SUBMITTED TO : SUBMITTED BY :
DR.YASMEEN SULTANA NIDA NEHAL
DEPARTMENT : Pharmaceutics IST SEMESTER
School Of Pharmaceutical School Of Pharmaceutical
Education and Research Education and Research
JAMIA HAMDARD JAMIA HAMDARD
SOLUBILITY IS THE PROPERTY OF
A SOLID, LIQUID, OR GASEOUS CHEMICAL
SUBSTANCE CALLED SOLUTE TO DISSOLVE IN A
SOLID, LIQUID, OR GASEOUS SOLVENT.
THE SOLUBILITY OF A SUBSTANCE
FUNDAMENTALLY DEPENDS ON THE PHYSICAL
AND CHEMICAL PROPERTIES OF THE SOLUTE
AND SOLVENT AS WELL AS ON TEMPERATURE,
• THE EXTENT OF SOLUBILITY RANGES WIDELY, FROM
INFINITELY SOLUBLE (WITHOUT LIMIT) (FULLY MISCIBLE)
SUCH AS ETHANOL IN WATER, TO POORLY SOLUBLE,
SUCH AS SILVER CHLORIDE IN WATER.
THE TERM INSOLUBLE IS OFTEN APPLIED TO POORLY OR
VERY POORLY SOLUBLE COMPOUNDS. A COMMON
THRESHOLD TO DESCRIBE SOMETHING AS INSOLUBLE IS
LESS THAN 0.1 G PER 100 ML OF SOLVENT.
THE IUPAC DEFINITION SOLUBILITY IS THE
ANALYTICAL COMPOSITION OF A SATURATED
SOLUTION EXPRESSED AS A PROPORTION OF A
DESIGNATED SOLUTE IN A DESIGNATED SOLVENT.
SOLUBILITY MAY BE STATED IN VARIOUS UNITS OF
CONCENTRATION SUCH AS MOLARITY,
MOLALITY, MOLE FRACTION, MOLE RATIO,
MASS(SOLUTE) PER VOLUME(SOLVENT) AND
The solubility of one substance in another is
determined by the balance of intermolecular
forces between the solvent and solute, and
the entropy change that accompanies the solvation.
Factors such as:-
will alter this balance, thus changing the solubility.
Depending on the nature of the solute the solubility may increase
or decrease with temperature.
For many solids dissolved in liquid water, the solubility increases
with temperature up to 100 °C.
In liquid water at high temperatures, the solubility of ionic solutes
tends to decrease due to the change of properties and structure
of liquid water; the lower dielectric constant results in a less polar
Gaseous solutes exhibit more complex behavior with
temperature. As the temperature is raised, gases usually become
less soluble in water, but more soluble in organic solvents.
The solubility of organic compounds nearly always increases with
Henry’s law is used to quantify the solubility of gases in solvents.
The solubility of a gas in a solvent is directly proportional to
the partial pressure of that gas above the solvent. This relationship
is written as:
where kH is a temperature-dependent constant
p is the partial pressure (atm)
c is the concentration of the dissolved gas in the liquid
IMPORTANCE OF STUDYING THE
PHENOMENON OF SOLUBILITY
Understanding the phenomenon of solubility helps the
Select the best solvents for a drug or mixture of drugs.
Overcome the problems arising during preparation of
Have information about the structure and intermolecular forces of
Many drugs are formulated as solutions or added as powder or
solution forms to liquid.
Drugs with low aqueous solubility often present problems related to
their formulation and bioavailability.
TECHNIQUES FOR SOLUBILITY
Solubility improvement techniques can be
categorized in to physical modification, chemical
modifications of the drug substance, and other
Physical Modifications —Particle size reduction like
micronization and nanosuspension, modification of
the crystal habit like polymorphs, amorphous form and
cocrystallization, drug dispersion in carriers like
eutectic mixtures, solid dispersions, solid solutions and
Chemical Modifications —Change of ph, use of
buffer, derivatization, complexation, and salt
Miscellaneous Methods —Supercritical fluid process,
use of adjuvant like surfactant, solubilizers, cosolvency,
hydrotrophy, and novel excipients.
