SOLUBILITY ENHANCEMENT TECHNIQUES


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INTRODUCTION

A number of methodologies can be adapted to improve
solubilization of poor water soluble drug and further to
improve its bioavailability. The techniques generally
employed for solubilization of drug includes
micronization, chemical modification, pH adjustment,
solid dispersion, complexation, co‐solvency, micellar
solubilization, hydrotropy etc. Solubilization of poorly
soluble drugs is a frequently encountered challenge in
screening studies of new chemical entities as well as in
formulation design and development.1, 2 Any drug to be
absorbed must be present in the form of an aqueous
solution at the site of absorption.


pH ADJUSTMENT

Poorly water soluble drugs with parts of the molecule
that can be protonated (base) or deprotonated (acid) may
potentially be dissolved in water by applying a pH change.
pH adjustment can in principle be used for both oral and
parenteral administration. Upon intravenous
administration the poorly soluble drug may be precipitate
because blood is a strong buffer with pH between 7.2 –
7.4. To assess the suitability of the approach, the buffer
capacity and tolerability of the selected pH are important
to consider. In the stomach the pH is around 1 to 2 and in
the duodenum the pH is between 5-7.5, so upon oral
administration the degree of solubility is also likely be
influenced as the drug passes through the intestines.
Ionizable compounds that are stable and soluble after pH
adjustment are best suited.


Advantages:

Simple to formulate and analyse.
Simple to produce and fast track.
Uses small quantities of compound, amenable to
high throughput evaluations.

Disadvantages:

Risk for precipitation upon dilution with aqueous
media having a pH at which the compound is less
soluble. Intravenously this may lead to emboli,
orally it may cause variability.
Tolerability and toxicity (local and systemic)
related with the use of a non physiological pH
and extreme pHs.
As with all solubilized and dissolved systems, a
dissolved drug in an aqueous environment is
frequently less stable chemically compared to
formulations crystalline solid. The selected pH
may accelerate hydrolysis or catalyze other
degradation mechanisms.
Commercial products using pH adjustment : Phenytoin
Injection (Epanutin® ready mixed, Pfizer) 50mg/ml with
propylene glycol 40% and ethanol 10% (1.1 mmol Na+ per
5 ml ampoule) is an example of a pH adjusted formulation
containing co-solvents.

CO-SOLVENCY

The solubility of a poorly water soluble drug can be
increased frequently by the addition of a water miscible
solvent in which the drug has good solubility known as cosolvents.
17 Co-solvents are mixtures of water and one or
more water miscible solvents used to create a solution
with enhanced solubility for poorly soluble compounds.
Historically, this is one of the most widely used
techniques because it is simple to produce and evaluate.
Examples of solvents used in co-solvent mixtures are PEG
300, propylene glycol or ethanol.



MICROEMULSIONS

Microemulsions have been employed to increase the
solubility of many drugs that are practically insoluble in
water, along with incorporation of proteins for oral,
parenteral, as well as percutaneous / transdermal use.30-31
A microemulsion is an optically clear pre-concentrate
containing a mixture of oil, hydrophilic surfactant and
hydrophilic solvent which dissolves a poorly water soluble
drug. Upon contact with water, the formulations
spontaneously disperse (or ‘self emulsifies’) to form a
very clear emulsion of exceedingly small and uniform oil
droplets containing the solubilized poorly soluble drug.
Microemulsions are isotropic, thermodynamically stable
transparent (or translucent) systems of oil, water and
surfactant, frequently in combination with a co-surfactant
with a droplet size usually in the range of 20-200 nm.
These homogeneous systems, which can be prepared
over a wide range of surfactant concentration and oil to
water ratio, are all fluids of low viscosity.


COMPLEXATION
Complexation of drugs with cyclodextrins has been used
to enhance aqueous solubility and drug stability.
Cyclodextrins of pharmaceutical relevance contain 6, 7 or
8 dextrose molecules (α, β, γ-cyclodextrin) bound in a 1,4-
configuration to form rings of various diameters. The ring
has a hydrophilic exterior and lipophilic core in which
appropriately sized organic molecules can form noncovalent
inclusion complexes resulting in increased
aqueous solubility and chemical stability.