Asymmetric transfer hydrogenation (ATH) is a commonly used transformation in the pharmaceutical industry for the reduction of ketones to establish key stereocenters. Yet, the potential for hydrogen gas generation during reaction, workup, and waste handling processes could be overlooked, resulting in serious safety issues such as waste container overpressurization or fire. In this study, multiple module calorimeter (MMC) testing along with micro-GC tests of small scale (1−2 mL) representative lab samples were performed to detect and predict the potential safety hazards associated with the scale-up of an ATH process. Due to the safety concern discovered in the early safety screening tests, methanesulfonic acid (MSA) quench was implemented at the end of the ATH reaction to suppress hydrogen generation, avoiding possible overpressurizing the waste drum and the need to use special hydrogenrated equipment at pilot-and production-scale. A safety assessment was performed to ensure that the subsequent vacuum distillation poses no risk of hydrogen combustion caused by using a standard pump/system. The process improvements and rigorous safety assessments enable the ATH reaction to be scaled-up using standard pilot plant equipment without the need for special handling and monitoring requirements for hydrogen gas. This study provides useful guidance and recommendations for safer scaling-up of similar organic synthetic reactions which may also generate flammable gas.
Process safety testing is critical for small molecule active pharmaceutical ingredient (API) scale-up and manufacturing by proactively identifying any process safety hazards, including environmental and industrial hygiene issues. The intent of this contribution is to describe how Merck & Co., Inc. Kenilworth, NJ (known as MSD outside of the U.S. and Canada) manages process safety testing for pilot plant and manufacturing scale operations with a stagewise approach. Several case studies will be discussed.
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