Development of Glecaprevir: Conformations, Crystal Structures, and Efficient Solid–Solid Conversion for a Highly Polymorphic Macrocyclic Drug

Glecaprevir (GLE) is an 18-membered macrocyclic potent NS3/4A protease inhibitor for the treatment of hepatitis C virus (HCV) infection. In this work, the molecular conformations, polymorphism, and implications of crystal structural features of GLE are evaluated through a combination of advanced computational and experimental methods in the context of commercial solid form selection and drying process development. The ability of GLE to adopt different conformations is found to hinge largely on the presence or lack of an intramolecular hydrogen bonding interaction between its macrocyclic ring and side chain. Consequently, two distinct molecular conformations, bound-chain and free-chain, can prompt crystallization of two separate classes of GLE forms in various solvents. Moreover, the preservation of the core macrocyclic ring conformation from solution to solid phases contributes favorably to the ease of crystallization of many isostructural forms of GLE including those highly relevant to drug substance process─hydrate Form 1 and MeOH/H2O mixed solvate Form 2. Detailed assessments of dynamic vapor sorption isotherms and energetics of host–guest solvent interactions help to establish a deep understanding of the desolvation and hydration behavior of GLE crystals. The characteristic of isostructural solvates and hydrates is fully leveraged to develop an efficient and robust synchronous humid drying process that achieves direct solid–solid conversion from Form 2 to Form 1 with minimized process-induced disorders and consistent form control. The learnings from this study are useful in building a deep understanding on structure and property relationships of crystalline macrocycle drugs and for developing their efficient and robust isolation and drying process.