluted, 1184
Powdered, 1183
Tincture, 1184
Opium Alkaloids
and Atropine Injection, 1187
and Scopolamine Injection, 1188
Hydrochlorides, 1185
Hydrochlorides Injection, 1186
Index
Orange
Oil, 1190
Peel Syrup, 1612
Peel Tincture, 1612
Orciprenaline Sulfate, 1191
Orengedokuto Extract, 1698, 2513
Oriental Bezoar, 1700
Oxapium Iodide, 1191
Oxaprozin, 1192
Oxazolam, 1193
Oxetacaine, 1194
Oxethazaine, 1194
Oxprenolol Hydrochloride, 1194
Oxybuprocaine Hydrochloride, 1195
Oxycodone
and Atropine Injection, Compound,
1197
Hydrochloride Hydrate, 1196
Injection, Compound, 1197
Oxydol, 1199
Oxygen, 1199
Oxymetholone, 1200
Oxytetracycline Hydrochloride, 1201
Oxytocin, 1203
Injection, 1205
Oyster Shell, 1701
Powdered, 1701
Ozagrel Sodium, 1206
for Injection, 1207
P
Panax Japonicus Rhizome, 1702,
2514
Powdered, 1702, 2514
Pancreatin, 1207
Pancuronium Bromide, 1208
Panipenem, 1208
Pantethine, 1210
Papaverine Hydrochloride, 1211
Injection, 1212
Paracetamol, 318
Paraffin, 1212
Light Liquid, 1214
Liquid, 1213
Paraformaldehyde, 1214
Paste, Dental, 1215
Parnaparin Sodium, 1216, 2462
Pas-calcium
Granules, 503
Hydrate, 502
Paste
Arsenical, 396
Paraformaldehyde, Dental, 1215
Triozinc, Dental, 1540
Peach Kernel, 1702, 2514
Powdered, 1703, 2515
Peanut Oil, 1218
Pemirolast Potassium, 1218
for Syrup, 1219
Ophthalmic Solution, 2462
Tablets, 1220
Penbutolol Sulfate, 1221
2597
2598
Index
Piperacillin
Hydrate, 1252
Sodium, 1254, 2465
Sodium for Injection, 1255
Piperazine
Adipate, 1256
Phosphate Hydrate, 1256
Phosphate Tablets, 1257
Pirarubicin, 1258
Pirenoxine, 1259
Pirenzepine Hydrochloride Hydrate,
1260
Piroxicam, 1261
Pivmecillinam Hydrochloride, 1262
Tablets, 1263
Plantago
Herb, 1711, 2517
Seed, 1711
Platycodon
Fluidextract, 1712
Root, 1712
Root, Powdered, 1712
Pogostemon Herb, 1713
Polyethylene Glycol
400, 1050
1500, 1051
4000, 1052
6000, 1052
20000, 1053
Ointment, 1053
Polygala Root, 1713, 2517
Powdered, 1714, 2517
Polygonatum Rhizome, 1714
Polygonum Root, 1714, 2517
Polymixin B Sulfate, 1263
Polyoxyethylene Lauryl Alcohol Ether,
1026
Polyoxyl 40 Stearate, 1264
Polyporus Sclerotium, 1715
Powdered, 1715
Polysorbate 80, 1265
Polyvidone, 1273
Polyvinylpyrrolidone, 1273
Poria Sclerotium, 1715
Powdered, 1716
Potash Soap, 1265
Potassium
Bromide, 1265
Canrenoate, 1266
Carbonate, 1267
Chloride, 1267
Clavulanate, 1268
Guaiacolsulfonate, 1269
Hydroxide, 1270
Iodide, 1270
Permanganate, 1271
Sulfate, 1272
Potato Starch, 1272, 2466
Povidone, 1273
-Iodine, 1275
Powder
Ascorbic Acid, 398
Chlordiazepoxide, 613
Supplement I, JP XVI
Chlorpheniramine and Calcium,
621
Chlorpheniramine Maleate, 623,
2386
Codeine Phosphate, 1z, 671, 2389
Codeine Phosphate, 10z, 672,
2390
Compound Diastase and Sodium Bicarbonate, 706
Compound Phellodendron, for
Cataplasm, 1709
Compound Rhubarb and Senna,
1725
Compound Scopolia Extract and Diastase, 1744
Compound Vitamin B, 1567
Diastase and Sodium Bicarbonate,
706
Dihydrocodeine Phosphate, 1z,
724, 2396
Dihydrocodeine Phosphate, 10z,
724, 2397
Diluted Opium, 1184
Diphenhydramine and
Bromovalerylurea, 736
Diphenylhydantoin, 1242
Ephedrine Hydrochloride, 783
Ephedrine Hydrochloride, 10z,
783, 2406
Famotidine, 825
Gentian and Sodium Bicarbonate,
1645
Hydralazine Hydrochloride, 924,
2425
Kainic Acid and Santonin, 999
dl-Methylephedrine Hydrochloride,
1101
dl-Methylephedrine Hydrochloride,
10z, 1101, 2451
Mosapride Citrate, 1134
Nicergoline, 1155
Nux Vomica Extract, 1696
Opium Ipecac, 1698
Phellodendron, Albumin Tannate
and Bismuth Subnitrate, 1709
Phenobarbital, 1235
Phenobarbital, 10z, 1235
Phenytoin, 1242
Reserpine, 1339
Reserpine, 0.1z, 1339, 2473
Riboflavin, 1342, 2473
Salicylated Alum, 1371
Scopolia Extract and Carbon, 1744
Scopolia Extract and Ethyl
Aminobenzoate, 1744
Scopolia Extract, 1743
Scopolia Extract, Papaverine and
Ethyl Aminobenzoate, 1745
Swertia and Sodium Bicarbonate,
1765
Thiamine Chloride Hydrochloride,
1485
Vitamin B1 Hydrochloride, 1485
Supplement I, JP XVI
Turmeric, 1769, 2527
Zanthoxylum Fruit, 1771, 2528
Pranoprofen, 1276
Pravastatin Sodium, 1277
Fine Granules, 1278, 2466
Solution, 1279
Tablets, 1281, 2467
Prazepam, 1282
Tablets, 1283
Prazosin Hydrochloride, 1284
Precipitated Calcium Carbonate, 495
Fine Granules, 495
Tablets, 496
Prednisolone, 1285
