Alfred Y. Lee
Department of Analytical Research & Development
Merck & Co., New Jersey USA

Keywords: Green Manufacturing, Gefapixant Citrate, Solid-State Chemistry, crystal structure prediction

Gefapixant citrate (or MK-7264) is a P2X3 receptor antagonist that is under investigation for the treatment of refractory and unexplained chronic cough. It has demonstrated significant efficacy in recent Phase 3 clinical trials in reducing the frequency of cough in patients with refractory chronic cough after 12 weeks of treatment compared to placebo.

A robust, green, and sustainable manufacturing process has been developed for the synthesis of gefapixant citrate. The newly developed commercial process features many advantages including low process mass intensity (PMI), short synthetic sequence, high overall yield, minimal environmental impact, and significantly reduced active pharmaceutical ingredient (API) costs.

This presentation provides a solid-state chemistry perspective on the development of a commercial manufacturing process for gefapixant citrate. Key innovations that will be discussed are: (1) exploitation of a cocrystal that enabled chemical purification and enhance the physical properties of a regulatory starting material; (2) utilization of crystal structure prediction (CSP) across the chemical synthesis to ensure that products are launched with the best chemical processes; (3) manipulation of a physical form for crystallization selectivity to purge chemical impurities; (4) a novel salt metathesis approach to consistently deliver the correct API salt form in high purity; and (5) navigation of a complex solid form landscape through knowledge of a process phase diagram.