IJPRD, 2012; Vol 4(05): July-2012 (103 - 110) International Standard Serial Number 0974 – 9446

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A REVIEW ON HYDROTROPY: A NOVEL CONCEPT FOR SOLUBILITY ENHANCEMENT

Thummar Jayesh M.1*,

Parmar Hardik , Prajapati Nirav 1 , Pradhan Prasanna1 , Upadhayay Umesh1
1

1
Department of Quality Assurance, Sigma Institute of Pharmacy, Bakrol, Ajwa-Nimeta road, Vadodara,
Gujarat, India.

ABSTRACT
Solubility is one of the important parameter to achieve desired Correspondence to Author
concentration of drug in systemic circulation for pharmacological
response to be shown. Drug efficacy can be severely limited by
poor aqueous solubility and some drugs also show side effects due
to their poor solubility. There are many techniques which are used
to enhance the aqueous solubility. The ability to increase aqueous
solubility can thus be a valuable aid to increasing efficiency and/or
reducing side effects for certain drugs. This is true for parentrally, Thummar Jayesh M.
topically and orally administered solutions. Use of the solubility
characteristics in bioavailability, pharmacological action and 65/Diwali Nagar, Near Radha Krishna
solubility enhancement of various poorly soluble compounds is a Temple,L.H. Rd., Surat-395010,
challenging task for researchers and pharmaceutical scientists. Gujarat, India
Hydrotropy is one of the solubility enhancement techniques which
enhance solubility to many folds with use of hydrotropes like Email: [email protected]
sodium benzoate, sodium citrate, urea, niacinamide etc. and have
many advantages like, it does not require chemical modification of
hydrophobic drugs, use of organic solvents or preparation of
emulsion system etc.

Key words: Hydrotropy, Hydrotropes, Solubility, Solubility

enhancement.

INTRODUCTION aqueous solubility of another solute. However,

The term hydrotropic agent was first introduced the term has been used in the literature to
by Neuberg (1916), to designate anionic organic designate non-micelle-forming substances, either
salts which, at high concentrations, considerably liquids or solids, organic or inorganic, capable of
increase the aqueous solubility of poorly soluble solubilizing insoluble compounds. The chemical
solutes[1]. Hydrotropy is a solubilization structure of the conventional Neuberg’s
phenomenon whereby addition of large amount hydrotropic salts (proto-type, sodium benzoate)
of second solute results in an increase in the consists generally of two essential parts, an

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International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446

anionic group and a hydrophobic aromatic ring or solubility in terms of number of milliliters of
ring system. The anionic group is obviously solvent required to dissolve 1g of solute. If exact
involved in bringing about high aqueous solubility, solubilities are not known, the Pharmacopoeia
which is a prerequisite for a hydrotropic provides general terms to describe a given range.
substance. The type of anion or metal ion These descriptive terms are listed in (Table1.1).
appeared to have a minor effect on the
phenomenon[2]. The pharmacopoeia lists
Table 1.1 Expression for approximate solubility[3]
Relative amounts of solvents to
Descriptive terms
dissolve 1 part of solute
Very soluble Less than 1
Freely soluble From 1-10
Soluble From 10-30
Sparingly soluble From 30-100
Slightly soluble From 100-1000
Very slightly soluble From 1000-10,000
nsoluble or practically insoluble More than 10,000
NEED OF SOLUBILITY candidates was due to poor “drug-like” properties.
Therapeutic effectiveness of a drug depends upon It is commonly recognized in the pharmaceutical
the bioavailability and ultimately upon the industry that on average more than 40% of newly
solubility of drug molecules. Solubility is one of the discovered drug candidates are poorly water-
important parameter to achieve desired soluble. Poor “drug like” properties of lead
concentration of drug in systemic circulation for compounds led to ineffective absorption from the
pharmacological response to be shown. Currently site of administration, which has been designated
only 8% of new drug candidates have both high as an important part of the high clinical failure due
solubility and permeability[4]. Due to advanced to poor pharmacokinetics [6]
research & development, there are varieties of new
drugs & their derivatives are available. But more MECHANISM OF HYDROTROPE ACTION [2]
than 40% of lipophilic drug candidates fail to reach A hydrotrope is a compound that solubilises
market due to poor bioavailability, even though hydrophobic compounds in aqueous solutions.
these drugs might exhibit potential Typically, hydrotropes consist of a hydrophilic part
pharmacodynamic activities. The lipophilic drug and a hydrophobic part (like surfactants) but the
that reaches market requires a high dose to attain hydrophobic part is generally too small to cause
proper pharmacological action. The basic aim of spontaneous self-aggregation. Hydrotropes do not
the further formulation & development section is have a critical concentration above which
to make that drug available at proper site of action selfaggregation 'suddenly' starts to occur. Instead,
within optimum dose[5]. As a matter of fact, more some hydrotropes aggregate in a step-wise self-
than one-third of the drugs listed in the U.S. aggregation process, gradually increasing
Pharmacopoeia fall into the poorly water-soluble aggregation size. However, many hydrotropes do
or water-insoluble categories. It was reported a not seem to selfaggregate at all, unless a
couple of decades ago that more than 41% of the solubilisate has been added.
failures in new drug development have been Maheshwari et al[7]; enhanced the aqueous
attributed to poor biopharmaceutical properties, solubility of paracetamol, a poorly water-soluble
including water insolubility, while it was still drug by use of concentrated solution of urea (a
indicated recently that about 50% failure of drug hydrotropic agent).

