Mechanistic analysis of pH-dependent solubility and trans-membrane permeability of amphoteric compounds: Application to sildenafil

This study was aimed at investigating the pH-dependent solubility and in vitro transmucosal permeability of sildenafil, an amphoteric compound with limited aqueous solubility, across parallel artificial membrane. The aqueous solubility and permeability of sildenafil as a function of solution pH were theoretically derived from the individual contributions of all species (cationic, neutral and anionic). The stability, octanol-water distribution coefficient (log D), and solubility of sildenafil were then determined at various pHs, the permeability study was also performed at different pHs using parallel artificial membrane. The pH-solubility and -permeability profiles were then fitted to theoretical equations using non-linear regression. The experimental pH-solubility profile was fitted very well to the theoretical equations (R-2=0.9996). The in vitro permeability of saturated sildenafil solution at different pH values also showed similar trend as the predicted one (R-2=0.7829). The two optimum pH (pH(max)) values were found to be 4.50 and 10.24, where the maximum solubility of either cationic or neutral species, or anionic and neutral species is simultaneously obtained, and the maximal transmucosal fluxes (J(ss)) are achieved. The above method can be applied to optimize the transmucosal delivery of other amphoteric drugs with low aqueous solubility. (C) 2007 Elsevier B.V. All rights reserved.