Slipping into Solvates: Structure-Surface-Solvent Interplay in the Mechanochemical Solvate Formation of Ivacaftor

Solvate formation in molecular crystals remains difficult to predict, particularly under non-equilibrium conditions, where the initial solid state, mechanically generated surfaces, anisotropic surface chemistry, and solvent properties collectively influence solid-solvent interactions. While mechanochemical processing is widely used to access new solid forms, the structural features that control solvent incorporation during mechanical activation are not yet well understood. In this work, we investigate mechanochemically induced solvate formation in ivacaftor as a model molecular crystal, focusing on the effects of solvent nature, liquid-additive volume, milling duration, and starting solid form. Form C transformed selectively to a solvate, in MeOH, THF, and DMSO, whereas the amorphous material exhibited broader solvate-forming behavior, including hydrate and non-polar solvate formation. The observed transformations could not be explained by solvent class or apparent dissolution capacity alone, demonstrating the importance of the starting solid state and specific host-solvent interactions. Crystal structure and surface analyses of form C identified the (200) plane as a plausible mechanically responsive plane whose alternative termination exposes polar groups involved in the resulting solvate structures. Overall, the results support a model in which mechanochemical solvate formation is governed by the interplay among the initial solid state, mechanically generated surfaces, and specific solid-solvent interactions.