Review on Novel Solubility Enhancement Technique Hydrotrophy


Introduction: The hydrotropic agent may also use of organic solvent so that a simple
accurate, novel, safe & precise method developed for estimation of poorly
soluble drug. The aqueous solubility of drug is the main big problem in
pharmaceutical industry; almost 70% drugs suffer from poor solubility. Solubility
is defined in quantitative term as concentration of solute in concentrated
solution at a certain temperature and in quantitative way it can be defined as
a spontaneous interaction of two or more substances to from a homogenous
molecular dispersion. The solubility of a
substance fundamentally depends on the physical and chemical properties of the
solute and solvent as well as on temperature, pressure and the pH of the
solution. Increasing the aqueous solubility of insoluble and poorly soluble
drug is major importance1. Maheshwari et al (2008) evaluate an experiment using hydrotropic solubilizing
technique to enhance the aqueous solubility of poorly water soluble drug. They
have various organic solvent like methanol, chloroform, dimethyl-formide &
ethanol for the solubilization of poorly water soluble drug2.

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Problems with poor solubility:

·       Reduce drug

·       Reduced
absorption of drug.

·       May cause side


agent: Neuberg
was first proposed the term Hydrotrophy in 19163.Hydrotrope is a
class of amphiphilic molecules they increase the aqueous solubility of organic
compound4.In the presence of large quantity of solute to enhance the
aqueous solubility another solute5.Hydrotropic agents are ionic
organic salt to increase or decrease the aqueous solubility of solute, several
salts are ionic they mostly soluble in water which have “salting in” of non
electrolytes called “hydrotropic salts” a phenomenon also known as




                              Fig.1. Structure
of hydrotropic agent 


They don’t have any
colloidal properties but increase aqueous solubility through weak interaction
of organic salts and hydrotropic agents 6-7.The Hydrotropes solubilization
technique refer to the ability of a concentrated solution of chemical
composition to increase the aqueous solubility of another composition through a
sparingly soluble organic composition also called hydrotropic technique. The
most popular example of hydrotropic agent is urea, Sodium benzoate,
sodium salicylate, nicotinamide, urea, sodium ascorbate, sodium acetate, sodium
citrate, niacenamide; N-dimethylurea8-26.Hydrotropic
agents have hydrophobic and hydrophilic properties27.

                         Table1. Expression for
approximate solubility28-32.


amount of solute to dissolve 1 part of solute


                                          <1   Freely soluble                                          1-10   Soluble                                          10-30   Sparingly soluble                                          30-100   Slightly soluble                                         100-1000  Very slightly soluble                                         1000-10000  Practically insoluble                                          >10000


Preparation of
hydrotrpes: hydrotropic
agent produced by sulfonation of an aromatic hydrocarbon e.g. – Toluene, Xylene,
or cumene. Sulfonic acid neutralized by using an appropriate base e.g. –
NaoH to reduce the Hydrotropes & Sulfonate. The hydrotropic agents are
“pure” compound. It produces and transport in either aqueous solution at 30-60%
level of activity or in granular solid at 90-95% level of activity. The
granular solid which includes sodium sulfate and w’ater. Granular Hydrotropes
products are produced by spray drying which include source control and dust collection.
Hydrotropic agents are manufactured for consumer/professional and industrial
use & they don’t used as derivatives33.

of hydrotropic agents: The following characteristic of hydrotropic agent are-

Hydrotropes practically soluble in

Hydrotropic agents are ecofriendly and

Hydrotropes are easily available.

Hydrotropes are non-toxic &

Hydrotropes is a class of amphiphilic
molecules. They increase the solubility of organic compounds.

Hydrotropes do not reduce in any
temperature, dissolve in water.

Hydrotropes are highly selectivity &
pH of solvent34.

the solubility:
determination of solid in liquid by using following steps-

of saturated solution: solubility indicates the maximum amount of a substance can be dissolve in a
solvent at given temperature also called saturated solution. Solubility is
measure either in g/100g of solvent or no of moles /L of the solution.

of saturated solution: The saturated solutions are
prepared and its analysis carried out to check solubility. Solubility depends
on the nature of solute & accuracy of method employed.

The following methods involve in the
analysis of saturated solution-

Evaporation method.

Volumetric method.

Gravimetric method.

Instrumental method35-37.

Enhancement ratio in
solubility were determine by following formula-

Ø Enhancement
ratio   = 
 Solubility of drug in hydrotropic
solution%           Solubility of drug in
distilled water


solubilization: Hydrotrophy is a solubilization process
which addition of large amount of solute to increase the aqueous solubility of
another solute. Solubilization can be defined as a preparation of
thermodynamically stable isotropic solution of a substance normally insoluble
or slightly soluble in a given solvent by introduction of an additional
component or components or by suitable methods38-41.

of solubilization: Solubility is the important parameter
desired concentration of drug. The following factors affect the solubility of
drug such as temperature, nature of solvent, nature of solute, particle size,
molecular size, pressure etc. The following steps involve in the process of

Ø Solubilization
process involves the breaking of inter-ionic of intermolecular bond in solute.

Ø  Separation of solvent molecules to provide
space for the solute in solvent.

