Priyanka Arjaria et al / Int. J. Pharm. Phytopharmacol. Res.

2013; 3 (1): 17-23

ISSN (Online) 2249-6084 (Print) 2250-1029

International Journal of Pharmaceutical and

Phytopharmacological Research (eIJPPR)
[Impact Factor 0.7826]
Journal Homepage: www.eijppr.com

Review Article
Hydrotropic Solubilization
1

Priyanka Arjaria , Manoj Goyal , Suman Jain

1

Shri Ram College of pharmacy,Banmore,Morena, India, IPS College of pharmacy, Gwalior, India, SOS Pharama.Scie.,JiwajiUniversity,Gwalior, India

Article info
Article History:
Received 2 August 2013
Accepted 25 August 2013

Keywords:
Hydrotropy, Solid dispersion,
Solubility, Poorly water soluble
drugs.

Abstract
Solubility is the major problem for various drugs in pharmaceutical industry. Many drugs show poor aqueous
solubility, which result in poor bioavailability of the drug. Solubility enhancement processes are widely used in
pharmaceutical industry to improve the dissolution and bioavailability of poorly water soluble drug. The efficacy
of drug response is mainly dependent on dissolution and bioavailability. Almost more than 90% drugs are orally
administered. Drug absorption, sufficient and reproducible bioavailability, pharmacokinetic profile of orally
administered drug substance is highly dependent on solubility of that compound in aqueous medium. It is
estimated that 40% of active new chemical entities identified in combinatorial screening programs employed by
many pharmaceutical companies are poorly water soluble. Therapeutic effectiveness of a drug depends upon
the bioavailability and ultimately upon the solubility of drug molecules. Solubility is one of the important
parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be
shown. Currently only 8% of new drug candidates have both high solubility and permeability. Due to advanced
research and development, there are varieties of new drugs and their derivatives are available. But more than
40% of lipophilic drug candidates fail to reach market due to poor bioavailability, even though these drugs might
exhibit potential pharmacodynamic activities. Hydrotropy is a unique and unprecedented solubilization
technique in which certain chemical compounds termed as hydrotropes can be used to affect a several fold
increase in the aqueous solubility of sparingly soluble solutes under normal conditions. This increase in
solubility in water is probably due to the formation of organized assemblies of hydrotrope molecules at critical
concentrations. A hydrotrope is a compound that solubilizes hydrophobic compounds in aqueous solutions.
Typically, hydrotropes consist of a hydrophilic part and a hydrophobic part (like surfactants) but the hydrophobic
part is generally too small to cause spontaneous self-aggregation. Hydrotropes do not have a critical
concentration above which self-aggregration 'suddenly' starts to occur. Instead, some hydrotropes aggregate in
a step-wise self-aggregation process, gradually increasing aggregation size. However, many hydrotropes do
not seem to self-aggregate at all, unless a solubilisate has been added.

1. INTRODUCTION
Almost more than 90% drugs are orally administered. Drug
absorption,
sufficient
and
reproducible
bioavailability,
pharmacokinetic profile of orally administered drug substance is
highly dependent on solubility of that compound in aqueous
1
medium . It is estimated that 40% of active new chemical entities
identified in combinatorial screening programs employed by many
pharmaceutical companies are poorly water soluble. Orally
administered drugs on the model list of the Essential Medicines of
the World Health Organization are assigned BCS classifications on
2
the basis of data available in the public domain .

known, the Pharmacopoeia provides general terms to describe a

6
given range. These descriptive terms are listed in (Table 1) .
Table-1: Solubility terms as per pharmacopoeia
Descriptive terms
Very soluble
Freely soluble
Soluble
Sparingly soluble
Slightly soluble
Very slightly soluble
Insoluble or practically insoluble

1.1 Meaning of Solubility

The term solubility can be defined quantitatively as well as
qualitatively. Quantitatively it is defined as the concentration of the
solute in a saturated solution at a certain temperature. In qualitative
terms, solubility may be defined as the spontaneous interaction of
two or more substances to form a homogenous molecular
dispersion. A saturated solution is one in which the solute is in
3-5
equilibrium with the solvent .
The pharmacopoeia lists solubility in terms of number of milliliters of
solvent required to dissolve 1g of solute. If exact solubilities are not

Relative amounts of solvents to dissolve

1 part of solute
Less than 1
From 1-10
From 10-30
From 30-100
From 100-1000
From 1000-10,000
More than 10,000

