Developing and Optimizing a Quench-Crystallization Operation in Drug Substance Manufacturing

We describe the development of a triphasic quench-crystallization operation to isolate an intermediate in the manufacture of the sotorasib drug substance. Using this case study, unique aspects of the quench-crystallization operation are highlighted and contrasted with the development of more commonly discussed cooling/antisolvent crystallization operations. A workflow for exploring and developing complex, reactive crystallization operations for commercial drug substance manufacture is proposed and illustrated. Within this framework, the utility of applying process analytical technology (PAT) is demonstrated.