Study on the formation mechanism and effective manipulation of polymorphs and solvates in Osimertinib-Caffeic acid multi-component crystal with distinct properties.

Investigating the formation mechanism and effective manipulation of multi-component crystal polymorphs is crucial for facilitating industrial drug development. Herein, five novel Osimertinib-caffeic acid forms were first strategically tailored by varying solvent selection. Theoretical analysis demonstrated this polymorphism is correlated with multiple hydrogen bond donors-acceptors within multi-component system, which provides manipulation space for reconfiguration of intermolecular interactions and structural competition, while solvent further induced or involved in hydrogen-bonded rearrangements. Molecular dynamics simulation and solvent characterization revealed strong solute-solvent interaction and hydrogen bond donor propensity promoted the generation of hydrate. Small molecular size or large cavity of crystal facilitated solvent entry, resulting in the generation of channel-type solvates. Higher solvation free energy implied faster reaction rate and poorer solvent removal ability for solvates. Thermal analysis confirmed removal of the solvent occupying crystal channels for precursor solvates led to polymorph formation while maintaining the structure. Properties assessments revealed multi-component crystals significantly enhanced the physicochemical properties of Osimertinib. Polymorphs and hydrate exhibited remarkable distinctions in solubility, dissolution rate and physical stability. Nanoindentation and tableting tests confirmed distinct mechanical properties of different forms. Overall, this exploration has the potential to reshape the landscape of multi-component crystal polymorph development, paving the way for manipulating intermolecular interactions.