1.2 Need of Solubility

Therapeutic effectiveness of a drug depends upon the
bioavailability and ultimately upon the solubility of drug molecules.
Solubility is one of the important parameter to achieve desired
concentration of drug in systemic circulation for pharmacological
response to be shown. Currently only 8% of new drug candidates
have both high solubility and permeability.Due to advanced
research and development, there are varieties of new drugs and
their derivatives are available. But more than 40% of lipophilic drug
candidates fail to reach market due to poor bioavailability, even
though these drugs might exhibit potential pharmacodynamic
activities. The lipophilic drug that reaches market requires a high
dose to attain proper pharmacological action. The basic aim of the
further formulation and developm ent section is to make that drug
7
available at proper site of action within optimum dose . To increase

*Corresponding Author:
Dr. Manoj Goyal,
Associate Professor,
Dept. of pharmaceutics, IPS College of pharmacy,
Gwalior, India
Email: [email protected]
Tel. No. +91-9425171687

17

Priyanka Arjaria et al / Int. J. Pharm. Phytopharmacol. Res. 2013; 3 (1): 17-23

20

the solubility of poorly water soluble drugs different solubilization

techniques have been used.
1.3 Process of Solubilization
The process of solubilization involves the breaking of inter-ionic or
intermolecular bonds in the solute, the separation of the molecules
of the solvent to provide space in the solvent for the solute,
8
interaction between the solvent and the solute molecule or ion .

Coffman et al. argued that nicotinamide can solubilize riboflavin

through a self-aggregation mechanism where aggregates of
nicotinamide grow by step wise monomer addition. At low
concentrations, dim erization predominates, whereas at higher
concentrations, trimerization, tetramerization, and so on, become
the predominant equilibria.
2.2 Selection of Hydrotropes for Poorly Water Soluble Drugs
In order to select suitable hydrotropes (for sufficient enhancement
in solubility) for various poorly water-soluble drugs, an approximate
solubility determination method is used. This is a modified form of
the m ethod used by Simamora et al. Twenty five ml of distilled
water/hydrotropic solution is taken in a 50 ml glass bottle and gross
weight (including the cap) is noted. Then, few mg (by visual
observation) of fine powder of drug is transferred to the bottle. The
bottle is shaken vigorously (by hand). When drug gets dissolved,
more drug (few mg by visual observation) is transferred to the bottle
and again the bottle is shaken vigorously. Same operation is
repeated till some excess drug remained undissolved (after
constant vigorous shaking for 10 minutes). Then, again gross
weight is noted. From the difference in two readings (of weight), an
approximate solubility is determined and solubility enhancement
ratios (solubility in hydrotropic solution/solubility in distilled water)
21
are calculated .
2.3 Advantages of Hydrotropic Solubilization Technique
1. Hydrotropy is suggested to be superior to other solubilization
method, such as miscibility, micellar solubilization, co
solvency and salting in, because the solvent character is
independent of pH, has high selectivity and does not require
emulsification.
2. It only requires mixing the drug with the hydrotrope in water.
3. It does not require chemical modification of hydrophobic drugs,
13
use of organic solvents, or preparation of emulsion system .

2. HYDROTROPY
Hydrotropy is a unique and unprecedented solubilization technique
in which certain chemical compounds termed as hydrotropes can
be used to affect a several fold increase in the aqueous solubility of
sparingly soluble solutes under normal conditions. This increase in
solubility in water is probably due to the formation of organized
assemblies of hydrotrope molecules at critical concentrations.
Hydrotropes in general are water-soluble and surface-active
compounds which can significantly enhance the solubility of organic
solutes such as esters, acids, alcohols, aldehydes, ketones,
9-12
hydrocarbons, and fats .

2.4 Mixed Hydrotropy

Mixed hydrotropic solubilization technique is the phenomenon to
increase the solubility of poorly water-soluble drugs in the blends of
hydrotropic agents, which may give miraculous synergistic
enhancement effect on solubility of poorly water soluble drugs,
utilization of it in the formulation of dosage forms of water insoluble
drugs and to reduce concentration of individual hydrotropic agent to
minimize the side effects in place of using a large concentration of
one hydrotrope a blend of, say, 5 hydrotropes can be employed in
1/5th concentrations reducing their individual toxicities.

