(302e) Crystallization Development for Molnupiravir, an Investigational Antiviral for the Treatment of COVID-19

Molnupiravir is a small molecule API (active pharmaceutical ingredient) pro-drug of a nucleoside analog which has shown potential for the treatment of COVID-19 in pre-clinical and clinical studies. Merck partnered with Ridgeback Biotherapeutics in May 2020 to accelerate development of the drug. Due to the high anticipated global demand, the team quickly worked on delivering a robust manufacturing route to reliably produce API of consistent quality. This talk will specifically focus on the development of a robust crystallization process which reliably delivers acceptable chemical purity and physical attributes, and is insensitive to equipment and scale of operation. The original isolation of API was achieved through a distillative crystallization, in which a solution of API, ethyl acetate, acetonitrile, and water is azeotropically dried to induce crystallization of the highly water-soluble API. The existing process was modified to give better control around the seeding point and initial de-supersaturation, which resulted in more consistent nucleation and growth, leading to more consistent API attributes across batches at different scales. To determine the level of control needed on API particle size for the capsule formulation, the impact of the high and low extremes of particle size ranges on bioavailability was assessed. Targeted experimentation also revealed how supersaturation controls the formation of the metastable and thermodynamically stable crystal forms. This presentation will discuss the methodology used to gain a thorough understanding of crystallization performance (morphology, particle size, bulk density, crystal form) over just a few months, ultimately producing API with consistent properties across various production sites in five different countries.