Molecular insights into the formation of drug-polymer inclusion complex

Drug-polymer inclusion complex (IC) has been viewed as a novel solid form of drugs for property modification. Nonetheless, our understanding of the formation mechanism remains limited. This work aims to provide insight into the molecular processes governing the structural construction of carbamazepine (CBZ) and griseofulvin (GSF) channel-type ICs in the presence of guest polymers. Leveraging microdroplet melt crystallization, we successfully unveiled the single-crystal structures of these ICs, enabling theoretical analysis. Our investigation, which encompasses structural analysis, density functional theory calculations, and molecular dynamics (MD) simulations, elucidates the disparity between CBZ and GSF channels in terms of their autonomy in the absence of guest polymers. CBZ molecules can spontaneously assemble into stable channel structures independently, capitalizing on their unique mortise-tenon architecture and robust π...π interactions. In contrast, GSF channels lack sufficient support from weak Cl...O and C-H...π intermolecular interactions and necessitate the insertion of guest molecules to stabilize their structures. Regardless of the structural reliance on guest polymers, channel size is determined by the size, shape, and conformation of the host molecules, as well as intermolecular interactions. Interestingly, while the eleven structurally determined drug-polymer ICs adopt diverse approaches to construct channel structures, their channel sizes consistently fall within a narrow range of 3.86-5.18 Å, slightly larger than the radial diameter of the guest polymers (2.83-3.50 Å). Consequently, we propose that a crucial prerequisite for the formation of drug-polymer ICs is that the host molecules have the capacity to self-assemble into a porous structure with accommodating channels for guest polymers. Additionally, our results confirm the efficacy of microdroplet melt crystallization in rapidly synthesizing drug-polymer ICs and cultivating their single crystals of high quality and sufficient size. This achievement overcomes the challenges associated with structure elucidation and promises to promote further research into the formation mechanism of drug-polymer ICs. We anticipate that these findings will inspire continued exploration of this novel solid form, facilitating theoretical predictions and practical applications in pharmaceutical development.