Acetate, 1287
Sodium Phosphate, 1288
Sodium Succinate for Injection,
1290
Succinate, 1289
Tablets, 1286
Primidone, 1291
Probenecid, 1292
Tablets, 1292
Probucol, 1293
Fine Granules, 1294
Tablets, 1295
Procainamide Hydrochloride, 1296
Injection, 1296
Tablets, 1297
Procaine Hydrochloride, 1298
Injection, 1299
Procarbazine Hydrochloride, 1299
Procaterol Hydrochloride Hydrate,
1300
Processed
Aconite Root, 1716
Aconite Root, Powdered, 1718
Ginger, 1719, 2517
Prochlorperazine Maleate, 1301
Tablets, 1302
Progesterone, 1303
Injection, 1304
Proglumide, 1304
L-Proline, 1305
Promethazine Hydrochloride, 1306
Propafenone Hydrochloride, 1307
Tablets, 1308
Propantheline Bromide, 1309
Propiverine Hydrochloride, 1310
Tablets, 1311
Propranolol Hydrochloride, 1312
Tablets, 1313
Propylene Glycol, 1315
Propyl Parahydroxybenzoate, 1314,
2467
Propylthiouracil, 1315
Tablets, 1316
Propyphenazone, 989
Prostaglandin
E1, 349
E1 a-Cyclodextrin Clathrate Compound, 352
F2a, 735
Index
Protamine Sulfate, 1316
Injection, 1317
Prothionamide, 1318
Protirelin, 1318
Tartrate Hydrate, 1319
Prunella Spike, 1720
Pueraria Root, 1720, 2518
Pullulan, 1320
Purified
Dehydrocholic Acid, 695
Gelatin, 880
Lanolin, 1023
Shellac, 1383
Sodium Hyaluronate, 1401
Water, 1572
Water in Containers, 1572
Water in Containers, Sterile, 1573
Pyrantel Pamoate, 1321
Pyrazinamide, 1322
Pyridostigmine Bromide, 1322
Pyridoxine Hydrochloride, 1323
Injection, 1324
Pyroxylin, 1324
Pyrrolnitrin, 1325
Q
Quercus Bark, 1721
Quetiapine Fumarate, 2469
Fine Granules, 2470
Tablets, 2471
Quick Lime, 501
Quinapril Hydrochloride, 1325
Tablets, 1326
Quinidine Sulfate Hydrate, 1328
Quinine
Ethyl Carbonate, 1329
Hydrochloride Hydrate, 1330
Sulfate Hydrate, 1331
R
Rabeprazole Sodium, 1332, 2473
Ranitidine Hydrochloride, 1333
Rape Seed Oil, 1335
Rebamipide, 1335
Tablets, 1336
Red Ginseng, 1721, 2518
Rehmannia Root, 1722, 2519
Reserpine, 1337
Injection, 1338
Powder, 1339
Powder, 0.1z, 1339, 2473
Tablets, 1339
Retinol
Acetate, 1340
Palmitate, 1341
Rhubarb, 1723
and Senna Powder, Compound,
1725
Powdered, 1724
Riboflavin, 1341
Butyrate, 1343
2599
Phosphate, 1344
Phosphate Injection, 1345
Powder, 1342, 2473
Sodium Phosphate, 1344
Sodium Phosphate Injection, 1345
Ribostamycin Sulfate, 1345, 2474
Rice Starch, 1346, 2474
Rifampicin, 1347
Capsules, 1348
Rikkunshito Extract, 1725
Ringer's Solution, 1350
Risperidone, 1351
Fine Granules, 1351
Oral Solution, 1353
Tablets, 1354
Ritodrine Hydrochloride, 1355
Tablets, 1357
Rokitamycin, 1358
Tablets, 1359
Rose Fruit, 1727
Powdered, 1728, 2519
Rosin, 1728
Roxatidine Acetate Hydrochloride,
1360
Extended-release Capsules, 1361
Extended-release Tablets, 1362
for Injection, 1363
Roxithromycin, 1364
Royal Jelly, 1728
Ryokeijutsukanto Extract, 1729
S
Saccharated Pepsin, 1366
Saccharin, 1366
Sodium, 1367
Sodium Hydrate, 1367
Safflower, 1731
Saffron, 1731
Saibokuto Extract, 1732
Saikokeishito Extract, 1734
Saireito Extract, 1737, 2520
Salazosulfapyridine, 1368
Salbutamol Sulfate, 1369
Salicylated Alum Powder, 1371
Salicylic Acid, 1370
Adhesive Plaster, 1372
Spirit, 1372
Spirit, Compound, 1372
Santonin, 1373
Saponated Cresol Solution, 681
Saposhnikovia Root and Rhizome,
1740
Sappan Wood, 1740
Sarpogrelate Hydrochloride, 1374,
2474
Fine Granules, 1375
Tablets, 1377
Saussurea Root, 1740
Schisandra Fruit, 1741
Schizonepeta Spike, 1741, 2520
Scopolamine
Butylbromide, 1378
2600
Index
Supplement I, JP XVI
Chloride, 1396
Chloride Injection, 0.9z, 1397
Chloride Injection, 10z, 1397
Chromate (51Cr) Injection, 1398
Citrate Hydrate, 1398
Citrate Injection for Transfusion,
1398
Cromoglicate, 1399
Fusidate, 1401
Hydrogen Carbonate, 1392
Hydrogen Sulfite, 1393
Hydroxide, 1403
Iodide, 1404
Iodide (123I) Capsules, 1404
Iodide (131I) Capsules, 1404
Iodide (131I) Solution, 1404
Iodohippurate (131I) Injection, 1405
Iotalamate Injection, 1405
L-Lactate Solution, 1406
Lauryl Sulfate, 1407
Metabisulfite, 1411
Pertechnetate (99mTc) Injection,
1408
Picosulfate Hydrate, 1409
Polystyrene Sulfonate, 1409
Prasterone Sulfate Hydrate, 1411
Pyrosulfite, 1411
Risedronate Hydrate, 1412
Risedronate Tablets, 1414
Salicylate, 1415
Starch Glycolate, 1415
Thiosulfate Hydrate, 1417
Thiosulfate Injection, 1417
Valproate, 1418
Valproate Syrup, 1419