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This hydrotropic phenomenon was employed to nicotine[10], ionic surfactants like diacids[11], SDS
prepare solid dispersion (SD) and syrup of (sodium dodecyl sulphate)[12] and dodecylated
paracetamol. SD was evaluated for dissolution rate oxidibenzene[13]. The aromatic hydrotropes with
and a marked increase in dissolution rate was anionic head groups are mostly studied
observed with SD. IR analysis revealed that there compounds. They are large in number because of
was no complexation/interaction between isomerism and their effective hydrotrope action
paracetamol and urea. Paracetamol syrups may be due to the availability of interactive pi-
prepared with urea showed good chemical orbitals. Hydrotropes with cationic hydrophilic
stabilities. group are rare, e.g. salts of aromatic amines, such
as procaine hydrochloride[14]. Besides enhancing
COMMONLY USED HYDROTROPES the solubilization of compounds in water, they are
The hydrotropes are known to self-assemble in known to exhibit influences on surfactant
solution[8]. The classification of hydrotropes on the aggregation leading to micelle formation, phase
basis of molecular structure is difficult, since a wide manifestation of multicomponent systems with
variety of compounds have been reported to reference to nanodispersions and conductance
exhibit hydrotropic behaviour. Specific examples percolation, clouding of surfactants and polymers,
may include ethanol[9], aromatic alcohols like etc.[8,14].
resorcinol, pyrogallol, catechol, a- and b-naphthols
and salicylates, alkaloids like caffeine and
Table 1.2: Hydrotropic solubilization study of various poorly water-soluble drugs[15-35]
Drug Hydrotropic agent
Riboflavin ProcaineHCl, PABAHCl,
CinchocaineHCl, Resorcinol,
Pyrogallol
Chartreusin Sodium benzoate, Sodium p-
hydroxybenzoate, Sodium m-
hydroxybenzoate, Sodium o-
hydroxybenzoate, Sodium 2,4-
dihydroxybenzoate, Sodium 2,5-
dihydroxybenzoate, Sodium 2,6-
dihydroxybenzoate, Sodium 2,4, 6-
trihydroxybenzoate
Diazepam, Medazepam, Oxazepam, Sodium salicylate
Nitrazepam, Clonazepam
Theophylline, Hydrocortisone, Sodium benzoate, Sodium o-
Prednisolone, Phenacetin hydroxybenzoate, Sodium m-
hydroxybenzoate, Sodium p-
hydroxybenzoate, Sodium 2,4-
dihydroxy benzoate, Sodium 2,5-
dihydroxybenzoate, Sodium 2,6-
dihydroxybenzoate, Sodium 3,4-
dihydroxybenzoate, Sodium 3,5-
dihydroxybenzoate, Sodium 3,4,5 –
trihydroxybenzoate
Paracetamol Sodium salicylate, Sodium glycinate,

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International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446

