Comparison of induction methods for supersaturation: pH shift versus solvent shift.

Abstract

In order to investigate the supersaturation propensity of drugs in a simple and small-scale setup, induction of supersaturation is often performed via solvent shift. For weak bases, a potentially more biorelevant induction method would be a pH shift, as it is often hypothesized that the induction method will impact the supersaturation and precipitation. However, this has not been investigated systematically in a pharmaceutical context. This study investigates the impact of the induction method of supersaturation for nine basic drugs, A0619, A2853, albendazole, cinnarizine, dipyridamole, intraconazole, JNJ39393406, ketoconazole, and posaconazole, on four parameters: highest apparent degree of supersaturation, induction time, precipitation rate and solid form of the precipitate, using a novel standardized small-scale supersaturation and precipitation method. For eight of the nine drugs, the same highest apparent degree of supersaturation was obtained with both induction methods. For the induction time, precipitation rate and the solid form of the precipitate, no systematic differences between the induction methods were detected, however individual drugs did show differences. The study shows that, if a drug is sufficiently soluble at low pH, the solvent shift and pH shift induction methods of supersaturation yield comparable results.