(341d) An Approach to Achieve Clarifying Filtration for the Reactive Crystallization of Poorly Soluble Organic Salts

In API manufacturing, removal of foreign particulates prior to the particle forming step is a pre-requisite under GMP conditions and is typically achieved by clarifying filtration of solutions of all the reagents. Drug dissolution in organic solvents requires ubiquitous solvation spheres between the solvent and the drug molecules. Recent trend of increasing lipophilicity of drug candidates can result in poor interaction drug-solvent which may explain the decreasing drug solubility observed in the last few decades¹. As a result of poor drug solubility, clarifying filtration is becoming increasingly challenging to achieve. In this presentation, we present an approach to achieve clarifying filtration for 2 drug candidates developed as salts and displaying poor solubility in most solvents. The approach is based on identifying co-solvents as solubility enhancers and takes advantage of the salt formation to achieve a full dissolution in a transient state with sufficient solution stability. The approach allowed the design of a GMP-compliant procedures that enable API deliveries to meet project needs.

1. Bergström et al., Adv. Drug Delivery Rev. 2016, 101, 6–21