Valproate Tablets, 1419
Solution
Adrenaline, 332
Alum, 358
Benzalkonium Chloride, 429
Benzethonium Chloride, 431
Butenafine Hydrochloride, 484
Chlorhexidine Gluconate, 616
Compound Thianthol and Salicylic
Acid, 1488
Cresol, 680
Dental Sodium Hypochlorite, 387
Diagnostic Sodium Citrate, 1399
Epinephrine, 332
Glycerin and Potash, 894
Isotonic Salt, 1397
Isotonic Sodium Chloride, 1397
Ketoconazole, 1008
Merbromin, 1085
Mercurochrome, 1085
Naphazoline and Chlorpheniramine,
1146
Pravastatin Sodium, 1279
Ringer's, 1350
Risperidone Oral, 1353
Saponated Cresol, 681
Silver Protein, 1387
Sodium Iodide (131I), 1404
Supplement I, JP XVI
Sultamicillin Tosilate Hydrate, 1445
Sultiame, 1447
Suppositories
Bisacodyl, 460
Indometacin, 962
Scopolia Extract and Tannic Acid,
1746
Suxamethonium Chloride
for Injection, 1448
Hydrate, 1447
Injection, 1449
Sweet Hydrangea Leaf, 1763, 2524
Powdered, 1763, 2524
Swertia
and Sodium Bicarbonate Powder,
1765
Herb, 1764, 2524
Herb, Powdered, 1765
Synthetic
Aluminum Silicate, 356
Camphor, 510
Syrup
Aciclovir, 326
Aciclovir for, 325
Amphotericin B, 382
Cefadroxil for, 535
Cefalexin for, 539
Cefatrizine Propylene Glycolate for,
542
Cefroxadine for, 584
Faropenem Sodium for, 828
Ipecac, 1667
Monosodium Trichloroethyl Phosphate, 1532
Orange Peel, 1612
Pemirolast Potassium for, 1219
Senega, 1749
Simple, 1388
Sodium Valproate, 1419
Tranilast for, 2488
Triclofos Sodium, 1532
T
Tablets
Acemetacin, 317
Acetylsalicylic Acid, 400
Ajmaline, 334
Alacepril, 336
Aldioxa, 2361
Alendronate Sodium, 342
Allopurinol, 344
Alminoprofen, 346
Amiodarone Hydrochloride, 366,
2362
Amitriptyline Hydrochloride, 367
Amlexanox, 370
Amlodipine Besilate, 372
Amlodipine Besilate Orally Disintegrating, 2363
Amosulalol Hydrochloride, 376
Amphotericin B, 382
Aspirin, 400
Index
Atorvastatin Calcium, 405
Auranofin, 2366
Azathioprine, 409, 2367
Baclofen, 418
Benidipine Hydrochloride, 425
Beraprost Sodium, 439
Betahistine Mesilate, 443
Betamethasone, 446
Bezafibrate Sustained Release, 456
Bisoprolol Fumarate, 463, 2369
Bucillamine, 473
Buformin Hydrochloride Entericcoated, 476
Buformin Hydrochloride, 478
Cadralazine, 488
Candesartan Cilexetil, 512
Carvedilol, 526
Cefcapene Pivoxil Hydrochloride,
551
Cefditoren Pivoxil, 556
Cefpodoxime Proxetil, 2380
Cefteram Pivoxil, 591
Cetirizine Hydrochloride, 607
Chlordiazepoxide, 614, 2386
Chlorphenesin Carbamate, 620
Chlorpheniramine Maleate, 624
Chlorpromazine Hydrochloride,
627
Chlorpropamide, 629
Cibenzoline Succinate, 632
Cilazapril, 638
Cilostazol, 640
Clarithromycin, 647
Clomifene Citrate, 660, 2389
Codeine Phosphate, 672
Colestimide, 2391
Diazepam, 707
Dichlorphenamide, 712
Diclofenamide, 712
Diethylcarbamazine Citrate, 714,
2396
Digitoxin, 718
Digoxin, 721
Dimenhydrinate, 732
Diphenylhydantoin, 1243
Distigmine Bromide, 741
Donepezil Hydrochloride, 747
Doxazosin Mesilate, 752
Dydrogesterone, 762
Ebastine Orally Disintegrating, 764
Ebastine, 765
Emorfazone, 774
Enalapril Maleate, 777
Epalrestat, 2405
Ephedrine Hydrochloride, 784
Ergometrine Maleate, 789
Erythromycin Enteric-Coated, 792
Estriol, 799
Etacrynic Acid, 801
Ethinylestradiol, 806
Etidronate Disodium, 814
Etilefrine Hydrochloride, 815
Etizolam, 819
2601
Famotidine, 826
Faropenem Sodium, 829
Fexofenadine Hydrochloride, 2415
Flecainide Acetate, 838
Flutoprazepam, 858
Fluvoxamine Maleate, 860
Folic Acid, 863
Furosemide, 873
Glimepiride, 886, 2420
Griseofulvin, 905
Haloperidol, 911
Hydralazine Hydrochloride, 924
Imidapril Hydrochloride, 950
Imipramine Hydrochloride, 955
Indapamide, 957
Ipriflavone, 976
Irsogladine Maleate, 978
Isoniazid, 986
Isosorbide Dinitrate, 991
Isosorbide Mononitrate, 2435
Isoxsuprine Hydrochloride, 993
Josamycin, 996
Labetalol Hydrochloride, 1015
Lafutidine, 2439
Lanatoside C, 1021
Levofloxacin, 2446
Levothyroxine Sodium, 1033
Liothyronine Sodium, 1040
Lisinopril, 1042
Losartan Potassium, 2448
Manidipine Hydrochloride, 1062
Mefruside, 1072
Metformin Hydrochloride, 1091
Methyldopa, 1099
Methylergometrine Maleate, 1102
Methyltestosterone, 1108
Metoclopramide, 1112
Metoprolol Tartrate, 1113
Metronidazole, 1115
Minocycline Hydrochloride, 1125
Mizoribine, 1128
Morphine Hydrochloride, 1132
Mosapride Citrate, 1136
Nabumetone, 1141
Nateglinide, 1149
