SOLUBILIZATION &

METHOD OF
SOLUBILIZATION
)
 SOLUBILITY
 It can be defined quantitatively as the conc. of solute in
a saturated solution at a certain temperature, and
qualitatively as the spontaneous interaction of two or
more substances to form a homogenous molecular
dispersion It can also be defined as the molecular
dispersion of solute in the solvent.
 Importance of solubility:

 It is an important physico-chemical property of the drug,

 It is an important parameter to achieve desired

concentration in systemic circulation .
 Solubility behavior of the drug is a one of the important
aspects of preformulation testing for poorly soluble drug
EXPRESSION FOR APPROXIMATE
SOLUBILITY
Descriptive terms Relative amounts of solvents to 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

Insoluble or practically More than 10,000

insoluble
PROBLEMS WITH POOR SOLUBILITY:
 Reduced drug efficiency
 Reduced absorption of drug

 May cause side effects

SOLUBILIZATION
 It can be defined as the preparation of a
thermodynamically stable isotropic solution of a
substance normally insoluble or very slightly
soluble in a given solvent by the addition of
component or components or by any suitable
methods
PROCESS OF
SOLUBILIZATION
1) Breaking of inter-ionic or inter–molecular bonds
in the solute
2) Separation of solute molecules to provide space
for the solute
3) Interaction between the solvent and solute
molecule or ion
a) Molecules of solids break away from bulk
b) Separation of solvent molecules
c) Freed solid molecules is integrated into the holes
of solvent molecule
 SOLUBILIZATION TECHNIQUES- CO-
SOLVENCY
 Substances like weak electrolytes and non-polar molecules
are poorly soluble in water .
 The solubility of these substances can be enhanced by the
addition of water miscible solvents in which the drug has
good solubility.
 This process of improving solubility is called as co-solvency
and the solvents used are known as co-solvents.
 This technique is mainly used in the formulation of
parenterals.
 Commonly used co-solvents are Ethanol, Sorbitol, Glycerin,
Polyethylene glycol, propylene glycol etc.
 The solubilizing effect by co-solvency is depends on the
polarity of the drug with respect to solvent and co-solvent.
That means more non-polar the solute the greater is the
solubilization achieved by the added solvents
• Mechanism responsible for solubility enhancement
through co-solvency is by reducing the interfacial tension
the predominantly aqueous solution and hydrophobic
solutes and reduces the contact angle between the solid and
liquid
• Co-solvents increases the solubility by reducing the
difference between the polarity of the drug and water
sustem
Ex. For co-solvency
The solubility of diazepam can be increased by using 10%
ethanol and 40% propylene glycol.
Phenobarbitone is relatively insoluble in water but it
solubility can be increased by using mixture of solvents
like water, alcohol and glycerin
 ADDITION OF SURFACTANTS
 Surfactants are very useful as absorption enhancers and
enhance both dissolution rate as well as permeability of
the drug .
 Surfactants act by reducing the surface tension and forms
colloidal aggregates known as micelles. Micelles are formed
at CMC .
 Ability of a surfactant solution to dissolve or solubilise
water insoluble materials starts at CMC and increases
with increase in conc. of micelles .
 Lipophilic surfactants with HLB value higher than 15 are
best solubilising agents Concentration of surfactant must
be controlled very less conc. Improper
solubilization
 very high conc. Affect on bioavailability
 SOLID DISPERSION TECHNIQUE
 It is the dispersion of one or more active ingredients in an
inert carrier or matrix in solid state prepared by fusion or
melting-solvent method.
 It is the dispersion of a drug or drugs in solid diluent or
diluents. Solid dispersions may also be called “ solid state
dispersions”. Solid dispersion provides particle size
reduction and increased rates of dissolution
 Various systems of solid dispersions:

