Theoretical exploration on the molecular configurations, solubilities and chemical reactivities of four flavonoid-based co-crystals

Four flavonoid-based co-crystals containing the active pharmaceutical ingredients Apigenin (AP), 4′,7-Dihydroxyflavone (DH), Genistein (GE), Daidzein (DA) and the co-crystal former Theophylline (TH) were constructed as the stoichiometric ratio of 1:2 form in theory. The structural parameters and chemical reactivities of the four co-crystals were systematically explored via the density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) methods. The intermolecular hydrogen bond lengths, frontier molecular orbitals, absorption spectra, electrostatic potential population, binding energies, solvent energies and global reactivity descriptors of the monomers and co-crystal systems were studied. In addition, the topological analysis of bond critical point based on the QTAIM, interaction region indicator and infrared (IR) spectrum analysis were adopted to investigate the intermolecular interaction between the APIs and CCF. The calculated results indicate that the APIs and CCF are bound via the intermolecular hydrogen bond interaction, and the drug activity and solubility of all co-crystals are significantly improved compared with that of the monomers. Interestingly, the isoflavone-based co-crystals (DA-TH and GE-TH) show the more excellent drug activities than that of the flavonoid-based co-crystals (AP-TH and DH-TH). This work can provide the reliable theoretical basis for the experimental synthesis of flavonoid-based drug co-crystal with more outstanding properties.