Sodium gentisate, Nicotinamide

Saquinavir Nicotinamide, Ascorbic acid,
Dimethyl urea, Resorcinol
Benzoic acid, Salicylic acid Urea, Methyl Urea, 1-3-dimethyl
urea
Rofecoxib, celecoxib, melocoxib Nicotinamide, Sodium benzoate,
Sodium salicylate
Riboflavin Nicotinamide
Temazepam Sodium salicylate, Nicotinamide
Ibuprofen Sodium salt of Ibuprofen
Nifedipine Urea, Methyl urea, Ehhyl urea,
Butyl urea, icotinamide, N-methyl
nicotinamide, N, N-dimethyl
nicotinamide
Ketoprofen Sodium benzoate, Sodium o-
hydroxybenzoate, Nicotinamide,
Sodium m-hydroxybenzoate, Sodium
ascorbate, Sodium 2,5-
dihydroxybenzoate
icam Sodium ascorbate, Sodium
benzoate, Sodium o-
hydroxybenzoate, Sodium m-
hydroxybenzoate, Sodium 2,5-
dihydroxybenzoate
Carbamazepine Sodium salicylate, Sodium benzoate
Each hydrotropic agent is effective in increasing the al[37], investigated the effect of various hydrotropes
water solubility of selected hydrophobic drugs. No such as urea, nicotinamide, resorcinol, sodium
universal hydrotropic agent has been found benzoate, sodium p-hydroxy benzoate on the
effective to solubilize all hydrophobic drugs. Thus solubility of indomethacin. The solubility
finding the right hydrotropic agent for a poorly enhancement of indomethacin by the hydrotropes
water-soluble drug requires screening of large was observed in decreasing order as sodium p-
number of candidate hydrotropes. However, once hydroxyl benzoate> sodium benzoate>
the effective hydrotropic agent is identified for a nicotinamide> resorcinol> urea. Aqueous injectable
series of structurally different drugs, the structure formulations using sodium p-hydroxyl benzoate,
activity relationship can be established. Agrawal et sodium benzoate and nicotinamide as hydrotropes
al.[36], investigated the effect of various were developed and studied for physical and
hydrotropes such as sodium benzoate, sodium chemical stability.
salicylate and piperzine on the solubility of Hydrotropes are used in detergent formulations to
nimesulide. The solubility enhancement of allow more concentrated formulations of
nimesulide by the hydrotropes observed in surfactants. Examples of hydrotropes include
decreasing order as piperazine>sodium ascorbate> sodium p-toluenesulfonate and sodium xylene
sodium salicylate> sodium benzoate> sulfonate. Poochikian et al[16], studied the
nicotinamide. Parenteral formulations using solubilization of chartreusin by hydroxybenzoate.
piperazine as a hydrotrope were developed and Plane to plane orientation of ligand molecules and
studied for physical and chemical stability. Jain et chartreusin brought together by electrostatic and

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hydrophobic interactions was suggested as possible reagent blanks at appropriate wavelengths.

