Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264). Part 6: Development of an Improved Commercial Salt Formation Process

• Published in: Organic process research & development Vol. 24; no. 11; pp. 2498 - 2504
• Main Authors: Maloney, Kevin M, Zhang, Si-Wei, Mohan, Anne E, Lee, Alfred Y, Larpent, Patrick, Ren, Hong, Humphrey, Guy R, Desmond, Richard, DiBenedetto, Michael, Liu, Wenjun, Lee, Ivan H, Sirota, Eric, Di Maso, Michael J, Alwedi, Embarek, Song, Siqing, Chang, Hsieh Yao D
• Format: Journal Article
• Language: English
• Published: American Chemical Society 20.11.2020
• Subjects: salt metathesis; co-feed crystallization; phase diagram; solvate; pure filtration; form control
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.0c00260

The development of a sustainable commercial salt formation process for gefapixant citrate (MK-7264), an investigational new P2X3 antagonist for the treatment of chronic cough, is described. Due to the low solubility of the gefapixant free base, the first-generation process for citrate salt formation was a slurry-to-slurry process with poor quality control, wherein impurities were not well rejected and unreacted free base often persisted in the citrate produced. The development of a controlled crystallization from a homogeneous solution, which overcame these deficiencies, was complicated by solubility constraints and a daunting solid form landscape. Herein, we report a novel solution to this problem where the free base is transiently converted to a highly soluble glycolate salt enabling complete dissolution, from which direct crystallization of the final citrate salt occurs in a high yield through salt metathesis. Robust crystallization control was ensured by conducting a comprehensive polymorph screen on the glycolate salt and demonstrating its metastability compared to the desired citrate salt. In addition, process-relevant solvates of the citrate salt were discovered and derisked via a thorough understanding of their stability regions. With this information, a second-generation process salt formation with robust crystalline form and purity control was achieved, utilizing a salt metathesis co-feed process that greatly reduces the amount of solvent required, the overall manufacturing time, and the energy consumption compared to the first-generation conditions.