Solvent-polymer guest exchange in a carbamazepine inclusion complex: structure, kinetics and implication for guest selection

Abstract

Solid forms play a central role in modulating and optimizing the physicochemical properties of drugs, among which crystalline inclusion complexes (ICs) represent an emerging subcategory. In this study, we confirmed the inclusion of linear polymer polytetrahydrofuran (PTHF) into carbamazepine (CBZ) Form II, an extensively studied crystal structure with unique channel voids in its unsolvated form. According to solid-state NMR, PTHF chains were located in the CBZ channels with an extended conformation. Guest exchange experiments were performed on the toluene-solvated CBZ Form II by agitation in PTHF solution. The guest exchange kinetics was monitored by solution NMR, which agreed with the three-dimensional diffusion model. Further investigation revealed that the guest exchange only occurred on the free surface of the toluene-solvated CBZ Form II crystals via a recrystallization mechanism, leading to the formation of a core–shell structure with PTHF merely located in the shell layer. The shell crystal acted as the barrier layer that controlled the diffusion of molecules and consequently the extent of guest exchange, validating the fitted diffusion kinetic model. These results give insight into the guest exchange process between the small molecule guest and polymer guest in a drug IC crystal, and provide implications for a better understanding of guest selectivity and controlling the solid-state properties of drug crystals.