2.1 Mechanism of Hydrotrope Action

A hydrotrope is a compound that solubilizes hydrophobic
compounds in aqueous solutions. Typically, hydrotropes consist of
a hydrophilic part and a hydrophobic part (like surfactants) but the
hydrophobic part is generally too small to cause spontaneous selfaggregation. Hydrotropes do not have a critical concentration
above which self-aggregration 'suddenly' starts to occur. Instead,
some hydrotropes aggregate in a step-wise self-aggregation
process, gradually increasing aggregation size. However, many
hydrotropes do not seem to self-aggregate at all, unless a
13
solubilisate has been added .
The chemical structure of the conventional Neubergs hydrotropic
salts (proto-type, sodium benzoate) consists generally of two
essential parts, an anionic group and a hydrophobic aromatic ring
or ring system. The anionic group is obviously involved in bringing
about high aqueous solubility, which is a prerequisite for a
hydrotropic substance. The type of anion or metal ion appeared to
have a minor effect on the phenom enon. On the other hand,
planarity of the hydrophobic part has been emphasized as an
14, 15
important factor in the mechanism of hydrotropic solubilization
.
Additives may either increase or decrease the solubility of a solute
in a given solvent. These salts that increase solubility are said to
salt in the solute and those salts that decrease the solubility salt
out the solute. The effect of an additive depends very much on the
influence, it has on the structure of water or its ability to compete
16
with the solvent water molecules . Other possible mechanisms
17
may be complexation , changes in the nature or structure of the
18
solvent .
For aromatic hydrotropes such as nicotinamide, sodium salicylate
and sodium p-toluene sulfonate, two main mechanisms have been
proposed. One is stacking complexation, and the other is selfaggregation. Strong evidence of complexation between a drug and
nicotinamide is that the complexation constants (K1:1 and K1:2)
17, 19
can be obtained from phase-solubility data
. On the other hand,
by showing temperature effects on the degree of self-association,

2.5 Advantages of Mixed Hydrotropic Solubilization

1. It may reduce the large total concentration of hydrotropic agents
necessary to produce modest increase in solubility by employing
combination of agents in lower concentration.
2. It is new, simple, cost-effective, safe, accurate, precise and
environmental friendly method for the analysis (titrimetric and
spectrophotometric) of poorly water-soluble drugs titrimetric and
spectrophotometric precluding the use of organic solvents.
3. It precludes the use of organic solvents and thus avoids the
problem of residual toxicity, error due to volatility, pollution, cost
22
etc .
2.6 Pharmaceutical Applications of Hydrotropic Solubilization
Technique
2.6.1 Quantitative Estimations of Poorly Water Soluble Drugs
Various organic solvents like methanol, chloroform, acetone,
dimethyl formamide and ethanol have been employed for
solubilization of poorly water-soluble drugs to conduct their
titrimetric analyses. Drawbacks of organic solvents include their
higher costs, toxicities and pollution. Similarly, various organic
solvents like methanol, chloroform, ethanol, dimethyl formamide,
benzene, hexane, acetone, toluene, carbon tetrachloride, diethyl
ether and acetonitrile are widely used in spectrophotometric
estimations of poorly water-soluble drugs. Most of these organic
solvents are toxic, costlier and sources of pollution. Inaccuracy in
spectrophotometric estimations due to volatility of organic solvents
is another drawback of these solvents.
As evident from Table 2 there is good enhancement in aqueous
solubility of selected poorly water-soluble drugs in presence of
large amounts of hydrotropic agents. Therefore, it was thought

18

Priyanka Arjaria et al / Int. J. Pharm. Phytopharmacol. Res. 2013; 3 (1): 17-23

worthwhile to make use of hydrotropic solubilization techniques in

development of new titrimetric and spectrophotometric methods for
the analysis of poorly water-soluble drugs.41

Part A is kept at room temperature for 48 h to check its chemical

stability and to observe precipitation, if any. Part B filtrate is diluted
appropriately with distilled water and is analyzed on UVspectrophotometer against reagent blank by noting the absorbance
at selected wavelength. The drug content of the tablet formulation
is calculated using regression equation. After 48h, filtrate of part A
is analyzed in the same way, to check the chemical stability of drug
in presence of hydrotropic agent. After first analysis, same
procedure is repeated for five times more. In these cases, filtrates
are not divided in two parts. Filtrates are analyzed in fresh
conditions only.

Table 2: Hydrotropic solubilization study of various poorly watersoluble drugs

S.
No.

Drug

Ibuprofen

2
3
4

Ketoprofen
Naproxen
Piroxicam

Olanzepine

7
8

Lornoxicam and
Paracetamol
Aceclofenac
Theophylline

Glipizide

10
11

Escitalopram
Chlorobenzene

12

1,1/1,2diphenylethane

13

L-Tyrosine

14
15
16
17
18

m/p amino
nitrobenzene
Methyl
benzoate
Furfural
Acetylsalicylic
acid
m/paminoacetophe
none

Hydrotrope
Sodium acetate, Sodium benzoate,
Sodium toluene sulfonate, Sodium
salicylate and Sodium toluate
Potassium acetate
Niacinamide
Ibuprofen sodium
Sodium benzoate, sodium acetate,
sodium bicarbonate, sodium chloride,
sodium gluconate, thiourea, trisodium
citrate and urea.

