Compound selection for development - is salt formation the ultimate answer? Experiences with an extended concept of the "100mg approach"

Abstract

In order to select the best candidates for development, physicochemical criteria such as solubility, chemical and physical stability, hygroscopicity, and thermal characteristics need to be evaluated as early as possible and balanced against other important criteria such as pharmacology or pharmacokinetics. It could be shown, that our miniaturized pharmaceutical profiling concept ("100mg approach"), is capable to reliably identify potential development issues of drug candidates, which, therefore, can be approached early on. Salt formation is a well established strategy to improve unfavorable properties, in particular poor solubility. This article describes our stepwise approach on salt screening, including selection criteria, and summarizes the observations we had during compound investigation. Considering a data base of 337 compounds (salts and uncharged substances), experiences with various counterions evaluated over the last 10years are discussed. We realized that salt formation usually improves poor solubility of a given candidate, but this is often at the cost of other attributes being relevant for pharmaceutical development. Surprisingly, in more than 50% of all cases the "free form" was finally selected after carefully weighing all compound characteristics. Therefore, we conclude that an early salt selection strategy is of utmost importance to predict potential development issues and to enable the provision of alternative physical forms. However, salt formation itself is not necessarily the best solution to meet all development requirements. The selection of a free form (acid or base) in combination with advanced formulation strategies should always be considered, sometimes as best compromise.

Keywords: Pharmaceutical evaluation; Physicochemical characterization; Salt selection.