Nicergoline, 1156
Nicomol, 1159
Nilvadipine, 1164
Nitrendipine, 1167
Nitroglycerin, 1169
Norgestrel and Ethinylestradiol,
1177
Omeprazole Enteric-coated, 2461
Pemirolast Potassium, 1220
Perphenazine Maleate, 1228
Perphenazine, 1227
Phenytoin, 1243
Pilocarpine Hydrochloride, 2463
Pioglitazone Hydrochloride, 1250
Piperazine Phosphate, 1257
Pivmecillinam Hydrochloride, 1263
Pravastatin Sodium, 1281, 2467
Prazepam, 1283
2602
Index
Tablets (continued )
Precipitated Calcium Carbonate,
496
Prednisolone, 1286
Probenecid, 1292
Probucol, 1295
Procainamide Hydrochloride, 1297
Prochlorperazine Maleate, 1302
Propafenone Hydrochloride, 1308
Propiverine Hydrochloride, 1311
Propranolol Hydrochloride, 1313
Propylthiouracil, 1316
Quetiapine Fumarate, 2471
Quinapril Hydrochloride, 1326
Rebamipide, 1336
Reserpine, 1339
Risperidone, 1354
Ritodrine Hydrochloride, 1357
Rokitamycin, 1359
Roxatidine Acetate Hydrochloride
Extended-release, 1362
Sarpogrelate Hydrochloride, 1377
Simvastatin, 2474
Sodium Risedronate, 1414
Sodium Valproate, 1419
Spironolactone, 1425
Sulpiride, 1443
Taltirelin, 2482
Taltirelin Orally Disintegrating,
2481
Tamsulosin Hydrochloride Extended-release, 1455
Temocapril Hydrochloride, 1470
Thiamazole, 1482
Tiapride Hydrochloride, 1495
Tiaramide Hydrochloride, 1496
Tipepidine Hibenzate, 1502
Tolbutamide, 1513
Tosufloxacin Tosilate, 1517
Tranexamic Acid, 1521
Trichlormethiazide, 1528, 2490
Trihexyphenidyl Hydrochloride,
1533
Trimetazidine Hydrochloride, 1536
Trimethadione, 1538, 2490
Troxipide, 1542
Ursodeoxycholic Acid, 1555
Valsartan, 2492
Verapamil Hydrochloride, 1562
Voglibose, 1568, 2493
Warfarin Potassium, 1571
Zaltoprofen, 1582
Zolpidem Tartrate, 1591
Tacalcitol
Hydrate, 2477
Lotion, 2479
Tacrolimus Hydrate, 1449
Talampicillin Hydrochloride, 1450
Talc, 1451
Taltirelin
Hydrate, 2480
Orally Disintegrating Tablets, 2481
Tablets, 2482
Supplement I, JP XVI
Tamoxifen Citrate, 1453
Tamsulosin Hydrochloride, 1454
Extended-release Tablets, 1455
Tannic Acid, 1456
Tartaric Acid, 1456
Taurine, 1457
Tazobactam, 1457
Teceleukin
for Injection (Genetical Recombination), 1465
(Genetical Recombination), 1459
Tegafur, 1465
Teicoplanin, 1466
Temocapril Hydrochloride, 1469
Tablets, 1470
Teprenone, 1471
Terbinafine Hydrochloride, 1472
Cream, 1473
Solution, 1474
Spray, 1475
Terbutaline Sulfate, 1475
Testosterone
Enanthate, 1476
Enanthate Injection, 1477
Propionate, 1477
Propionate Injection, 1478
Tetracaine Hydrochloride, 1479
Tetracycline Hydrochloride, 1480
Thallium (201Tl) Chloride Injection,
1481
Theophylline, 1481
Thiamazole, 1482
Tablets, 1482
Thiamine Chloride Hydrochloride,
1483
Injection, 1484
Powder, 1485
Thiamine Nitrate, 1485
Thiamylal Sodium, 1486
for Injection, 1487
Thianthol, 1488
and Salicylic Acid Solution, Compound, 1488
Thiopental Sodium, 1489
for Injection, 1490
Thioridazine Hydrochloride, 1491
Thiotepa, 1491
L-Threonine, 1492
Thrombin, 1492
Thymol, 1493
Tiapride Hydrochloride, 1494
Tablets, 1495
Tiaramide Hydrochloride, 1496
Tablets, 1496
Ticlopidine Hydrochloride, 1497
Timepidium Bromide Hydrate, 1498
Timolol Maleate, 1499
Tincture
Bitter, 1613
Capsicum, 1617
Iodine, 966
Iodine, Dilute, 967
Nux Vomica, 1697
Opium, 1184
Orange Peel, 1612
Tinidazole, 1500
Tipepidine Hibenzate, 1500
Tablets, 1502
Titanium Oxide, 1503, 2484
Tizanidine Hydrochloride, 1504
Toad
Cake, 2524
Venom, 1766, 2524
Tobramycin, 1505
Injection, 1506
Tocopherol, 1506
Acetate, 1507
Calcium Succinate, 1508
Nicotinate, 1509
dl-a-Tocopherol, 1506
Acetate, 1507
Nicotinate, 1509
Todralazine Hydrochloride Hydrate,
1510
Tofisopam, 1511
Tokishakuyakusan Extract, 2524
Tolazamide, 1512
Tolbutamide, 1513
Tablets, 1513
Tolnaftate, 1514
Solution, 1514
Tolperisone Hydrochloride, 1515
Tosufloxacin Tosilate
Hydrate, 1516
Tablets, 1517
Tragacanth, 1767
Powdered, 1767
Tranexamic Acid, 1518
Capsules, 1519
Injection, 1520
Tablets, 1521
Tranilast, 2484
Capsules, 2485
Fine Granules, 2487
for Syrup, 2488
Ophthalmic Solution, 2489
Trapidil, 1521
Trehalose Hydrate, 1522
Trepibutone, 1523
Tretoquinol Hydrochloride, 1539
Triamcinolone, 1524
Acetonide, 1525
Triamterene, 1526
Tribulus Fruit, 1767
Trichlormethiazide, 1527
Tablets, 1528, 2490
Trichomycin, 1530
Trichosanthes Root, 1768
Triclofos Sodium, 1531
