Supersolubilization by Using Nonsalt-Forming Acid-Base Interaction

Abstract

A novel approach of greatly increasing the solubility of basic drugs by interacting them with weak acids has been described. In this method, which is termed supersolubilization, it is essential that the acids used are highly water-soluble and would not normally form salts with the basic drugs used. The aqueous solubility of a model drug, haloperidol, which has an intrinsic solubility of 2.5 µg/mL in water, could be increased to > 300 mg/g of solution by using such weak acids as citric acid, malic acid, and tartaric acid. When the concentrated aqueous solutions of haloperidol in the presence of acids were dried, they formed amorphous solid dispersions, where the drug loads could be as high as 40–50 % w/w. The solid dispersions were physically stable as the drug did not convert to the crystalline form during stability testing. It was, however, observed that, when the drug load was very high, the solid dispersions could exist as the viscous semisolid mass, and might not be processable into tablets. Such materials could be converted into free-flowing and tabletable powders by adsorbing them onto a metasilicate, such as Neusilin® US2. The method is also applicable to supersolubilizing weakly acidic drugs in acidic media by using such weak bases as lysine, arginine, etc., and subsequently converting them into solid dispersions.