Reference
23
24
25
26
27

Urea

28

Urea and sodium citrate

Urea and sodium citrate
PEG (Polyethylene glycol) 4000, mannitol
and urea
Niacinamide
Citric acid, sodium benzoate and urea
Diethylnicotinamide, sodium
pseudocumenesulfonate and sodium
thiocyanate
Caffeine, Nicotinamide, Sodium salicylate
and Sodium
Benzoate
Sodium benzoate, sodium saccharin,
dimethyl benzamide

29
30

Citric acid, urea and nicotinamide

37

Urea, tri-sodium citrate, sodium toluate

and sodium benzoate
Sodium salicylate, sodium benzoate,
nicotinamide and urea
Diethyl nicotinamide,
sodium pseudocumenesulfonate and
sodium thiocyanate

2.7 Recovery Studies of Marketed Tablet formulations Using

Hydrotropic Solubilization Technique
In order to validate the proposed method, the recovery studies are
performed. For this, preanalyzed tablet powder equivalent to
selected quantity of drug is accurately weighed and transferred to a
25 ml volumetric flask. Then, 10 mg of bulk drug sample is added to
this volumetric flask, as spiked drug. Then, selected quantity of
hydrotropic solution is added and the flask is shaken for about 10
min and the volume is madeupto the mark with distilled water. After
shaking the volumetric flask to mix the contents, filtration is done
through Whatman filter paper No. 41. Filtrate is collected, rejecting
the first few ml. The filtrate is appropriately diluted with distilled
water and absorbance of this solution is noted at selected
wavelength against respective reagent blank. The recovery studies
are performed for six times (using 10 mg spiked drug). Similar
recovery studies are performed using 20 mg of bulk drug sample as
41
the spiked drug .

31
32
33
34

35

Earlier history of spectrophotophotometric estimation of water

insoluble drugs using hydrotropic solubilization method is as
follows:
Pandey S. and Maheshwari R.K. developed a new, simple,
environment friendly, cost effective, safe and sensitive
spectrophotometric method for the determination of
ketoprofen in tablet dosage form using hydrotropic solution.
The potassium acetate enhanced the solubility of ketoprofen
(more than 210 folds) and hence was used for the
24
solubilization of poorly water soluble drugs .
Maheshwari et al. developed a new method for
spectrophotometric determination of the poorly water-soluble
naproxen tablets using niacinamide as hydrotropic
solubilizing additive. The result reveals the aqueous solubility
of naproxen using 2.0 M niacinamide solution was more than
110 fold. The standard solution (500g/ml) of naproxen was
prepared using 2.0 M niacinamide solution. This solution was
further diluted to Beer's law range 50-250 g/ ml for
naproxen. Absorbance was noted at 331 nm. The same
procedure was followed for the naproxen tablets
25
determination .
Maheshwari et al. employed hydrotropic solubilization
technique to solubilize the poorly water-soluble NSAID,
piroxicam. Determination of solubilities of the drug in 1.5 M
ibuprofen sodium hydrotropic solution and distilled water was
carried out at 281C. There was more than 50-fold
enhancement in aqueous solubility of piroxicam with 1.5M
ibuprofen sodium (as compared to aqueous solubility).
Therefore, it was thought worthwhile to solubilize the poorly
water-soluble piroxicam from fine powder of its tablets to
carryout spectrophotometric analysis at 358 nm. Ibuprofen
sodium does not show any absorbance above 300 nm.
Beers law was obeyed in the concentration range of 5-35
g/ml. Tablets containing piroxicam have been analyzed
successfully. Recovery studies and statistical data proved the
accuracy, reproducibility and the precision of the proposed
method. Based on the same principle a large number of
drugs having max above 300 nm can be estimated by 1.5 M
26
ibuprofen sodium (inexpensive hydrotropic agent) .
Sable et al. developed ultraviolet absorption employed
spectrophotometric method for the estim ation of poorly
water soluble drug like Olanzepine in pharmaceutical
formulations. Aqueous solubility of this selected model drug
was found to be increased to a great extent (6 to 98 fold) in
1M sodium benzoate, 1M sodium acetate, 1M sodium
bicarbonate, 1M sodium chloride, 1 M sodium gluconate,
1M thiourea, 1M trisodium citrate and 1 M urea