PARTICLE SIZE REDUCTION
The solubility of drug is often intrinsically related to drug
particle size; as a particle becomes smaller, the
surface area to volume ratio increases. The larger
surface area allows greater interaction with the
solvent which causes an increase in solubility.
Micronization is another conventional technique for
the particle size reduction.
Micronization of drugs is done by milling techniques
using jet mill, rotor stator colloid mills .
Solid dispersions represent a useful pharmaceutical
technique for increasing the dissolution, absorption,
and therapeutic efficacy of drugs in dosage forms.
The term solid dispersion refers to a group of solid
products consisting of at least two different
components, generally a hydrophilic matrix and a
The most commonly used hydrophilic carriers for solid
dispersions include polyvinylpyrrolidone (Povidone,
PVP), polyethylene glycols (PEGs), Plasdone-S630.
Nanosuspension technology has been developed as a promising
candidate for efficient delivery of hydrophobic drugs.
This technology is applied to poorly soluble drugs that are
insoluble in both water and oils.
A pharmaceutical nanosuspension is a biphasic system consisting
of nano sized drug particles stabilized by surfactants for either
oral and topical use or parenteral and pulmonary administration.
The particle size distribution of the solid particles in
nanosuspensions is usually less than one micron with an average
particle size ranging between 200 and 600 nm.
SUPERCRITICAL FLUID (SCF) PROCESS
Another novel nanosizing and solubilisation technology whose
application has increased in recent years is particle size
reduction via supercritical fluid (SCF) processes.
Supercritical fluids are fluids whose temperature and pressure are
greater than its critical temperature (Tc) and critical pressure (Tp),
allowing it to assume the properties of both a liquid and a gas.
Once the drug particles are solubilised within the SCF (usually
carbon dioxide), they may be recrystallised at greatly reduced
Current SCF processes have demonstrated the ability to create
nanoparticulate suspensions of particles 5–2,000 nm in diameter.
Cryogenic techniques have been developed to
enhance the dissolution rate of drugs by creating
nanostructured amorphous drug particles with high
degree of porosity at very low-temperature
After cryogenic processing, dry powder can be
obtained by various drying processes like spray freeze
drying, atmospheric freeze drying, vacuum freeze
drying, and lyophilisation.
INCLUSION COMPLEX FORMATION
Among all the solubility enhancement techniques,
inclusion complex formation technique has been
employed more precisely to improve the aqueous
solubility, dissolution rate, and bioavailability of poorly
water soluble drugs.
Inclusion complexes are formed by the insertion of the
nonpolar molecule or the nonpolar region of one
molecule (known as guest) into the cavity of another
molecule or group of molecules (known as host).
The most commonly used host molecules are
The use of surfactants to improve the dissolution performance of
poorly soluble drug products is probably the basic, primary, and
the oldest method.
Surfactants reduce surface tension and improve the dissolution of
lipophilic drugs in aqueous medium.
They are also used to stabilise drug suspensions.
When the concentration of surfactants exceeds their critical
micelle concentration (CMC, which is in the range of 0.05–0.10%
for most surfactants), micelle formation occurs which entrap the
drugs within the micelles.
This is known as micellization and generally results in enhanced
solubility of poorly soluble drugs. Surfactant also improves wetting
of solids and increases the rate of disintegration of solid into finer
Hydrotrophy is a solubilisation process, whereby
addition of a large amount of second solute, the
hydrotropic agent results in an increase in the
aqueous solubility of first solute.
Hydrotropic agents are ionic organic salts, consists of
alkali metal salts of various organic acids.
Hydrotrophy designate the increase in solubility in
water due to the presence of large amount of
This particle size, which is critical to drug dissolution rate, is
dependent on the conditions of crystallization or on methods of
comminution such as impact milling and fluid energy milling.
The comminution techniques can produce particles which are
highly heterogeneous, charged, and cohesive, with the potential
to cause problems in downstream processing and product
Hence, crystal engineering techniques are developed for the
controlled crystallization of drugs to produce high purity powders
with well-defined particle size distribution, crystal habit, crystal
form (crystalline or amorphous), surface nature, and surface