New cocrystals of daidzein with enhanced solubility: Preparation, characterization, calculation and analysis

Daidzein (DAI) is characterized by poor solubility, which greatly limits its clinical application and market potential. In order to overcome the limitation, DAI cocrystals with solubility advantage were prepared by means of green mechanized method and melt crystallization method, which were daidzein-4,4 '-vinylenedipyridine (DAI4VDP) cocrystal and daidzein-4,4 '-ethylenedipyridine (DAI-4EDP) cocrystal. Systematic characterization, structural analysis and comparison, theoretical calculation, stability evaluation and dissolution test of these cocrystals were carried out. The structures of the two cocrystal structures were analyzed by single crystal X-ray diffraction. Quantum chemical calculations, including Hirshfeld surface analysis, atoms in molecules theory, independent gradient model based on Hirshfeld partitioning, frontier molecular orbitals, and molecular electrostatic potentials surface, were employ to investigate the intermolecular interactions at the microscopic level. It was worth noting that the solubilities of DAI-4VDP cocrystal and DAI-4EDP cocrystal were enhanced to 1.2-fold and 30.4- fold, respectively, compared to DAI in pH 6.8 phosphate buffer. Among the cocrystals reported hitherto, the solubility of the DAI-4EDP cocrystal demonstrated a significant improvement in solubility, which offered a novel opportunity for the formulation development of daidzein and innovative strategies for addressing insoluble drugs.