(302b) New Insights on the Effects of Molecular Rigidity and Purity on Crystallization Pathways

In recent years, there has been a steady increase both in molecular rigidity and molecular weight of substances with potential therapeutic benefits transiting from medicinal chemistry. It is believed that this increase had led to an increase of challenges to crystallization due in part to molecular rigidity and complexity¹. In addition, increasing molecular weight is expected to result in increasing challenges to achieving acceptable chemical purity due to the increase in the number of related impurities and synthetic steps required to produce relatively large drug substances. In this talk, we present a case study of a drug candidate that displayed unique challenges to crystallization. Investigations revealed that molecular rigidity and impurities levels dictate the outcome of the crystallization attempts to either crystalline nucleation or oiling-out. An NMR-based approach is presented that proved critical in identifying operating conditions that steer the system toward crystallization. This approach, along with understanding the causes of oiling-out, allowed the development of a robust crystallization procedure that was critical for the progression of the drug substance into clinical trials.

1. Derdour L., A pathway to first crystals for substances prone to Liquid-Liquid phase separation, Chem. Eng. Technol., 44(3), 488–494, 2021