(243a) Problem Solving Strategies for Heterogeneous Reactions. A Case Study on a Pharmaceutical Intermediate

A case study is presented of a problematic heterogeneous reaction step in the synthesis of a pharmaceutical intermediate compound in the plant. A base mediated ring closure reaction using solid Cs₂CO₃ exhibited several issues, including reaching completion without excess base or the use of a wet mill in the plant, variability in performance depending on the Cs₂CO₃ source in the lab, and rapid product degradation in the presence of the base. The engineering approaches used both in the lab and in the plant to understand and address these issues included solid suspension and mixing studies, particle characterization and product stabilization studies. Application of the key learnings into subsequent plant implementions resulted in successful scale-up of the step. Since the issues and approaches used are common to many heterogeneous reactions they are summarized into general problem solving strategies that can be applied to other systems involving the suspension of a solid reagent that causes product degradation.