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USP 39 Official Monographs / Ketoconazole 4461

Change to read: IDENTIFICATION

• A. INFRARED ABSORPTION 〈197K〉
•Bacterial Endotoxins Test 〈85〉• (CN 1-May-2016)—It contains • B. The retention time of the major peak of the Sample
solution corresponds to that of the Standard solution, as
.

not more than 0.4 USP Endotoxin Unit per mg of ketamine

hydrochloride. obtained in the Assay.
pH 〈791〉: between 3.5 and 5.5. ASSAY
• PROCEDURE
Buffer: 3.4 mg/mL of tetrabutyl ammonium hydrogen
Change to read: sulfate in water
Solution A: Acetonitrile and Buffer (5:95)
Other requirements—It meets the requirements under Solution B: Acetonitrile and Buffer (50:50)
•Injections and Implanted Drug Products 〈1〉• (CN 1-May-2016).
.

Mobile phase: See Table 1.

Assay—Transfer an accurately measured volume of Injec-
tion, equivalent to about 500 mg of ketamine hydrochlo- Table 1
ride, to a 200-mL volumetric flask, dilute with water to vol-
ume, and mix. Transfer 20.0 mL of this solution to a 125-mL Time Solution A Solution B
separator, add 3 mL of 0.1 N sodium hydroxide, and extract (min) (%) (%)
with three 15-mL portions of chloroform. Collect the chloro- 0 100 0
form extracts in a second 125-mL separator, and extract 20 0 100
with three 30-mL portions of 0.1 N sulfuric acid, collecting 25 0 100
the acid extracts in a 200-mL volumetric flask. Dilute with
26 100 0
0.1 N sulfuric acid (saturated with chloroform) to volume,
and mix. Concomitantly determine the absorbances of this 30 100 0
solution and a Standard solution of USP Ketamine Hydro-
chloride RS in the same medium having a known concentra- Diluent: Methanol
tion of about 250 µg per mL, in 1-cm cells at the wave- Standard solution: 0.1 mg/mL of USP Ketoconazole RS
length of maximum absorbance at about 269 nm, with a in Diluent
suitable spectrophotometer, using 0.1 N sulfuric acid (satu- Sample solution: 0.1 mg/mL of Ketoconazole in Diluent
rated with chloroform) as the blank. Calculate the quantity, Chromatographic system
in mg, of ketamine (C13H16ClNO) in each mL of the Injec- (See Chromatography 〈621〉, System Suitability.)
tion taken by the formula: Mode: LC
Detector: UV 225 nm
(237.73 / 274.19)(2C / V)(AU / AS) Column: 4.6-mm × 10-cm; 3-µm packing L1
Flow rate: 2.0 mL/min
in which 237.73 and 274.19 are the molecular weights of Injection volume: 10 µL
ketamine and ketamine hydrochloride, respectively; C is the System suitability
concentration, in µg per mL, of USP Ketamine Hydrochlo- Sample: Standard solution

USP Monographs
ride RS in the Standard solution; V is the volume, in mL, of Suitability requirements
Injection taken; and AU and AS are the absorbances of the Tailing factor: NMT 2.0
solution from the Injection and the Standard solution, re- Relative standard deviation: NMT 0.73%
spectively. Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of ketoconazole
(C26H28Cl2N4O4) in the portion of Ketoconazole taken:
Result = (rU/rS) × (CS/CU) × 100
.

Ketoconazole
rU = peak response from the Sample solution
rS = peak response from the Standard solution
CS = concentration of USP Ketoconazole RS in the
Standard solution (mg/mL)
CU = concentration of Ketoconazole in the Sample
solution (mg/mL)
Acceptance criteria: 98.0%–102.0% on the dried basis
IMPURITIES
• RESIDUE ON IGNITION 〈281〉
Sample: 2 g
Acceptance criteria: NMT 0.1%

Delete the following:

•• HEAVY METALS, Method II 〈231〉: NMT 20 ppm• (Official 1-
C26H28Cl2N4O4 531.43 .

Piperazine, 1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H- Jan-2018)

imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-, • ORGANIC IMPURITIES

cis-; Buffer, Solution A, Solution B, Mobile phase, Diluent,
(±)-cis-1-Acetyl-4-(p-[[2-(2,4-dichlorophenyl)-2-(imidazol-1- and Chromatographic system: Proceed as directed in
ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl)piperazine the Assay.
[65277-42-1]. Standard solution: 0.01 mg/mL each of USP
Ketoconazole RS and USP Terconazole RS in Diluent
DEFINITION Sample solution 10.0 mg/mL of Ketoconazole in
Ketoconazole contains NLT 98.0% and NMT 102.0% of Diluent
ketoconazole (C26H28Cl2N4O4), calculated on the dried
basis.

