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Investigation of a Flow Step Clogging Incident: A Precautionary Note on the Use of THF in Commercial-Scale Continuous Process

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posted on 2019-10-21, 20:15 authored by Nelo R. Rivera, Brittany Kassim, Plamen Grigorov, Heather Wang, Marco Armenante, Xiaodong Bu, Azzeddine Lekhal, Narayan Variankaval
Despite the many benefits that flow chemistry brings in the context of commercial manufacturing, a major issue for such continuous processing can be the clogging of flow equipment. In the case of verubecestat (MK-8931), the development of a flow chemistry process for the Mannich step greatly increased the reaction yield and the purity of the isolated product. However, in one of the plant-scale solvent runs in advance of process validation, an unforeseen and isolated clogging incident occurred. Herein, we report the methodical troubleshooting leading to the location of the clog, the structural elucidation of the solids, and eventual root cause analysis. The culprit was eventually tied to poly­(THF), which was present in extremely low levels in a specific lot of THF solvent used. An interesting observation with regards to the deposition of solids in the filter cartridge and static mixer element with respect to solvent flow led us to speculate that the precipitation of the solids is caused by a phenomenon known as hydrodynamic cavitation.

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