(419d) Development and Scale-up of Flow Chemical Syntheses for Drug Substance Manufacturing

This presentation will survey recent applications of chemical reaction engineering in small molecule process development and manufacturing at Merck in honor of the career contributions to this field by Professor Klavs Jensen.

The installment of continuous processing unit operations in the synthesis of active pharmaceutical ingredient (API) has rapidly increased over the past decade, in part due to the pioneering work of academics such as Professor Klavs Jensen. In this presentation, several flow chemistry case studies from Small Molecule Process Research and Development at Merck will be highlighted to illustrate how chemical reaction engineering approaches lead to innovative solutions for the manufacturing of drug substance materials. Using the work of the Klavs Jensen Lab as an aspirational model, this presentation will show how industrial research has similarly progressed from using flow chemistry as a process intensification tool for traditional chemical reactions to a powerful and enabling technology to build complex molecules.

The first case study will review challenges and learnings from scaling up a reaction with rapid kinetics and an unstable intermediate. Merck’s development work on this project leveraged fundamental engineering knowledge, often taking guidance from research in the Jensen Lab, to build the framework for expanded use of flow reactions across scales. With the adoption of flow reaction tools in process chemistry, methods to streamline synthesis of API by integrating flow chemistry with nascent technologies have been explored. Case studies around flow processes that leveraged immobilized biocatalysis and photochemistry will be presented to illustrate such synergies. As will be discussed, success in each of these demonstrations required novel engineering solutions and close collaboration across multi-functional groups – two elements that have become a trademark of Klavs Jensen’s research.