36

38
39
40

2.6.2 Spectrophotometric Estimation of Drugs Determination of

Interference of Hydrotropic Agent in the Spectrophotometric
Estimation of Drugs
A UV-Visible recording spectrophotometer with 1cm matched silica
cells is employed for spectrophotometric determinations. For
determination of interference of hydrotropic agents in the
spectrophotometric estimation drugs, the absorbances of the
standard solutions of drugs are determined in distilled water alone
and in the presence of the maximum concentration of the
hydrotropic agent employed for spectrophotometric analysis /
41
formulation purpose in the present investigation .
2.6.3 Regression Equations for Drugs
Stock solution of drug is prepared by dissolving specified quantity
of drug in appropriate volume of concentrated aqueous solution of
hydrotropic agent and making up the volume by using more water.
Stock solution is further diluted with distilled water to get standard
solutions containing concentrations of drug in the range of Beers
law. Absorbance values of these solutions are noted at max against
distilled water blank. These values of absorbances of standard
21
solutions are used to obtain regression equation.
2.6.4 Spectrophotometric Analysis of Marketed Tablet Formulations
of Drug using Hydrotropic Solubilization Technique
Twenty marketed tablets of drug are weighed and ground to a fine
powder. An accurately weighed tablet powder equivalent to quantity
of drug which was used for obtaining regression equation is
transferred to a 25 ml volumetric flask. Then volume of aqueous
solution of concentrated hydrotropic agent which was used for
obtaining regression equation is added and the flask is shaken for
about 10 min to solubilize the drug present in tablet powder and the
volume is made up to the mark with distilled water. After shaking
the volumetric flask to mix thecontents, filtration is done through
Whatman filter paper No. 41. Filtrate is collected, rejecting the first
few ml and divided in two parts A and B.

19

Priyanka Arjaria et al / Int. J. Pharm. Phytopharmacol. Res. 2013; 3 (1): 17-23

solutions. The selected max for Olanzapine was 329.5 nm.

The hydrotropic solutions used did not show any absorbance
above 306nm, and therefore, no interference in the
estimation was seen. The results of analysis have been
validated statistically, and by recovery studies. The proposed
methods are new, simple, economic, accurate, safe and
27
precise .
Banerjee et al. developed a simple, sensitive, economical
analytical method for the determination of Lornoxicam and
Paracetamol in bulk and tablet formulations. Urea solution
(Hydrotropic agent) was employed to solubilize, Lornoxicam
and Paracetamol (a poorly water soluble drug), from fine
powder of its tablets to carryout spectrophotometric analysis.
max for Lornoxicam and Paracetamol is 384 nm and 244 nm
respectively. Both Lornoxicam and Paracetamol obey Beers
2
law in the concentration range of 2-10 g/ml (r =0.9992) and
2
20-60g/ml (r =0.9990) in 8M Urea (Hydrotropic agent)
respectively. The developed methods were validated
according to ICH guidelines and values of accuracy, precision
and other statistical analysis were found to be in good
28
accordance with the prescribed values .

maintaining a temperature of 60-65C. Then the trituration is done

with pestle and mortar and after drying passes it through sieve
30
no.100 and kept in desiccators for 6 days .
Earlier history of formulation of solid dispersions of water insoluble
drugs using hydrotropic solubilization method is as follows:
Tiwari et al. prepared solid dispersion of water insoluble drug
aceclofenac using mixed hydrotropy. The reason behind
using blend of hydroropic agents was to keep the
concentration of individual hydrotropic agent below toxic
level. They used different ratio of 20%urea+10%sodium
29
citrate .
Jaikumar et al. used different solubilization techniques like,
hydrotropic solubilization, mixed hydrotropy and hydrotropic
solid dispersions in order to improve solubility and dissolution
rate of theophylline. The objective was also aimed to explore
the application of different hydrotropic agents at their
optimum concentration; thus decreases the chances of their
own toxicity. Result concluded that the toxic level of
hydrotropic agents was decreased because their minimum
concentrations were found to be sufficient to produced
desired results. Solubility enhancement ratio was found to be
89.20 times and 145.26 times more as compared to pure
drug (theophylline) in different blends A (5% urea+5% sodium
citrate) and blend B (5% urea+10% sodium citrate)
respectively. It was also concluded that the solubility of
30
theophylline increased synergistically by mixed hydrotropy.
Shukla et al. performed a comparative study of solubility of
glipizide
by
using
different
solubilization techniques such as solid dispersion, hydrotropy
and micellar solubilization. Solid dispersion of glipizide
was
prepared
by
solvent
evaporation
method;
PEG (Polyethylene glycol) 4000, mannitol and urea were use
d as carriers. Hydrotropic studies were carried out using differ
ent hydrotropic agents (sodium acetate, sodium benzoate an
d salicylate) and Micellar solubilization was carried out using
different surfactant solutions (sodium lauryl sulphate, tween 8
0 and cetrimide).The solubility enhancement of glipizide by
different solubilization technique was observed in decreasing
order as hydrotropic solubilization > solid dispersion > micell
ar solubilization. It was observed that the solubility increased
with the increase in the concentration of hydrotropic agents a
nd amongst the various hydrotropic agents used the solubility
was glipizide was enhanced greatest to 55 folds with sodium
31
salicylate .
Choudhary et al. enhanced the solubility enhancem ent of
escitalopram oxalate using hydrotrope. In spite of oxalate
form it is sparingly soluble in water. The efficacy and
bioavailability of Escitalopram oxalate is limited by its poor
aqueous solubility and dissolution rate. The effect of
hydrotropic (niacinamide) on the solubility of escitalopram
oxalate was investigated. The saturation solubility indicate
that enhancement in solubility was more than eight folds in
2M niacinamide compared to distilled water. Tablets of
escitalopram oxalate with and without niacinamide were
prepared and dissolution study was performed. Dissolution
studies indicate that dissolution rate was remarkably
increased with tablet containing niacinamide compared to
32
tablets without niacinamide .