Ø Interaction
between solvent and the solute molecule or ion5-9.

contain both properties hydrophobic and hydrophilic. Hydrotropes have small
hydrophobic fraction in compression with surfactant14.the
hydrophobic and hydrophilic properties of hydrotrpes affect the efficiency of
hydrotropic solubilization42.







of Hydrotrophy: Every hydrotropic agent has selective
ability to a particular component in mixture. They increase the solubility
after addition of hydrotrpes in aqueous phase but on subsequent increasing the
concentration of hydrotropic agent. The minimum hydrotrpes concentration termed
as the critical concentration hydrotrpes which required hydrotrpes in aqueous
phase43-46. Hydrotropic agent consists of hydrophilic and
hydrophobic such as surfactant but spontaneous self-aggregation caused by
hydrophobic surfactant2. Hydrotropic agent also called coupling
agent. The addition of hydrotrpes to turbid liquid through relatively high
content cause transport liquid because of phase transaction47.The
mechanism of Hydrotrophy involved following steps-

potential: Self aggregation of hydrotrpes molecules formed by
aggregates. The aggregates depend on the amphiphilic properties and nature of
solute. It also attract the molecules inside the aqueous phase48-50.Hydrotropic
agent interact with solute to formed a complex and the complex have higher
aqueous solubility. These outcomes evolved from fluorescence emission method51.
Hydrotrpes may act as bridging agent by reducing Gibbs energy to increase
aqueous solubility of solute52. Finally the structure of hydrotrpes
around the dry molecules is a true key of understanding the origin of self
aggregation potential53.


breaker & structure maker: changing the structure
of solvent through alerting the ability of changing in structure formation of
intro-molecule H-bonding.  Hydrotrpes play a vital role in
hydrotrophy solubilization like an   
electrostatic force of the donor and acceptor molecule. They also called
structure breaker and structure maker54-55. Solutes are capable for
both hydrogen donor and acceptor helps to increase the solubility56.



3.    Ability to form micelles like
structure: This mechanism is   based on the self aggregation of hydrotropic
agent with solute80. The solute formed the micelles by exhibit self
aggregation of hydrotrpes like alkyl benzene sulfonate, and alkyl sulfates. Improve
solubility of riboflavin (via self association) through aromatic anionic
hydrotrpes e.g. nicotinamide57.

Hydrotropic solubilization
technique: The following solubilization techniques
are –

1.    Physical modification-

size reduction: The solubilization of drug depends upon
the particle size of drug. The larger particle size has larger surface area
create greater interaction with solvent and increase the solubility of drug. Particle
size reduction can be achieved by following method.

·       Micronization: In
this method increasing the
dissolution rate of drug through surface area.


·       In
Micronization of drug involved following steps milling technique using jet
mill, rator stator colloid mills etc.

·       Micronization
is not suitable for drug have a high dose no because it does not change the
saturation solubility of drug58-60.

dispersion: It is a group of solid product contains
two different components like hydrophobic and hydrophilic. Preparation of solid
dispersion involves solvent or co-precipitation method. In guest solute
addition with solid carrier solvent as dissolve in common volatile liquid solid
such as alcohol. The liquid solvent is 
removed by evaporation under reduce pressure by freeze drying which
resulting in amorphous precipitation of guest in crystalline carrier which
solubilize rapidly e.g. Amorphous sulfathiazole in crystalline urea61-62.

suspension: Nano suspension technique is applied for
poorly soluble drug that are insoluble in water and oils. Nano suspension has
biphasic system contain Nano sized drug particle stabilize by surfactant. The
following method involve in nanosuspension…

·       Precipitation

·       Media

·       High
pressure homogenization.

·       Combined
precipitation & homogenization63-65.

2.    Chemical modification:

For organic solute that are ionizable changing the pH of the system is simplest
and most effective means of increasing aqueous solubility.

·       Change
of pH by 1 fold increase solubility by 10 fold.

of buffer: The pH of solute measured by buffer of potential
for precipitation on dilution pH alteration occur that decrease solubility.

·       If
one pH unit change it that decrease ionization of drug and solubility decrease
by 10 fold66-67.

The ability to formation of molecules inclusion complexes through beta &
gamma cyclodextrin with hydrophilic drug has poor aqueous solubility e.g.
barbiturates benzodiazeoine68.

formation: Salts have improved solubility in compression to
the original drug e.g. alkali metal salts of acidic drug like penicillin69-70.

3.    Miscellaneous method:

Supercritical fluid (SCF) 71-72.

Inclusion complex formation

Micellar solubilization.

 Other solubilization technique:

1.    Salting

2.    Salting

3.    Co-solvency.

4.    Micellar

5.    Hydrotrophy74-75.

of Hydrotropes:

Ø Hydrotropes
increase unprecedented solubilization.

Ø Hydrotropic
agent very high selectivity.

Ø Easy
recovery of solute from solution.

Ø Economical
& cost effective.

Ø Absence
of emulation.

Ø Absence
of hazard present in other solvent used in extracted separation76.

of hydrotropic solubilization:

Ø Hydrotropic
solubilization technique is superior to other solubilization method like
Micellar solubilization salting in and co-solvency because solvent independent
of pH has high selectivity.

Ø Hydrotropic
solubilization only require for mixing the drug with hydrtope in water.

Ø  It does not require chemical modification of
hydrophobic drug use of organic solvent or preparation of emulsion system77.

of solubilization:

Ø It
used for solubility enhancement.

Ø Hydrotropic
solvent used to enhance the permeation.

Ø It
is used for extraction.

Ø Preparation
of injection of poorly water soluble drug.

Ø Hydrotropes
used in the preparation of dry syrup of poorly water soluble drug.

Ø It
is used in suppositories for fast release of poorly water soluble drug.

Ø Quantitative
estimation of poorly water soluble drug by UV-visible spectrophotometric
analysis titrimetric analysis precluding the use of organic solvent78-79.     










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