1) Simple eutectic mixtures

2) Solid solutions
3) Glass solution and glass suspension
4) Amorphous precipitation of drug in crystalline carrier
5) Compound or complex formation between drug and
carrier
6) Any combination among the above
 COMPLEXATION
 It is reversible association of a substrate and
ligand molecule.
 The most common complexing ligands are
cyclodextrins, caffeine, urea, polyethylene glycol,
N methylglucamide.
 cyclodextrin are unique since they increase the
water solubility of poorly soluble drugs by fitting
them into the hydrophobic cavity of the
cyclodextrin molecule.
 These cyclodextrins have the ability to form
molecular inclusion complexes with hydrophobic
drugs having poor aqueous solubility.
 CHANGING TEMPERATURE
 The solubility of a solute or solid in a liquid is dependent
on temperature, nature of solute and nature of solvent
 ∆Hs( heat of solution) represents the heat released or
absorbed when a mole of solute is dissolved in a large
amount of solvent
 If the solution process is endothermic, increase in
temperature increases the solubility of the solute
 And if the solution process is exothermic, increase in
temperature decreases the solubility of the solute
 HYDROTROPHY
 Addition of large amount of a second solute results in an
increase in the aqueous solubility of another solute.
 Concentrated aqueous hydrotropic solutions of sodium
benzoate, sodium salicylate, urea, nicotinamide, sodium citrate
and sodium acetate have been observed to enhance the aqueous
solubilities of many poorly water-soluble drugs.
 Advantages:

1. Hydrotropy is suggested to be superior to other Solubilization

method, such as miscibility, micellar Solubilization, cosolvency
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,
use of organic solvents, or preparation of emulsion system
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 , Sodium salicylate
Oxazepam , Nitrazepam ,
Clonazepam
 SOLID STATE MANIPULATIONS
 Polymorphic modifications
 Solubility of each form depends upon the ability of the
molecules to escape from the crystal to solvent.
 The stable form posses the lower free energy at a
particular temperature and therefore has the lower
solubility or escaping tendency where as the meta stable
forms posses higher free energy hence has higher
solubility.
 About fifty to hundred percent increase in the dissolution
rate can be achieved through polymorphic modifications.
Examples: Chloramphenicol palmitate (form B)
Methyl prednisolone (form 2)
Chlor tetracycline (form B)
 NON CRYSTALLINE SOLUTES
(AMORPHOUS)
As the term implies they will not contain internal crystal
lattice structure.
 These are thermodynamically unstable.

 Amorphous solid forms give faster dissolution rates and

higher solubility than polymorphic modifications.
Eg : Novobiocin
Thus, the order for dissolution of different solid forms of
drug is
Amorphous > Metastable >Stable
SOLVATES (PSEUDO POLYMORPHISM )
 The recrystallization of many drug substances
from solution will results in the formation of
solids containing solvent molecules as an integral
part of their crystal structure. Majority of these
crystalline materials referred as pseudo
polymorphs, contain stoichiometric amount of
solvent.
Anhydrates > hydrates
Organic solvates > organic non-solvates
Enhances the solubility of drug markedly.
Examples: Pentanol solvates of fludrocortisone
Chloroform solvates of griseofulvin
Cephalexin hydrate
Salt formation
Salts have improved solubility and dissolution
characteristics in comparison to the original drug. Alkali
metal salts of acidic drugs like penicillin and strong acid
salts of basic drugs like atropine are water-soluble than
the parent drug.

Precipitation:
In this method, the poorly aqueous soluble drug is
dissolved in a suitable organic solvent followed by its
rapid mixing with a non-solvent to effect precipitation of
drug in nano size particles. The product so prepared is
also called as hydrosol. Ex. Cyclosporine
Other techniques
•Micronization
•Nanonisation
• Supercritical Fluid Recrystallization
• Spray freezing into liquid and lyophilization
•Evaporative precipitation into aqueous solution
•Use of precipitation inhibitors
•Selective Adsorption on Insoluble Carriers
•Solvent Deposition
• Drug derivatisation
Conclusion
The aqueous solubility of drug is often a limiting
factor in developing most desirable dosage form.
A highly solubilized formulation is highly desired
to minimize dissolution limited absorption .Often,
these early stage formulations become the
backbone for the later stage commercial
formulations. But still there has been a lot of
research going on in this topic and many newer
and advanced methods are used to enhance the
solubility of the drug.