2.8 Titrimetric Estimation of Drugs

Accurately weighed quantity of bulk drug sample is transferred to a
conical flask. The flask is shaken for 5 min after adding 100 ml of
hydrotropic solution to solubilize the drug. Titration is performed
with selected titrant using suitable indicator. Blank determination is
carried out and necessary correction is done to calculatethe drug
content. Analysis is performed six times.
2.8.1 Recovery Studies of Marketed Tablet Formulations Using
Hydrotropic Solubilization Technique
In order to validate the proposed method, the recovery studies are
performed. For this, pre-analyzed tablet powder equivalent to
quantity of drug used in titrimetric analysis is accurately weighed
and transferred to conical flask. Then, 40 mg of bulk drug sample is
added to the conical flask, as spiked drug and whole analysis
procedure is repeated to find out the recovery of the added drug
41
sample. This recovery analysis is performed six times .
Maheshwari et al. used 0.5 M ibuprofen sodium (an economic
hydrotropic agent) to solubilize a poorly water soluble drug
naproxen for its titrimetric analysis.The proposed method is new,
rapid, simple and reproducible. The proposed method of analysis
does not involve the use of an organic solvent; hence it is eco42
friendly and safe method .
2.9 Formulations
Solid dispersion technology is one of the methods of increasing the
dissolution rate and hence the rate of absorption and/or total bioavailability of poorly water-soluble drugs. The common methods of
making solid dispersions are solvent evaporation, fusion and
fusion-solvent methods. In the solvent method, an organic solvent
(volatile) is used to dissolve the drug as well as carrier. Then
solvent is removed by suitable evaporation technique to obtain solid
dispersion. Toxicity of residual solvent, cost of solvent and pollution
are major drawbacks of this method. Newly developed hydrotropic
solid dispersion technology precludes the use of organic solvent.
Salient feature of the new method is that the hydrotropic agent
(carrier) is water-soluble whereas the drug is insoluble in water.
However, in presence of large amount of hydrotropic agent in
water, the drug gets solubilized. Then, water is rem oved by suitable
evaporation technique to get solid mass (a solid dispersion). Since
in absence of hydrotropic agent, water is not a solvent for poorly
water-soluble drug, therefore, the proposed method is different from
common solvent method and is a novel application of hydrotropic
solubilization phenom enon. The so formed solid dispersions shall
43
be denoted as hydrotropic solid dispersions .

2.9.2 Liquid Oral Formulations (Solutions)

The formulation of solutions presents many technical problems to
the industrial pharmacist. Special techniques are required to
solubilize poorly water-soluble drugs. The final preparation must
satisfy the requirements of pharmaceutical elegance with regard to
taste, appearance and viscosity. To solve the formulation problems
encountered with pharmaceutical liquids, an interesting dichotomy
of investigative skill is required. On the one hand, solubility and
stability factors can be approached with the precision long
associated with the exact sciences; on the other hand flavouring
and other organoleptic characteristics remain subjective factors for
which the application of the scientific method still plays a
distressingly minor role. Thus, the successful formulation of liquids
as well as other dosage forms, requires a blend of scientific acuity
and pharmaceutical art.
The oral use of liquid pharmaceuticals has generally been justified
on the basis of ease of administration to those individuals who have
difficulty in swallowing solid dosage forms. A more positive