mechanism. Jain et al.[30], investigated the Titrimetric analysis method employed for
solubilization of ketoprofen, by means of various determining equilibrium solubility at room
physiologically active hydrotropic agents. In order temperature. Enhancement ratios in solubilities
to gain an insight into probable mechanism of were determined by following formula -
solubilization, solubility, spectral, typical properties Enhancement ratio = Solubility in hydrotropic
of hydrotropes, solution properties, gel formation, solution÷ Solubility in distilled water Smita Sharma,
paste formation, TLC and IR spectral studies were Mukesh C. Sharma[39] were investigate that
carried out with structural variation in hydrotropes. hydrotropic solution of 8M urea has been
The results indicated that the enhanced solubility employed as solubilizing agent to solubilisation
of ketoprofen in presence of hydrotropes in low poorly water soluble drug Pseudoephedrine
concentration is due to weak ionic interaction. At Sulphate, Desloratidine, from fine powder of its
higher concentration, the formation of molecular tablet dosage form for spectrophotometric
aggregates seemed to be the possible mechanism determination in ultraviolet region.
of hydrotropic solubilization. Rawat et al.[25], Pseudoephedrine Sulphate, Desloratidine shows
studied the effects of various hydrotrops such as maximum absorbance at resulting solutions were
nicotinamide, sodium benzoate, sodium salicylate measured at 274.4 nm and 289.1nm. R. K.
in the solubility of rofecoxib, celecoxib and Maheshwari, s. R. Bishnoi, d. Kumar, murali
meloxicam, and were investigated to gain an krishna[40] , in the present investigation,
insight into the mechanism of solubilization. The hydrotropic solution of ibuprofen sodium (0.5M)
results indicated that the enhanced solubility of was employed as solubilizing agent to solubilize the
these drugs in the presence of hydrotropes in low poorly water-soluble drug, ornidazole from fine
concentration is due to weak ionic interaction. At powder of its tablets for spectrophotometric
high hydrotropic concentration the formation of determination. Ornidazole shows its maximum
molecular aggregation seems to be the possible absorbance at 320 nm and Beer’s law was obeyed
mechanism of solubilization. Coffman et al.[26], in concentration range of 5-25 mcg/ml.
studied the effect of nicotinamide and urea on the ADVANTAGES OF HYDROTROPIC SOLUBILIZATION
solubility of riboflavin in various solvents. Their TECHNIQUE[2]
study examined the mechanism of hydrotropic 1. Hydrotropy is suggested to be superior to other
solubilization. The most commonly proposed solubilization method, such as miscibility,
mechanism for hydrotropic solubilization is micellar solubilization, co solvency and salting
complexation. in, because the solvent character is independent
DETERMINATION OF INTERFERENCE OF of pH, has high selectivity and does not require
HYDROTROPIC AGENTS IN THE emulsification.
SPECTROPHOTOMETRIC ESTIMATION OF DRUGS 2. It only requires mixing the drug with the
[38]
hydrotrope in water.
A UV-Visible recording spectrophotometer with 1 3. It does not require chemical modification of
cm matched silica cells was employed for hydrophobic drugs, use of organic solvents, or
spectrophotometric determinations. For preparation of emulsion system.
determination of interference of hydrotropic MIXED HYDROTROPY
agents in the spectrophotometric estimation of the Mixed hydrotropic solubilization technique is the
standard solutions of drugs were determined in phenomenon to increase the solubility of poorly
distilled water alone and in the presence of the water-soluble drugs in the blends of hydrotropic
maximum concentration of the hydrotropic agent agents, which may give miraculous synergistic
employed for spectrophotometric analysis. The enhancement effect on solubility of poorly water
absorbances were recorded against respective soluble drugs, utilization of it in the formulation of
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dosage forms of water insoluble drugs and to 2. Quantitative estimations of poorly watersoluble
reduce concentration of individual hydrotropic drugs by titrimetric analysis.such as ibuprofen,
agent to minimize the side effects in place of using flurbiprofen and naproxen using sodium
a large concentration of one hydrotrope a blend of, benzoate[42] .
say, 5 hydrotropes can be employed in 1/5th 3.Preparation of hydrotropic solid dispersions of
concentrations reducing their individual poorly water-soluble drugs precluding the use of
[41]
toxicities . Maheshwari observed miraculous organic solvents. Such as felodipine[43] using
synergistic effect on enhancement in solubility of a poly-ethylene glycol 6000 and poly-vinyl alcohol.
poorly water-soluble drug (aceclofenac) by mixing 4. Preparation of dry syrups (for reconstitution) of
two hydrotropic agents (urea and sodium citrate) poorly water-soluble drugs.
and mixed hydrotropic blend was employed to 5. Preparation of topical solutions of poorly water-
solubilize a poorly water-soluble drug, aceclofenac soluble drugs, precluding the use of organic
from fine powder of its tablets to carryout solvents. Such as tinidazole, metronidazole and
spectrophotometric analysis precluding the use of salicylic acid using sodium benzoate and sodium
organic solvents. citrate.
6. Preparation of injection of poorly water soluble
ADVANTAGES OF MIXED HYDROTROPIC drugs.
SOLUBILIZATION 7. The use of hydrotropic solubilizers as
1. It may reduce the large total concentration of permeation enhancers.
hydrotropic agents necessary to produce 8. The use of hydrotropy to give fast release of
modest increase in solubility by employing poorly water-soluble drugs from the
combination of agents in lower concentration. suppositories.
2. It is new, simple, cost-effective, safe, accurate, 9. Application of mixed- hydrotropy to develop
precise and environmental friendly method for injection dosage forms of poorly water soluble
the analysis (titrimetric and spectrophotometric) drugs.
of poorly water-soluble drugs titrimetric and 10.Application of hydrotropic solubilization in
spectrophotometric precluding the use of nanotechnology (by controlled precipitation).
organic solvents. 11. Application of hydrotropic solubilization in
3. It precludes the use of organic solvents and thus extraction of active constituents from crude
avoids the problem of residual toxicity, error drugs (in pharmacognosy field).
due to volatility, pollution, cost etc. 12.Hydrotropic solutions can also be tried to
Maheshwari[41], investigated the application of develop the dissolution fluids to carry out the
mixed hydrotropy. There was miraculous dissolution studies of dosage forms of poorly
synergistic effect on enhancement in solubility water-soluble drugs.
of a poorly water-soluble drug by mixing two
hydrotropic agents. Solubility of aceclofenac in CONCLUSION
blends of two hydrotropic agents was much Drugs and solubility is also the basic requirement
larger than the sum of the solubilities of for the formulation and development of different
aceclofenac in individual hydrotropic solutions. dosage form of different drugs. Solubility can be
NOVEL PHARMACEUTICAL APPLICATIONS OF enhanced by many techniques and number of folds
HYDROTROPIC SOLUBILIZATION IN VARIOUS increase in solubility is reported too. Because of
FIELDS OF PHARMACY[02] solubility problem of many drugs the bioavailability
1.Quantitative estimations of poorly watersoluble of them gets affected and hence solubility
drugs by UV-Visible spectrophotometric analysis enhancement becomes necessary. It is now
precluding the use of organic solvents. possible By this article we conclude that, Solubility
is a most important parameter for the oral
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the help of various techniques as mentioned above 16. Badwan A.A. et al, “The solubility of
benzodiazepines in sodium salicylate solution
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