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

Abstract

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.