Supramolecular Binary Systems of Flavonoids: Design, Structure, and Physicochemical Properties

In this study, an environmentally friendly mechanochemical approach was used to prepare and characterize a series of new cocrystals and salt cocrystals with a 1:2 stoichiometry. The flavonoids apigenin (APG), luteolin (LUT), fisetin (FIS), kaempferol (KAE), and quercetin (QUE) were mixed with pyridarone [4-(1-benzofuran-2-yl)pyridine (BZFP)] as the coformer. Single-crystal X-ray diffraction (SCXRD), combined with Fourier transform infrared (FT-IR) and Fourier transform Raman (FT-Raman) spectroscopy, confirmed the formation of well-defined supramolecular architectures stabilized predominantly by intermolecular O−H···N bonds. These interactions involve the terminal hydroxyl groups of the flavonoids (7OH and 3′OH/4′OH) acting as hydrogen bond donors and the pyridyl nitrogen atoms of BZFP serving as acceptors. The nature and dynamics of the hydrogen bonding network were further investigated using X-ray photoelectron spectroscopy (XPS). Analysis of the N 1s spectra revealed proton transfer in the LUT/BZFP, KAE/BZFP, and QUE/BZFP binary systems, indicating the presence of a mixed neutral−salt character. The remaining cocrystals were neutral. Thermal analysis showed that the obtained cocrystals have greater thermal stability than the pure components. Dissolution kinetics, solubility, and octanol−water partition coefficient studies (using chromatographic methods)compared to the parent flavonoidsrevealed a significant increase in dissolution rates, saturation concentrations, and solubility of the neutral and salt cocrystals under simulated gastric conditions (pH 1.9). Dissolution rates, saturation concentrations, and solubility values change with acidity in a complex manner. These variations can be explained by two opposing effects: on one hand, increased acidity protonates BZFP, making both pure BZFP and the cocrystals highly soluble, while the flavonoids become neutral and only sparingly soluble. Conversely, when acidity decreases, BZFP becomes neutral, reducing its solubility but increasing that of the flavonoids due to ionization. Overall, these results demonstrate that mechanochemical synthesis is a practical, effective, and sustainable strategy for improving the physicochemical properties of potent bioactive natural compounds, which can possibly be used in pharmaceutical formulations.