2.9.1 Method of Preparation of Hydrotropic Solid Dispersion

It is a relatively new technique in which the drug and selected
hydrotropes are taken in different ratio in beaker, distilled water is
added at a temperature ranging between 80-85C. Then the
selected hydrotrope is taken and added to water. Then slowly add
drug to the beaker and teflon coated magnetic bead is dropped in
beaker, temperature is to be maintained for optimum stirring and
stirring is continued until semisolid mass is obtained. This semisolid
mass is spread on several watch glasses and is placed in oven

20

Priyanka Arjaria et al / Int. J. Pharm. Phytopharmacol. Res. 2013; 3 (1): 17-23

argument can be made for the use of hom ogenous liquids (systems
in which the drug or drugs are in solution). With rare exceptions, a
drug must be in solution in order to be absorbed. A drug
administered in solution is immediately available for absorption and
in most cases is more rapidly and efficiently absorbed than the
same amount of drug administered in a tablet or capsule.
The oral liquid dosage forms of poorly water-soluble drugs available
in market are mostly in the form of suspensions. Liquid oral
solutions (syrups) show better bioavailability and quick onset of
action in comparison to the suspensions.
Hydrotropic solubilization has been explored to develop liquid oral
solutions (syrups) of poorly water-soluble drugs, to give quick onset
of action and better bioavailability (in comparison to suspensions).

assemblies of amphiphilic block copolymers in aqueous media.

Many advantages of using polymer micelles have been
demonstrated with their unique core-shell archi-tecture. The
hydrophobic cores are segregated by hydrophilic shells from the
aqueous exterior. Hydrophobic drugs can be solubilized into the
hydrophobic core structures of polymer micelles at concentrations
much higher than their intrinsic water-solubility. Polymer micelles
are known to have high drug loading capacity, high water-solubility,
55, 56
and appropriate size for long circulation in blood
.
The hydrophilic shell surrounding the micellar core can protect
undesirable phenomena, such as inter-micellar aggregation or
precipitation, protein adsorption, and cell adhesion. The chemical
composition of polymer micelles can be tailor-made to have
desirable physico-chemical properties for drug solubilization. In
most polymer micelles, hydrophobic drugs are incorporated into the
hydrophobic core of micelles by hydrophobic inter-action as well as
other additional interactions such as metal-ligand coordination
57, 58
59
bonding
and electro-static interaction . The extent of drug
solubility depends on the compatibility between the drug and the
60
micelle core . One of the limitations of drug-loaded polymer
micelles is low stability in aqueous solution, and the stability
61
becomes even lower as the drug loading content increases .
Therefore, new polymer micelle systems were explored to maintain
long-term stability of polymer micelles with high drug loading. A
large number of hydrotropic agents were screened and identified
for their abilities to increase water-solubility of paclitaxel62 .
Nicotinamide derivatives were found to increase the water-solubility
of paclitaxel by several orders of magnitude. It was also found that
low molecular weight hydrotropic agents maintained their
hydrotropic property in their polymeric structures (hydrotropic
63
polymers) .
In new polymer micelle systems a new hydrotropic polym er, poly (2(4-vinylbenzyloxy)-N, N-diethylnicotinamide) (PDENA), was used as
a building block for constructing amphiphilic block copolymers that
can form micelles in aqueous media. Poly (ethylene glycol) (PEG)
was chosen as a hydrophilic block for its well-known
biocompatibility and unique aqueous properties. The hydrotropic
block copolymers self-assembled to form micelles in aqueous
media. The size of the prepared polymer micelles was in the range
of 3050 nm, and increased to 100120 nm after paclitaxel loading.
The critical micelle concentrations (CMCs) of the block copolymers
were higher by an order of magnitude than those of other typical
polymer micelles, due to less hydrophobicity of the hydrotropic
blocks. The drug loading capacity and physical stability of the
polymer micelles were characterized and compared with those of
other polymer micelles. The hydrotropic polymer micelles
containing hydrotrope-rich cores showed not only higher loading
capacity but also enhanced physical stability in aqueous media.
They could be redissolved in aqueous media by simple vortexing
and/or a mild heating. The hydrotropic polymer micelles provide an
64
alternative approach for formulation of poorly soluble drugs .

