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NOVEL PHARMACEUTICAL APPLICATION OF HYDROTROPY

Introduction
Hydrotropy is the method to increase the solubility of a substance or solute.

Hydrotropy is the term originally put forward by Neuberg1 to describe the increase in the solubility of a solute by the addition of fairly high concentrations of alkali metal salts of various organic acids. However, the term has been used in the literature to designate non-micelle-forming substances, either liquids or solids, organic or inorganic, capable of solubilizing insoluble compounds.

The chemical structure of the conventional Neuberg’s hydrotropic salts (proto-type, sodium benzoate) consists generally of two essential parts, an anionic group and a hydrophobic aromatic ring or ring system. The anionic group is obviously involved in bringing about high aqueous solubility, which is a prerequisite for a hydrotropic substance. The type of anion or metal ion appeared to have a minor effect on the phenomenon1. On the other hand, planarity of the hydrophobic part has been emphasized as an important factor in the mechanism of hydrotropic solubilization2, 3.

Additives may either increase or decrease the solubility of a solute in a given solvent. These salts that increase solubility are said to ‘salt in’ the solute and those salts that decrease the solubility ‘salt out’ the solute. The effect of an additive depends very much on the influence, it has on the structure of water or its ability to compete with the solvent water molecules.4 A convenient quantitation of the effect of a solute additive on the solubility of another solute may be obtained by the

Setschetow equation:5

Log S0/S = K.Ca where

S0 = solubility in the absence of the additive

S = solubility in the presence of the additive

Ca = concentration of the additive

K = salting coefficient, which is a measure of the sensitivity of the activity coefficient of the solute towards the salt

Several salts with large anions or cations which are themselves very soluble in water result in a salting in of non electrolytes and are called ‘Hydrotropic Salts’ and the phenomenon is known as ‘HYDROTROPISM’.6

This should imply that hydrotropic agents are molecules having a planar hydrophobic structure brought into solution by a polar group. Hence, it seems rational to propose that molecules with a planar hydrophobic part and a polar group, which is not necessarily anionic, can act as hydrotropic agents. Saleh and El-Khordagui7 suggested that the phenomenon of hydrotropy is not confined to the metal salts of organic acids, certain cationic salts and neutral molecules may be equally involved. They used procaine.HCl, PABA.HCl and cinchocaine.HCl as cationic salts and resorcinol and pyrogallol as neutral molecules in their studies.