Development of Glecaprevir:\nConformations, Crystal\nStructures, and Efficient Solid–Solid Conversion for a Highly\nPolymorphic Macrocyclic Drug

Glecaprevir (GLE) is an 18-membered macrocyclic potent\nNS3/4A protease\ninhibitor for the treatment of hepatitis C virus (HCV) infection.\nIn this work, the molecular conformations, polymorphism, and implications\nof crystal structural features of GLE are evaluated through a combination\nof advanced computational and experimental methods in the context\nof commercial solid form selection and drying process development.\nThe ability of GLE to adopt different conformations is found to hinge\nlargely on the presence or lack of an intramolecular hydrogen bonding\ninteraction between its macrocyclic ring and side chain. Consequently,\ntwo distinct molecular conformations, bound-chain and free-chain,\ncan prompt crystallization of two separate classes of GLE forms in\nvarious solvents. Moreover, the preservation of the core macrocyclic\nring conformation from solution to solid phases contributes favorably\nto the ease of crystallization of many isostructural forms of GLE\nincluding those highly relevant to drug substance processhydrate\nForm 1 and MeOH/H<sub>2</sub>O mixed solvate Form 2. Detailed assessments\nof dynamic vapor sorption isotherms and energetics of host–guest\nsolvent interactions help to establish a deep understanding of the\ndesolvation and hydration behavior of GLE crystals. The characteristic\nof isostructural solvates and hydrates is fully leveraged to develop\nan efficient and robust synchronous humid drying process that achieves\ndirect solid–solid conversion from Form 2 to Form 1 with minimized\nprocess-induced disorders and consistent form control. The learnings\nfrom this study are useful in building a deep understanding on structure\nand property relationships of crystalline macrocycle drugs and for\ndeveloping their efficient and robust isolation and drying process.