Development of an impurity and hydrate form controlling continuous crystallization to telescope a two-step batch recrystallization in the GDC-4379 drug substance process

• A continuous process is developed to improve the rejection of a key regioisomer impurity during API crystallization. • The mechanism of regioisomer contamination in the crystallization product is experimentally determined. • Studies on the impurity contamination mechanism and kinetics drive the selection of an MSMPR crystallizer for the design. • 97.9% of the regioisomer is rejected in the continuous crystallization compared to 32.4% in the equivalent batch process. • The capability to selectively crystallize the required hydrate form of the API in the continuous process is demonstrated. The development of an impurity and form controlling continuous crystallization process to deliver the JAK1 inhibitor GDC-4379 is described. Explored as a next generation process for the two-step batch recrystallization procedure used in production, the translation of the impurity control step to a continuous mixed suspension, mixed product removal (MSMPR) crystallizer enabled superior kinetic rejection of a key regioisomer impurity (97.9%) versus the batch process (32.4%). By operating the MSMPR crystallizer at sufficient water content and temperature it was verified that the target hydrate form A of GDC-4379 for the active pharmaceutical ingredient (API) could be selectively crystallized from the DMSO/MeOH solvent system of the purification step. This demonstration provided proof of concept for a telescoped continuous crystallization process for GDC-4379 to replace the separate batch impurity and form control recrystallizations carried out in production.