Revealing the role of anisotropic solvent interaction in crystal habit formation of nifedipine

Abstract

The modification of the crystal habits by the solvent selection approach has been widely applied. However, the underlying regulation mechanism by solvents, specifically solute recognition and assembly process at crystal-solution interface is not yet well-understood. Herein, the effects of solvents on crystal habit and interface assembly of nifedipine (NFD) were investigated by growth experiments in five selected organic solvents of distinct hydrogen bond affinity properties. It was found that the crystal habits of NFD can be tuned by the hydrogen bond acceptor (HBA) ability of solvents, which elevates the aspect ratio of the crystals. The X-ray diffraction (XRD) and differential scanning calorimeter (DSC) further confirmed that no polymorphs were involved and related with the morphology changes. The face indexing calculated by single crystal XRD of experimental morphologies, Hirshfeld surface analysis, and the surface chemistry of the different crystal facets revealed a directionality of solvent interactions with crystal faces, induced by the solute-solvent hydrogen bonding interactions. Further, the strength of the solute-solvent interactions quantified by the adsorption energy calculations and the RDF analyses correlates well with the HBA ability of the solvents and the experimental morphology. In all, it was unveiled that the directionality of solute-solvent hydrogen bonding interactions interrupts anisotropically the recognition and assembly of solutes at the crystal-solution interface, resulting in the modification of the crystal morphology.