Understanding the formation mechanism of drug-polymer inclusion complex by structure elucidation and theoretical calculation

Drug-polymer inclusion complex (IC) has been considered a novel solid-state of drugs for properties modification. However, the formation mechanism is poorly understood. This work aims to explore the molecular mechanism that determines the dependence of carbamazepine (CBZ) and griseofulvin (GSF) channel structures on guest polymers. With the aid of microdroplet melt crystallization, we successfully elucidated the single-crystal structures of the two groups of ICs, which enables theoretical calculation. Structural analysis, density functional theory calculation, and molecular dynamics simulations together indicated that CBZ molecules can self-assemble into stable channel structures in the absence of guest polymers, benefiting from the special mortise-tenon structure and strong π…π interactions, while GSF channels cannot be sufficiently supported by the weak Cl…O and C-H…π intermolecular interactions, and thus need the insertion of guest molecules to stabilize the structure. This answers the question of why CBZ channels can independently exist in the absence of guest polymers, but GSF channels cannot. Despite the dependence of channel structures on guest polymers, the channel size was determined by the size, shape, and conformation of host molecules, together with the intermolecular interactions. Interestingly, although the eleven structurally determined drug-polymer ICs have different ways to build channel structures, their channel sizes lie in a narrow range of 3.86-5.18 Å, slightly larger than the radial diameter of five guest polymers (2.83-3.50 Å). Our results also verify that microdroplet melt crystallization can rapidly synthesize drug-polymer ICs and efficiently grow their single crystals with sufficient quality and size, thus solving the bottleneck of structure elucidation. We believe that these findings will encourage further research on the formation mechanism of drug-polymer IC, thereby promoting the theoretical prediction and practical application of this novel solid form in pharmaceutical development.