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Development of Glecaprevir: Conformations, Crystal Structures, and Efficient Solid-Solid Conversion for a Highly Polymorphic Macrocyclic Drug
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DOI：10.1021/acs.cgd.4c00638.png)
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Abstract
En 中文
This work investigated the molecular conformations, polymorphism, and crystal structure features of a synthetic macrocycle HCV protease inhibitor glecaprevir. It was unearthed that the significant difference in the side-chain orientation, relating to the presence or lack of intramolecular hydrogen bond interaction between the side chain and the macrocyclic ring, led to two distinct GLE molecular conformations: bound-chain and free-chain. These two conformations were responsible for the origination of two classes of crystallographically different GLE forms where diverse interactions among GLE-GLE, GLE-solvent, and solvent-solvent molecules were present. The core macrocyclic ring conformation of glecaprevir was preserved from solution to solid phases, leading to the ease of crystallization of many isostructural crystal forms including hydrate Form 1 and MeOH/H2O mixed solvate Form 2 that were exploited for drug substance manufacturing. The results from the detailed solid-state evaluation justified the nonconventional selection of labile hydrate Form 1 as the commercial solid form. This study also highlighted the importance of understanding the energetics, relative strength of host-guest solvent interactions, and implications thereof on desolvation and hydration behaviors of macrocycle crystals. The characteristic of isostructural solvates and hydrates was fully leveraged to develop a synchronous humid drying process, achieving direct solid-solid conversion from Form 2 to Form 1 that yielded GLE drug substance with consistent form control and minimized process-induced disorders.
Keywords:
INITIO MOLECULAR-DYNAMICS
HIGH-RESOLUTION
PERMEABILITY
DISCOVERY
SOLUBILITY
INFECTION
SOLVENT