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 drug 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, DFT calculation, and theoretical simulation together indicated that CBZ molecules can self-assemble into stable channel structures benefiting from the special mortise-tenon joints 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 the insertion of guest molecules is essential for structure stabilization.This answers the question of why CBZ channels can independently exist in the absence of guest polymers, but GSF channels cannot. Moreover, our results verify that microdroplet melt crystallization can grow single crystals of IC with sufficient quality and size, thus solving the bottleneck of structure elucidation. These findings will encourage further research on the formation mechanism of drug-polymer IC that facilitates the prediction and application of this novel solid form in drug development.