This document discusses various techniques for enhancing the solubility of drugs, including physical alterations like micronization, use of surfactants to form micelles, co-solvency using water-miscible solvents, complexation, inclusion complexes, hydrotrophy, chemical modifications, and adjusting the pH or temperature. The mechanisms of several methods are described, like surfactants forming micelles that solubilize insoluble substances, co-solvents reducing interfacial tension, and complexation or inclusion complexes encapsulating drug molecules. Common examples of solubility enhancement methods and their applications are provided.

1. Solubility enhancement
techniques
VASANTH KUMAR S
ASSISTANT PROFESSOR
K.K COLLEGE OF PHARAMCY

2. Solubility
• The maximum quantity of solute that can dissolve in a definite
volume of solvent or of a solution at a definite temperature.
• Poor aqueous solubility is the major difficulty in oral
administration
• Factors like drug property, site of absorption and required dosage
form characteristics determine the type of solubility enhancement
method to be employed

3. Mechanism of solubilisation
• When a surfactant is dissolved in water up to a certain concentration, its molecule
tend to concentrate at the oil-water interface. Beyond that concentration, the
surfactant molecules descend into the lower surface of the solvent phase, where they
tend to aggregate into groups of 100-150 molecules known as “micelles”
• The concentration at which the colloidal aggregation occurs is called “critical miscelle
concentration”(CMC). These micelles interact with insoluble substances dissolve and
go into solution. The solubilisation increases with an increase in the concentration of
micelles.
• Applications:
Many-water insoluble drugs such as vitamin A,D,E and K. Chloramphenicol,
amphotericin-B, sulphonamides etc., can be formulated as a clear aqueous solution by
the process of solubilisation.

4. Methods for enhancing solubility
• Physical alteration
• Solubilization by using surfactant
• Co-solvency
• Complexation
• Inclusion complex
• Hydrotropy
• Chemical modification
• PH adjustment and buffers
• Temperature/pressure

5. METHODS
• Physical alterations:
It includes size reduction, micronisation, nanonisation,
polymorphs and solid dispersion etc.
• Solubilisation by surfactant:
the addition of surfactants can increase the solubility of water-
soluble drugs. (ex) chloramphenicol, vitamin A,D are solubilised in
this way.

6. • The solubility of water-soluble substances can be increased by the addition
of one more water miscible solvents such as propylene glycol, sorbitol etc.
This method is known as co-solvency. It sis mainly applied to the solubility
of weak electrolytes, non-polar molecules and volatile constituents.
Mechanism of action: Reduction of interfacial tension between the aqueous
phase and oily phases.
(ex) sorbitol,PG,PEG200 series
Co-Solvency

7. Complexation
Some drugs containing metallic ions are less soluble in water. If some
other substance is added to this vehicle, the insoluble drugs and the added
substance react together to form a complex. This complex is more in a given
vehicle.
For example, EDTA combines with any metal ion to form a readily soluble
complex in water.
(ex) Potassium iodide will be added to increase the solubility of iodine

8. Inclusion complex
• In this process, the drug molecules are inserted into another molecule’s
cavity (host).
(ex) Beta cyclodextrin (BCD).
It has glucose monomers arranged in donut shaped ring.
Chemical modification:
Many poorly soluble drugs in water can be converted into their
derivatives, which are more soluble in water
(ex) alkaloids are poorly water-soluble. If they are converted into alkaloidal
salts, they are more soluble.

9. Hydrotropy
• The solubility of water-insoluble substances can be increased by the
addition of some additives which are not surface active agents. This
phenomenon is known as Hydrotropy.
(ex) the solubility of caffeine is increased by adding sodium benzoate .
Other examples: sodium citrate, urea
The mechanism of solubilization is related to complexation
Advantage : no chemical modification is needed.
Disadvantage: it requires a large amount of hydrotropic agents (20-50%)

10. PH adjustment and buffers
• Most of the acids are weak acid and base . The solubility depends on the
degree of ionisation. The ionization depends on the Ph of the environment.
• The buffering agents which resist the PH upon dilution or addition of acid or
alkali in the liquid preparation.
(ex) Acetate buffer-PH 2.8 to 6 (glacial acetic acid)
Phosphate buffer-PH 2 to 8 ( disodium hydrogen phosphate).

11. • Temperature:
If increase the temperature the solubility of solid in solute also
increase.
Pressure:
Gaseous products get increased solubility by increasing pressure.

12. Other methods
• Supercritical fluid process
• Functional polymer technology
• Solvent deposition
• Porous microparticle technology
• Sonocrystallisation
• Prodrug approach
• Derivatisation.