(336f) Practical Challenges and Solutions to Continuous Grignard Chemistry

The Grignard reaction is one of the most powerful techniques for creating new C-C bonds and involves the formation of a highly reactive organometallic Grignard reagent. Despite its utility, Grignard chemistry presents significant safety hazards on large batch scales, such as runaway exotherms and magnesium handling concerns. Over the past several years, flow chemistry and continuous manufacturing methods have been applied to Grignard chemistry to create continuous modes that promote its utility while reducing the hazards.

Continuous operation of Grignard chemistry is not without its challenges, however. The development of an optimized Grignard reagent formation reaction necessitates careful consideration of many variables. For example, the heterogeneity of the Grignard reagent formation reaction requires special considerations for agitation and liquid separation. Creating a successful Grignard reagent formation process is further complicated by the inert and dry chemical condition requirements.

At CONTINUUS Pharmaceuticals, we have developed a laboratory-scale Grignard reagent platform to investigate the impacts of and address these challenges. The result is a workflow for process development, PAT model development, and scale-up. This workflow includes a method for converting a batch Grignard formation reaction to continuous on the 100 mL to 1 L scale, how to investigate activation and initiation techniques, practical IR model development strategies, common impurity forms to test for, Mg feed schedule considerations, among other topics. The CONTINUUS team has successfully used this workflow to generate a Grignard reagent at >95% yield throughout a multi-day campaign. Finally, the workflow informs a scale-up procedure with considerations for designing a 10 L commercial-scale Grignard reagent formation CSTR for a high potency API.