Syrup, 1532
Trihexyphenidyl Hydrochloride, 1533
Tablets, 1533
Trimebutine Maleate, 1534
Trimetazidine Hydrochloride, 1535
Tablets, 1536
Trimethadione, 1538
Supplement I, JP XVI
Tablets, 1538, 2490
Trimetoquinol Hydrochloride Hydrate,
1539
Tropicamide, 1540
Troxipide, 1541
Fine Granules, 1541
Tablets, 1542
L-Tryptophan, 1543
Tulobuterol Hydrochloride, 1544
Turmeric, 1768, 2527
Powdered, 1769, 2527
Turpentine Oil, 1545
L-Tyrosine, 1545
U
Ubenimex, 1546
Capsules, 1547
Ubidecarenone, 1548
Ulinastatin, 1549
Uncaria Hook, 1770, 2527
Urapidil, 1551
Urea, 1552
Urokinase, 1552
Ursodeoxycholic Acid, 1554
Granules, 1554
Tablets, 1555
Uva Ursi Fluidextract, 1609
V
Vaccine
BCG, Freeze-dried, (for Percutaneous Use), 421
Cholera, 630
Diphtheria-Purified Pertussis-Tetanus Combined, Adsorbed, 739
Hepatitis B, Adsorbed, 909
Influenza HA, 963
Inactivated Tissue Culture Rabies,
Freeze-dried, 1333
Japanese Encephalitis, 995
Japanese Encephalitis, Freeze-dried,
995
Live Attenuated Measles, Freezedried, 1065
Live Attenuated Mumps, Freezedried, 1137
Live Attenuated Rubella, Freezedried, 1365
Live Oral Poliomyelitis, 1263
Purified Pertussis, Adsorbed, 1230
Smallpox, Freeze-dried, 1390
Index
Smallpox, Freeze-dried, Prepared in
Cell Culture, 1390
Weil's Disease and Akiyami Combined, 1574
L-Valine, 1557
Valsartan, 2490
Tablets, 2492
Vancomycin Hydrochloride, 1558
for Injection, 1559
Vasopressin Injection, 1560, 2493
Verapamil Hydrochloride, 1561
Tablets, 1562
Vinblastine Sulfate, 1563
for Injection, 1564
Vincristine Sulfate, 1565
Vitamin A
Acetate, 1340
Capsules, 1566
Oil, 1566
Oil Capsules, 1566
Palmitate, 1341
Vitamin B
Powder, Compound, 1567
Vitamin B1
Hydrochloride, 1483
Hydrochloride Injection, 1484
Hydrochloride Powder, 1485
Nitrate, 1485
Vitamin B2, 1341
Phosphate Ester, 1344
Phosphate Ester Injection, 1345
Powder, 1342
Vitamin B6, 1323
Injection, 1324
Vitamin B12, 684
Injection, 685
Vitamin C, 397
Injection, 398
Powder, 398
Vitamin D2, 787
Vitamin D3, 630
Vitamin E, 1506
Acetate, 1507
Calcium Succinate, 1508
Nicotinate, 1509
Vitamin K1, 1244
Voglibose, 1567
Tablets, 1568, 2493
W
Warfarin Potassium,
Tablets, 1571
1569
2603
Water, 1572
for Injection, 1572
for Injection in Containers, Sterile,
1573
in Containers, Purified, 1572
in Containers, Sterile Purified,
1573
Purified, 1572
Weak Opium Alkaloids and Scopolamine Injection, 1189
Weil's Disease and Akiyami Combined
Vaccine, 1574
Wheat Starch, 1574, 2494
White
Beeswax, 422
Ointment, 1575
Petrolatum, 1232
Shellac, 1384
Soft Sugar, 1432
Whole Human Blood, 1575
Wine, 1575
Wood Creosote, 1577
X
Xylitol, 1579
Injection, 1580
Y
Yellow
Beeswax, 423
Petrolatum, 1232
Z
Zaltoprofen, 1581
Tablets, 1582
Zanthoxylum Fruit, 1771, 2528
Powdered, 1771, 2528
Zedoary, 1771
Zidovudine, 1583
Zinc
Chloride, 1584
Oxide, 1585
Oxide Oil, 1585
Oxide Ointment, 1586
Oxide Starch Powder, 1586
Sulfate Hydrate, 1586
Sulfate Ophthalmic Solution, 1587
Zinostatin Stimalamer, 1588
Zolpidem Tartrate, 1590, 2494
Tablets, 1591
B
Belladonnae Radix, 1609
Benincasae Semen, 1611
Benzoinum, 1611
Bezoar Bovis, 1700
Bufonis
Crustum, 2524
Venenum, 1766, 2524
Bupleuri Radix, 1613
C
Calumbae Radix, 1615
Radix Pulverata, 1615
Cannabis Fructus, 1661
Capsici Fructus, 1615
Fructus Pulveratus, 1616
Cardamomi Fructus, 1618
Carthami Flos, 1731
Caryophylli Flos, 1625
Flos Pulveratus, 1625
Cassiae Semen, 1618
Catalpae Fructus, 1619
Cera
Alba, 422
Carnauba, 522
Flava, 423
Chrysanthemi Flos, 1622
Cimicifugae Rhizoma, 1622
Cinnamomi Cortex, 1623
Cortex Pulveratus, 1623
Citri Unshiu Pericarpium, 2501
Clematidis Radix, 1625
Cnidii
Monnieris Fructus, 1626
Rhizoma, 1626
Rhizoma Pulveratum, 1627
Coicis Semen, 1627
Semen Pulveratum, 1627
Condurango Cortex, 1628
Coptidis Rhizoma, 1628
Rhizoma Pulveratum, 1629
Corni Fructus, 1630
Corydalis Tuber, 1631
Tuber Pulveratum, 1632
Crataegi Fructus, 1632
Crocus, 1731
Curcumae Rhizoma, 1768
Rhizoma Purveratum, 1769
Cyperi Rhizoma, 1633
Rhizoma Pulveratum, 1633
D
Digenea, 1635
Dioscoreae Rhizoma, 1635
Rhizoma Pulveratum, 1636
Dolichi Semen, 1636
E
Eleutherococci senticosi Rhizoma,
1636
Ephedrae Herba, 1637
Epimedii Herba, 1638
Eriobotryae Folium, 1685
Eucommiae Cortex, 1638
Euodiae Fructus, 1639
F
Fel Ursi, 1608
Foeniculi Fructus, 1639
