(173a) Implementation of Continuous Crystallization As a Processing Method for Robust Control of API Purity and Crystal Form

The control of purity and crystal form in the crystallization of active pharmaceutical ingredients (APIs) is essential for the provision of therapeutic products that are safe for patients to use and perform as intended during formulation, storage, and administration. In this presentation, we describe the design and proof of concept (POC) development of a continuous crystallization process to replace the consecutive impurity and form controlling batch recrystallizations used in the manufacturing of GDC-4379, a small molecule Janus kinase 1 (JAK1) inhibitor designed to treat severe asthma.¹ The main driver for translating the two-step batch procedure to a continuous crystallization was the need to establish a robust and scalable methodology to reject a key regioisomer impurity, the purging of which had become challenging in the batch recrystallization for impurity control implemented in 100 kg scale production. A further aim of the development effort was to demonstrate that the target hydrate form of the API could be continuously crystallized from the solvent system of the impurity purging recrystallization (DMSO/MeOH), thereby providing scope that a streamlined continuous GDC-4379 crystallization could accomplish the respective impurity and form control objectives of the penultimate and final batch recrystallizations.

A detailed investigation into the mechanism of regioisomer contamination in the impurity purging recrystallization identified that the regioisomer contaminated the solid phase by developing supersaturation during the batch process and crystallizing as a physically separate solid to the API. This understanding of the regioisomer contamination mechanism provided justification for the pursuit of an impurity control strategy that was based on operating in the nonequilibrium environment of a continuous mixed suspension, mixed product removal (MSMPR) crystallizer to purge the regioisomer by kinetic impurity rejection. Impurity desupersaturation rates were characterized in batch mode to guide the selection of operating conditions for a continuous crystallization experiment to demonstrate POC for regioisomer control. Operating parameter selection for a POC continuous process to selectively crystallize the hydrate form of the API was informed by mapping the anhydrate/hydrate form conversion landscape in terms of temperature and water content in 1.5:1 w/w DMSO:MeOH.

Superior regioisomer rejection (97.9%) was achieved in the continuous crystallization demonstration run for regioisomer control versus the batch process (32.4%). By operating at 60 °C and incorporating water as an additional antisolvent component to target 30 w% water in the solvent matrix of the MSMPR crystallizer, the target hydrate form of the API was continuously produced over the course of a 1.8 h demonstration run. The results provided POC that a continuous processing adaptation of the two-step batch recrystallization process had the capacity to meet the regioisomer purge and API form control requirements for the GDC-4379 drug substance.

References

[1] Morris, G.; Keogh, A.P.; Farid, U.; Stumpf, A. Development of an impurity and hydrate form controlling continuous crystallization to telescope a two-step batch recrystallization in the GDC-4379 drug substance process. Chem. Eng. Res. Des. 2022, 183, 608–622.