Chiral Resolution by Salt/Cocrystal Formation

Most of the drug molecules are chiral compounds with enantiomers. Each enantiomer may show significant differences in biological activities, such as pharmacodynamics, pharmacokinetics and toxicity. It is therefore recommended to market chiral drugs containing only the desired enantiomer. It is thus critical to develop a production process that leads to enantiopure dug substance. In this context, chiral resolution has become a crucial step in pharmaceutical development and crystallization-based resolutions are widely utilized to produce enantiopure drug substance of high purity. This presentation will review the concept of conglomerate, racemic compound and solid solution as well as how to differentiate them using phase diagrams and analytical techniques. It will discuss chiral resolution methods though salt and cocrystal formation followed by crystallization using a couple of case studies. One case study was to identify a cocrystal conglomerate followed by development of a chiral resolution process based on preferred crystallization. The other case study is to perform classic chiral resolution by diastereomeric salt formation which is considered one of the most effective methods for production of chirally pure drugs at large scale.

• Understand why classical resolution by salt formation is often considered as one of the most efficient methods to produce enantiopure pharmaceuticals on a large scale
• strategically design a rational approach to a solid form screening study
• Optimize a crystallization process to be scaled up to various scales