Fructus Pulveratus, 1639
Forsythiae Fructus, 1640
Fossilia Ossis Mastodi, 1684
Ossis Mastodi Pulveratus, 1685
Fritillariae Bulbus, 1641
Fructus Hordei Germinatus, 2513
G
Gambir, 1641
Pulveratum, 1641
Gardeniae Fructus, 1642
Fructus Pulveratus, 1642
Gastrodiae Tuber, 1643
Gentianae
Radix, 1644
Radix Pulverata, 1644
Scabrae Radix, 1669
Scabrae Radix Pulverata, 1669
Geranii Herba, 1645
Herba Pulverata, 1645
Ginseng Radix, 1646
Radix Pulverata, 1647
Radix Rubra, 1721
Glehniae Radix cum Rhizoma, 1649
Glycyrrhizae Radix, 1649
Radix Pulverata, 1650
Gummi Arabicum, 1593
Arabicum Pulveratum, 1593
Gypsum Fibrosum, 1655
H
Houttuyniae Herba,
1665
2605
2606
I
Imperatae Rhizoma, 1665
Ipecacuanhae Radix, 1666
Radix Pulverata, 1667
Supplement I, JP XVI
Olivae, 1182
Rapae, 1335
Ricini, 527
Sesami, 1381
Sojae, 1422
Terebinthinae, 1545
Ophiopogonis Tuber, 1698
Opium Pulveratum , 1183
Oryzae Fructus, 1613
Ostreae Testa, 1701
Testa Pulverata, 1701
Kasseki, 1598
Koi, 1681
P
L
M
Magnoliae Cortex, 1687
Cortex Pulveratus, 1687
Flos, 1688
Malloti Cortex, 1688
Mel, 1664
Menthae Herba, 1689
Mori Cortex, 1693
Moutan Cortex, 1690
Cortex Pulveratus, 1691
Myristicae Semen, 1695
N
Nelumbis Semen, 1693
Notopterygii Rhizoma, 1694
Nupharis Rhizoma, 1694
O
Oleum
Arachidis, 1218
Aurantii, 1190
Cacao, 487
Camelliae, 508
Caryophylli, 1626
Cinnamomi, 1623
Cocois, 670
Eucalypti, 822
Foeniculi, 1640
Maydis, 678
Menthae Japonicae,
1685
Q
Quercus Cortex,
1721
1689
1728
S
Saposhnikoviae Radix, 1740
Sappan Lignum, 1740
Saussureae Radix, 1740
Schisandrae Fructus, 1741
Schizonepetae Spica, 1741
Scopoliae Rhizoma, 1741
Scutellariae Radix, 1747
Radix Pulverata, 1748
Senegae Radix, 1749
Radix Pulverata, 1749
Sennae Folium, 1750
Folium Pulveratum, 1751
Sesami Semen, 1752
Sevum Bovinum, 422
Sinomeni Caulis et Rhizoma, 1761
Smilacis Rhizoma, 1762
Rhizoma Pulveratum, 1762
Sophorae Radix, 1762
Radix Pulverata, 1763
Strychni Semen, 1695
Swertiae Herba, 1764
Herba Pulverata, 1765
T
Tinctura Amara, 1613
Tragacantha, 1767
Pulverata, 1767
Tribuli Fructus, 1767
Trichosanthis Radix, 1768
U
Uncariae Uncis Cum Ramulus,
Uvae Ursi Folium, 1608
V
Valerianae Radix, 1670
Radix Pulverata, 1670
Z
Zanthoxyli Fructus, 1771
Fructus Pulveratus, 1771
Zedoariae Rhizoma, 1771
Zingiberis
Processum Rhizoma, 1719
Rhizoma, 1645
Rhizoma Pulveratum, 1646
Zizyphi
Fructus, 1670
Semen, 1671
1770
INDEX IN JAPANESE
1586
1586
1688
D 331, 2360
327
330
328, 2360
329, 2360
408
409, 2367
1170
323
326
325
2359
412
334
334
387
397
398
398
413, 2368
L- 399
400
401
400
402
314
319
322
318
320
313
315
316
317
410
411
2367
1641
1641, 2504
403
405
404, 2364
331
332
332
407
407
396
388
389
333
1187
1188
1185
1186
1184
1184
1698
1183
1763, 2524
1763, 2524
358
364
366, 2362
361
362
360
1074
367
367
809
363
363
B 380
B 382
B 382
370
2363
372
377
379
378
375
376
373
335
336
L- 337
1593
1593
343
1393
392
L- 394
L- 394
L- 395
339, 2360
2361
2361
347
348
349
352
350
390
392
345
346
342
340
341
1596
1597
396
344
344
432
1392
491
434
1611
388
384
385
359
1640
373
368
370
1440
1440
1441
972
1405
1073
973
971
2430
2432
944
810
980
981
992
993
989
985
986
986
2607
2608
Index in Japanese
982
l- 987
988
989
L- 983
984
945
2435
70z 2433
947
947
994
948
943
944
2428
2428
2429
974
975
976
949
950
954
955
952
976
977
978
1625
959
959
956
957
1602
958
960
961
962
HA 963
1638, 2504
1639
1639, 2504
1640
1768, 2527
1769, 2527
1546
1547
1683
1551
1549
1554
1554
1555
1552
1608, 2498
1609
Supplement I, JP XVI
1727
1728, 2519
805
767
768
1237
769
795
796
797
796
798
799
798
800
801
802, 2413
2400
2401
801
807
817
817
819
813
814
806
806
L- 809
813
815
815
812
1400
804
808
820
821
770
770
775
777
779
763
764
765
2404
2405
785
786
782
10z 783,
2406
784
783
781
2407
2410
2402
2403
774
774
791
793
794
792
793
771
787
790
788
789
789
1584
111In 960
1267
497
497
201Tl 1481
1396
10z 1397
1631, 2503
1632, 2503
925
926
780
778
1604
1747, 2520
1748, 2521
1232
1714
1707, 2516
1709
1708, 2516
2500
1628, 2502
1698, 2513
1629, 2502
1193
1191
1192
1196
1201
1203
1205
1199
1195
Supplement I, JP XVI
1200
1194
1194
1206
1181
1182
2461
2364
2366
1182
1191
1190
1713, 2517
1714, 2517
999
998
2496
1004
487
528
1720
1714, 2517
1771
1022
878
1713
1720, 2518
1674
1598
99mTc
1408
870
870
487
488
