(336b) Flow Chemistry As an Enabling Tool for Scale-up of API Processes

Flow chemistry offers advantages to batch chemical processes that may have limitations in safety, heat transfer, and selectivity for the preparation of intermediates or active pharmaceutical ingredients (APIs). Herein we describe two case studies on the application of flow chemistry in process development and manufacturing.

Case 1: The use of flow chemistry to prepare an intermediate of remdesivir, an antiviral therapeutic approved for the treatment of COVID-19, includes a cyanation process that is demanding to perform as a batch process at production scale due to large quantities of hydrogen cyanide and cryogenic conditions. The reaction parameter control afforded by the flow process provides improved selectivity and yield. Additionally, the flow process and the flow reactor system design supported rapid scale-out in response to increasing production demand.

Case 2: Development of a flow chemistry process for the scale-up of an investigational drug candidate intermediate. A selective diisobutylaluminium hydride (DIBAL-H) reduction of a heterocyclic diester had acceptable selectivity and yield at laboratory scale, but lower regioselectivity, chemoselectivity, and yield were observed at pilot-plant scale under batch conditions. A flow chemistry process was developed with DoE that improved control of mass and heat transfer and provided better control of reaction time. This was quickly scaled up, allowing for the successful manufacturing of the intermediate at pilot-plant scale.

Reference:

1. Vieira, T.; Stevens, A. C.; Chtchemelinine, A.; Gao, D.; Badalov, P.; and Heumann, L.; Development of a Large-Scale Cyanation Process Using Continuous Flow Chemistry En Route to the Synthesis of Remdesivir OPRD 2020 24 (10) 2113-2121
2. Uhlig, N.; Martins, A.; Gao, D.; Selective DIBAL-H Monoreduction of a Diester Using Continuous Flow Chemistry: From Benchtop to Kilo Lab OPRD 2020 24 (10) 2326–233