THE TRANSDERMAL DELIVERY OF ZWITTERIONIC DRUGS .1. THE SOLUBILITY OF ZWITTERION SALTS

The use of selected salts of zwitterions of varying polarizability, size, hydrogen-bonding ability and lipophilicity as criteria to improve skin permeation of zwitterionic drugs is described. Prior to this study, it was not appreciated that salts of zwitterions have substantially reduced dipole moments compared to the free zwitterionic species. Consequently, it was demonstrated that typically for the salt form, the melting point decreased, the solubility in both polar and nonpolar media increased and the solubility in polyurethane membranes and in stratum corneum increased dramatically. To study this effect systematically, phenylalanine, baclofen and two diacid angiotensin converting enzyme inhibitors were selected as model zwitterionic compounds. Covalency was the key determinant in the counterion to optimize the increase in solubility of the salt. Rigidity of the zwitterion was related to the size of the enhancement.