1002
1003, 2436
1670
1670
490
514
514
875
1271
1676
509
b-
876
b-
876
1000
1265
492
522
522
516
515
517
525
Index in Japanese
526
L- 518
2376
2378
519
519
520
523
521
1768
1719, 2517
1649, 2507
1417
1651
1494
1580
1390
738
1137
1365
1065
353
354
1651
1333
1395
1390
995
1479
908
BCG 421
469
1650, 2508
1061
357
511,
2376
512
1594
1595
1366
d- 510
dl- 510
674
1266
925
1712
1712
1712
1622, 2500
1619
1665
1579
1580
1010
1012
2609
1013
1325
1326
1328
1329
1330
1331
422
313
1694
1600, 2496
1601
967
1391
906
907
908
1269
2469
2470
2471
67Ga 878
645, 2388
1398
1686
1762
1763
1762
1613
1268
903
646
647
883
895
904
905
892
894
654
883
884
886, 2420
650, 2388
651
652
653
499
891
L- 890
L- 889
680
680
681
649
650
2610
Index in Japanese
656
668
669
681
682
2392
666
667
661
662
657
658
657
655
663
659, 2389
660,
2389
661
51Cr
1398
1399
664
665
610
612
611
613
613
614, 2386
621
622
d-
625
623, 2386
624
623
619
620
629
629
626
627
627
616
616
617
618
Supplement I, JP XVI
1741, 2520
1263
1056
1385
1214
1679
1623, 2500
1623
1623
1005
599
901
1618
1005
1008
1006
1007
1009
1008
609
878
1707, 2515
881
882
1644, 2505
1645
1644
1645
1645, 2505
1681
1731
934
1721, 2518
356
1633
1633
1613
1687, 2512
1687, 2513
1700
670
1594
1652
1639
1z 671, 2389
10z 672, 2390
672
671
895
1614
1752
1381
1741
1574, 2494
1346, 2474
676
677
679
674
630
2390
2391
631
630
1615
1615
1628, 2502
1628
687
1613, 2499
1734
1602
1732
1737, 2520
319
1390
1366
1367
1731
617
422
1368
1370
1372
1415
1372
1106
1371
1581
1582
1369
1374, 2474
1375
1377
1585
501
1503, 2484
1055
1762, 2523
1762, 2523
1632, 2503
397
1642
1642, 2505
1630
1771, 2528
1771, 2528
1199
1671
1373
1635
1636
706
Supplement I, JP XVI
706
706
707
683
684
685
713
714, 2396
1722, 2519
387
1540
1215
1237
968
717
718
634
713
634
710
711
712
686
686
1636
719
721
720
1686, 2512
1683
462
741
741
L- 2394
L- 688
L- 689
644
742
740
690
1384
1767
1583
762
762
642
643
1588
735
725
726
723
1z
724, 2396
10z
724, 2397
739
715
Index in Japanese
735
737
736
737
709
738
739
715
688
708, 2395
709
632
632
641
730
732
733
731
732
461
733
734
1189
1704
1752
1705
1626, 2501
1711
1711, 2517
1265
1394
1671
1665
1599
1599, 2495
1456
1645, 2505
1646, 2506
1756, 2522
990
991
1386
1387
1572
1618
1758
1655
804, 2413
1236
1238
1622
995, 2436
996
997, 2436
638
637
636
2611
728
729
639
640
325
542
535
539
584
2488
828
1219
1688
934
1231
1399
1388
2474
1753
1270
500
1403
1447
1449
1429
1379
1427
1426
508
40 1264
1057,
2449
1427,
2476
1424
1425
1425
1423
1441
1445
1447
1433
1442
1442
1443
1444
1444
1435
1436
1436
1437
1438
1434
2612
Index in Japanese
1438
1439
738
1572
1572
880
1383
695
1430, 2476
1401
1023
1397
1233
605
606
607
1655
2385
608
1749
1749
1749, 2522
528
529
531
532
543, 2379
545
541
534
535
536
537
540
561
560
557
566
576
569
575
572
570
568,
2380
550
551
548
555
556,
2379
556
Supplement I, JP XVI
552, 2379
553
554
585
586
593
592, 2382
589, 2382
590
591
594
578
580
546
581
2380
565
564
562
582
596
1382
598, 2384
879
1380
L- 1380
602
1626, 2501
1627, 2501
1706, 2515
1694
1766, 2524
1750, 2522
1751, 2522
1764, 2524
1765
1765
1604
1605, 2497
1693
1740
1706
1420
1590, 2494
1591
D - 1421
D - 1421
1723
1634
1724
1422
1670
692, 2394
1457
2477
2479
1595, 2495
1596, 2495
1449
1457
691
1454
1455
1453
1450
1451
2481
2482
2480
1267
1392
1393
1395
1054
1043
1388
691
1388
1456
338
738
441
1494
1495
1482
1482
1486
1483
1485
1484
1485
1496
1496
1488
1491
1489
1491
1417
1417
1702, 2514
1702, 2514
1497
1504
1168
1500
1500
1502
1498
1599
1493
1499
2359
414
322
Supplement I, JP XVI
362
B 381
374, 2364
386
946
953
1207
903
1572
1573
1448
1428, 2476
544
559
577
576
588
565
1487
1490
1465
756
2456
1559
899
923
1255
1564
823
1244
1290
840
1226
437
868
C 1127
1124
1087
1363
1625
1625, 2501
1626
1770, 2527
1619
1715
1715
L- 1545
1585
739
Index in Japanese
739
1230
495
495
496
1479
908
B 909
1624, 2501
508
1544
1466
937
1481
1465
699
40 700
40 701
70 702
5 703
18 704
704
705
1476
1477
1477
1478
698
698
1459
1479
1480
694
696
693
1471
696
1469
1470
1472
1474
1473
1475
1475
1545
354
2613
1415
1643
1603, 2497
1611, 2499
1615
1618
1617
1616, 2499
1668, 2511
2524
1669, 2512
1702, 2514
1703, 2515
1612
1612
1612
678, 2392
678
751
752
750
757
753
754
755
1601, 2496
1506
1508
1507
1509
1666, 2511
