Polymorphs, Particle Size, and a Pandemic: Development of a Scalable Crystallization Process for Molnupiravir, an Antiviral for the Treatment of COVID-19

Molnupiravir is a small-molecule active pharmaceutical ingredient (API) prodrug of a nucleoside analog that was demonstrated to be efficacious for the treatment of patients with COVID-19. Early in the pandemic, Merck & Co. Inc. partnered with Ridgeback Biotherapeutics to accelerate the development of a manufacturing process for the drug in anticipation of high global demand for the treatment. It was essential to quickly establish a robust manufacturing process, as well as a rigorous physical attribute control strategy, to enable rapid delivery of metric tons of molnupiravir. Given the drug load of >50% (w/w) API in the formulation, there was high potential for the physical attributes to have a strong effect on drug product performance. Molnupiravir can also exist as multiple polymorphs and has the potential for wide variations in particle size. To address these challenges, we performed extensive derisking of these attributes with respect to the impact on drug product performance and were ultimately able to demonstrate the acceptability of a wide range of API physical attributes. In parallel, we strategically designed a scalable crystallization process that consistently delivered drug substance within our derisked range of attributes, across multiple manufacturing sites and scales. Thus, we were able to demonstrate that the API's physical attributes did not affect the drug product's critical quality attributes or therapeutic efficacy, giving our multiple manufacturing sites greater flexibility to deliver metric tons of molnupiravir to patients in need.