2.9.3 Procedure for the Preparation of Syrup (Solution)

Hydrotropic agent and warm distilled water (to rapidize the
dissolution process) are shaken in a volumetric flask of suitable
capacity to dissolve hydrotropic agent. Then bulk drug is added and
the flask is shaken to solubilize the drug. After this, preservative
and sucrose are added and the flask is shaken tocomplete their
dissolution. Then, flask is kept aside for some time. Whenthe
temperature is lowered till room temperature; the volume is made
up to the mark with distilled water. Flask is shaken to geta
homogeneous solution. This syrup is filtered through filter paper.
First few ml of syrup is discarded. Filtered syrup is preserved in airtight glass container44-46.
3.3 Dry Syrups for Reconstitution [Dry Syrup Formulations]
Several medicinal agents have insufficient stability in aqueous
solutions or suspensions to meet extended shelf-life periods. Thus,
the pharmaceutical manufacturers provide them in dry powder or
granule form for reconstitution with a prescribed am ount of purified
water immediately before use. Several drugs have been developed
in the form of dry syrups and their stabilities have also been
studied.
In these formulations, a hydrotopic agent is selectedto produce
solutions of such poorly water-soluble drugs after reconstitution
with water (solutions give better bioavailability than suspensions).
2.9.4 Procedure for the Preparation of Dry Syrup
Sufficient excess of drug, hydrotropic agent, sucrose and
preservative are finely powdered and passed through sieve # 100,
separately. Weighed quantity of drug, hydrotropic agent, sucrose
and preservative are kept in separate containers. Then, drug and
preservative are mixed for about 5 min with the help of glass pestle
and mortar. Then, about one fifth of sucrose powder is added and
contents in m ortar are again mixed for about 5 min by trituration.
Remaining sucrose powder is added and again the contents are
mixed for about 5 min by trituration. Then, about half portion of
hydrotropic agent is added in the mortar and mixed by trituration for
about 5 min. Then, remaining portion of hydrotropic agent is added
and triturated for about 10 min for proper mixing. While trituration,
spatula is used frequently, to remove the powder adhering to the
45-47
inner wall of the mortar
.

2.9.7 Aqueous Suspension

Shete et al. enhanced the solubility of griseofulvin using the
technique of hydrotropic solubilization technique and converted
them into suitable oral liquid dosage form (suspension) useful for
enhancement of bioavailability. 0.5M, 1M, 2M of the hydrotropes (tri
sodium citrate, urea, sodium acetate, sodium benzoate and sodium
salicylates) were used to study the saturation solubility. Solubility
was found to be greater with sodium benzoate. Suspensions were
prepared by using sodium benzoate solution, greseofulvin, xanthan
gum, acacia, sodium alginate as a aqueous phase, dispersed
65
phase and suspending agents respectively .

2.9.5 Injection Formulation

Maheshwari and Indurkhya investigated the effect of hydrotropes
such as urea and sodium citrate and blends (Urea + Sodium citrate)
on the solubility of aceclofenac. The enhancement in the solubility
of aceclofenac was more than 5 and 25 folds in 30% sodium citrate
solution and 30% urea solution, respectively, as compared to its
solubility in distilled water. The enhancement in the solubility of
aceclofenac in a mixed hydrotropic solution containing 20% urea
and 10% sodium citrate solution was more than 250 folds
(compared to its solubility in distilled water). This proved a
synergistic enhancement in solubility of a poorly water- soluble drug
due to mixed hydrotropy. Synergistic combination of hydrotropic
agents can minimize the amount of hydrotropic agents employed,
minimizing the chances of their toxicities. Aqueous injection of
aceclofenac, using the mixed hydrotropic solubilization technique,
was developed and by using the lyophilization method, the problem
of inadequate stability of aceclofenac in aqueous solution was
overcome. The developed formulation was studied for physical and
48
chemical stability .
2.9.6 Hydrotropic Polymer Micelle System
Polymer micelles have attracted increased attention as a promising
53, 54
vehicle for poorly soluble drugs
. Polymer micelles are self-

3. CONCLUSION
By this article we conclude that, solubility of the drug is the most
important factor that controls the formulation of the drug as well as
therapeutic efficacy of the drug, hence the most critical factor in the
formulation development. Dissolution of drug is the rate determining
step for oral absorption of the poorly water soluble drugs and
solubility is also the basic requirement for the formulation and
development of different dosage form of different drugs. The
hydrotropic solubilization techniques described above alone or in
combination can be used to enhance the solubility of the drug.
Solubility can be enhanced by many techniques and number of
folds increase in solubility. Because of solubility problem of many
drugs the bioavailability of them gets affected and hence solubility

21

Priyanka Arjaria et al / Int. J. Pharm. Phytopharmacol. Res. 2013; 3 (1): 17-23

enhancement becom es necessary. It is now possible that to

increase the solubility of poorly soluble drugs with the help of
various techniques as mentioned above.

25)

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