(243b) Accelerated Process Design and Optimization for a Small Molecule COVID-19 Therapeutic

Molnupiravir is an investigational oral antiviral treatment for SARS-COV-2 that works as a ribonucleoside analog to inhibit replication of RNA viruses. The proposed commercial manufacturing route is a five step synthetic route from the regulatory starting material. This presentation will discuss the optimization of the final transformation on a highly accelerated timeline to ensure metric-ton supply of high purity molnupiravir during the coronavirus pandemic. This step begins with an acid-catalyzed deprotection reaction to form molnupiravir from the penultimate intermediate which also forms impurities due to acid-sensitive hydrolysis. Small-scale high throughput experimentation was used to build kinetic models which were used to optimize impurity generation and yield productivity. The workup of the reaction also introduces the risk of producing lightly purple colored active pharmaceutical ingredient (API) through trace metal coordination, which was mitigated through the addition of a chelating agent. The chelated metal and other aqueous-soluble impurities are rejected through extractions. Remaining impurities are then rejected into the mother liquor during the azeotropic distillative crystallization. Because of the potential variability of the distillation across several equipment trains and scales, the crystallization was designed for better control and less sensitivity to these variations. The resulting process performance has been monitored at four clinical and commercial manufacturing sites. In summary, this talk will discuss the development of control strategies across the last step of the molnupiravir synthesis to ensure the critical quality attribute of purity is met.