Mapping Polymorphic Behavior of Process Intermediates, an Often-Overlooked Exercise

• Published in: Organic process research & development 2022-04, Vol.26 (4), p.1258-1267
• Main Authors: Morrison, Henry, Regens, Christopher S, Dunetz, Joshua R, Lapina, Olga, Shah, Nisha P, Burke, Brenda J, Wenderski, Todd, Asselin, Sylvie M, Vieira, Tiago
• Format: Article
• Language: English
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.2c00003

Presented are two case studies where polymorphic behavior of a process intermediate was identified and the relationship was investigated for form control. Case study I: 1 is a process intermediate for a novel apoptosis signal-regulating kinase 1 (ASK1) inhibitor that was isolated as an unsolvated hydrochloride salt (1-HCl). Initial research lots and the first delivery batch yielded form I of 1-HCl; however, during process optimization to support a second delivery, form II was identified. This discovery left limited time to map the thermodynamic relationship between the two phases prior to the second production, and based on limited knowledge at the time, form I was selected and successfully scaled even though it was determined to be the room temperature metastable phase. Case study II: 2 is a process intermediate for a novel toll-like receptor 8 (TLR8) agonist. Applying lessons learned from case study I, polymorph screening identified unsolvated forms I and II, whose relative stabilities were mapped so that a crystallization could be designed to ensure phase control for the thermodynamically most stable form at room temperature prior to production, which ultimately benefited superior impurity rejection.