Official from May 1, 2016

Copyright (c) 2015 The United States Pharmacopeial Convention. All rights reserved.
 Accessed from 10.6.1.1 by ebsc0sa on Fri Nov 13 01:43:51 EST 2015

4462 Ketoconazole / Official Monographs USP 39

System suitability fied Water, and dilute quantitatively, and stepwise if neces-
Sample: Standard solution sary, with Purified Water to obtain 10 mL of a solution
Suitability requirements containing 10 mg of Cetylpyridinium Chloride. Transfer this
Resolution: NLT 2.0 between ketoconazole and ter- solution, in divided portions, to the mortar containing the
conazole peaks powder, and mix to form a smooth paste. Place 20 mL of
Relative standard deviation: NMT 5.0% for the Purified Water in a beaker. Using moderate heat, stir to
ketoconazole peak form a vortex, and slowly sprinkle the Xanthan Gum into
Analysis the vortex to obtain a uniform dispersion. Add the disper-
Samples: Standard solution and Sample solution sion to the wetted powder paste, and mix until smooth.
Calculate the percentage of any impurities in the por- Add a sufficient quantity of the Suspension Structured Vehi-
tion of Ketoconazole taken: cle or Sugar-Free Suspension Structured Vehicle to bring to
final volume. Mix well.
Result = (rU/rS) × (CS/CU) × 100
ASSAY
rU = peak response of any impurities from the • PROCEDURE
Sample solution Mobile phase: Acetonitrile and 0.01 M tetrabutylam-
rS = peak response of Ketoconazole from the monium hydrogen sulfate (25:75). Pass through a filter
Standard solution of 5-µm or finer pore size, and degas.
CS = concentration of USP Ketoconazole RS in the Diluent: Methanol and water (50:50)
Standard solution (mg/mL) System suitability solution: Dissolve 4 mg of USP
CU = concentration of Ketoconazole in the Sample Ketoconazole RS in 1.0 mL of a solution of potassium
solution (mg/mL) sorbate in water (1 in 5000). Dilute with Diluent to
Acceptance criteria: Disregard any peak less than 10.0 mL.
0.05%. Standard solution: 0.4 mg/mL of USP Ketoconazole RS
Any individual unspecified impurity: NMT 0.10% in Diluent
Total impurities: NMT 2.0% Sample solution: [NOTE—If the Oral Suspension has
settled, invert the container 10–15 times, and sonicate
SPECIFIC TESTS for 5 min, or stir on a magnetic stirrer until the Oral
• OPTICAL ROTATION, Specific Rotation 〈781S〉 Suspension appears homogeneous. Examine the mix-
Sample solution: 40 mg/mL in methanol ture for the presence of bubbles and unsuspended
Acceptance criteria: −1° to +1° at 20° solids before sampling.] Transfer 5.0 mL of homogene-
• LOSS ON DRYING 〈731〉 ous Oral Suspension to a 250-mL volumetric flask, add
Analysis: Dry under vacuum at 80° for 4 h. 100 mL of water, and stir for 15 min to dissolve the
Acceptance criteria: NMT 0.5% xanthan gum. Add 135 mL of methanol, and stir for an
additional 15 min. Cool, and dilute with methanol to
ADDITIONAL REQUIREMENTS volume.
• PACKAGING AND STORAGE: Preserve in well-closed Chromatographic system
containers. (See Chromatography 〈621〉, System Suitability.)
USP Monographs

• USP REFERENCE STANDARDS 〈11〉 Mode: LC

USP Ketoconazole RS Detector: UV 223 nm
USP Terconazole RS Columns
Piperazine, 1-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2, Guard: 5-µm packing L1
4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methox- Analytical: 4.6-mm × 25-cm; 5-µm packing L1
y]phenyl]-4-(1-methylethyl)-, cis-; Column temperature: 30°
cis-1-(p-{[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol- Flow rate: 1 mL/min
1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)- Injection volume: 5 µL
4-isopropylpiperazine. System suitability
C26H31Cl2N5O3 532.46 Samples: System suitability solution and Standard
solution
[NOTE—The relative retention times for ketoconazole
and sorbate are 1.0 and 1.7, respectively.]
Suitability requirements
.

Ketoconazole Oral Suspension Resolution: NLT 2.0 between sorbate and

ketoconazole, System suitability solution
DEFINITION Relative standard deviation: NMT 2.0% for replicate
Ketoconazole Oral Suspension contains NLT 90.0% and injections, Standard solution
NMT 110.0% of the labeled amount of ketoconazole Analysis
(C26H28Cl2N4O4). Calculate the percentage of ketoconazole
Prepare Ketoconazole Oral Suspension 20 mg/mL as follows (C26H28Cl2N4O4) in the portion of Oral Suspension
(see Pharmaceutical Compounding—Nonsterile Preparations taken:
〈795〉).
Result = (rU/rS) × (CS/CU) × 100
Ketoconazole 2.0 g
rU = peak response from the Sample solution
Cetylpyridinium Chloride 10 mg rS = peak response from the Standard solution
Xanthan Gum 0.15 g CS = concentration of ketoconazole in the Standard
Purified Water 30 mL solution (mg/mL)
Suspension Structured Vehicle or Sugar- CU = nominal concentration of ketoconazole in the
Free Suspension Structured Vehicle, a suf- Sample solution (mg/mL)
ficient quantity to make 100 mL Acceptance criteria: 90.0%–110.0%
Place the required number of tablets in a glass mortar, and ADDITIONAL REQUIREMENTS
comminute to a fine powder such that they pass through • PACKAGING AND STORAGE: Package in tight, light-resistant
a 40-mesh or 45-mesh sieve, or add Ketoconazole powder amber containers. Store at controlled room temperature.
to the mortar. Dissolve the Cetylpyridinium Chloride in Puri-

Official from May 1, 2016

Copyright (c) 2015 The United States Pharmacopeial Convention. All rights reserved.