1667
1667, 2511
1517
1516
1638
1510
745, 2397
746
747
749
749
1511
743
1505
1506
1767
1767
1512
2484
2485
2487
2489
1518
1519
1521
2614
Index in Japanese
1520
1521
1524
1525
1526
1531
1532
1527
1528, 2490
1530
L- 1543
1533
1533
1538
1538, 2490
1535
1536
1539
1534
2397
2399
1514
1514
1513
1513
1515
L- 1492
1522
1523
759
760
761
1541
1541
1542
1540
758
1492
1024
744
1180
1335
1148, 2457
1149
1142
1145
1146
1146
1143
1139
1141
1147
1144
2454
1145
Supplement I, JP XVI
1710, 2516
1710
1152
1153
1695
1161
1160
1162
1158
1159
1159
1171
1172
518
1157
1154
1155
1156
1166
1166
1167
1169
1162
2459
2457
2458
995
1016
L- 1017
500
L- 1406
1019
1552
1163
1164
1646, 2507
1647, 2507
1685
1151
1151
893
50 429
1179
1180
1173
1174
1175, 2461
1176
1177
1178
1175
1641, 2504
415
2513
1384
1575
1232
1432
1698
1606
417
418
416
1560, 2493
1656
1664
1689
1690
1689
1709
1208
1211
1212
1649
419
503
502
811,
2413
486,
2372
1314,
2467
1103,
2451
1212
1214
L- 1557
2490
2492
1216, 2462
419
1418
1419
1419
1272, 2466
913
912
909
910
911
1207
1208
1711
1659
2508
1558
1210
501, 2374
Supplement I, JP XVI
1249
1250
458
1409
459
460
L- 920
L- 920
462
463,
2369
A 1566
A 1566
963
899,
2421
897
1575
923
923
924, 2425
924
938
938
935
935
926
933
927
932
931
928
929
929
930
1262
1263
940
2426
942
1251
1252
1254, 2465
1256
1257
1256
459
457
527
1246
939
1247
1682
Index in Japanese
1599
1605, 2498
1606, 2498
320
1322
1258
1321
1323
1324
1322
1259
1260
1411
1245
2463
1261
1324
1325
1685
1565
1248
1563
1602
822
825
826
824
829
827
1244
2416
2419
833,
2414
2415
1242
1242
1243
L- 1240
1240
1241
1233
1234
10z 1235
1236
1237
1238
1238
1239
831
832
831
330
1197
1197
1372
2615
1107
706
1725
1488
B 1567
967
1744
474
1715
1716
1716
1401
1718
472
473
482
1378
483
484
484
485
1575
888
888
485
479
2371
475
480
481
476
478
476
479
869
1411
1282
1283
1284
1276
1277
1279
1278, 2466
1281,
2467
834
836
1291
852
848
847
849
851
850
843
845
844
874
2616
Index in Japanese
856
857
858
845
846
853
859
860
853, 2420
855
854, 2420
1320
855
465
467
836
838
1285
1289
1287
1286
1288
1296
1297
1296
1298
1299
1300
1299
1304
1301
1302
1303
1304
871
873
872
1316
1317
1318
2370
1318
1319
1387
1387
1307
1308
1309
1310
1311
1315
1316
1315
1293
1294
1295
1312
Supplement I, JP XVI
1313
841
842
1292
1292
469
470
1306
839
471
471
L- 1305
602
423
421
455
456
454
455
443
443
453
445
449
450
452
447
446
448
1230
1231
424
425
914, 2422
916, 2423
919,
2425
1224
1218
1220
2462
1610
1609, 2498
1561
1562
438
439
1226
1227
1228
1228
440
428
429
432, 2369
436
434
1636
430
431
431
427
1221
1223
427
1222
1221
1761, 2523
1665
1394
468
610
1740
1721
1567
1568, 2493
865
867
1690
1691, 2513
1661
1273
1275
921
1695
1696
1696
1697
922
506
1409
80 1265
498
B 1263
864
864
865
1701
1701
C 1126
1637, 2504
1084
1085
1635, 2503
400 1050
1500 1051
4000 1052
Supplement I, JP XVI
6000 1052
20000 1053
1053
1661, 2511
805
1061
1062
1065
1060
D- 1063
D- 1064
1122
1119
1118
1118
1127, 2452
1128
423
1120
1121
1123
1125
358
1691
383
803, 2413
489
645, 2387
1018, 2436
504,
2375
1137
1139
1117
1083
1073
1065
1066
1087
1067
1091
L- 1092
1109
1116
dl- 1100
dl-10z
1101, 2451
1101
1102
1110
1096
1107
Index in Japanese
1108
1099
1098
1104
1104
1096
1105
1573
1089
1089
1088
1095
1111
1112
1093
1093
1113
1113
1090
1091
1114
1115
1077
1080
1081
1082
1069
1071
1072
1070, 2450
1079
1083
1076
1085
dl- 1078
l- 1079
1577
1595, 2495
1134
1136
1133
1740
356
894
1130
1132
1131
1131
2453
1611
1682, 2512
1069
1068
670
2617
1608
822
1398
1548
1270
1404
123I
1404
131I 1404
131I
1404
131I
966
131I
1405
861
863
862
966
1627
1627, 2501
965
1075
969
966
971
1407
1026
1020
1024
1218
C 1021
C 1021
1333
2438
2439
1014
1015
1332,
2473
1039
1040
1042
1041
L- 1049
L- 1048
1351
1351
2618
Index in Japanese
1354
1353
1414
1412
1050
1725
1034
1035
1355
1357
1347
1348
1345, 2474
1341
1342, 2473
1343
1344
1345
1036
1684
1684
1685
1586
1587
357
1272
832
420
1059
1058
1059
1669
1669
1213
Supplement I, JP XVI
1598, 2495
1729
1350
1037
1038
504,
2375
1408
505
1337
0.1z 1339, 2473
1339
1338
1340
1341
1026
2440
1335
1336
1029
1029
1033
1032
1030
2443
2446
1031
2445
1032
1640
1693
L-
1028
1360
1361
1362
1364
1047
1358
1359
1045
2448
1728
1742
1744
1744
1746
1745
1743
1741
2447
1728
1045
1574
1569
1571