Synthesis And Properties Of Natural Pharmaceutical Co-crystals Of Polyhydroxy Flavonoids

Objective Based on design,syntheses and properties study on natural active pharmaceutical co-crystals of flavonoids,to explore the synthesis condition and formation law,and analyze the intrinsic relationship between structure and property.For artificial controllable designing and synthesizing more flavonoids co-crystals with clinical applicability provide a theoretical guidance.Methods Four representative flavonoids as research object to form flavonoids co-crystal with 4,4’-bipyridine by solvent evaporation method,namely,flavonols（kaempferol,quercetin and myricetin）,flavones（luteolin）,flavanonols（dihydroquercetin）and isoflavones（genistein）.These synthesized co-crystals have been structurally characterized by using single crystal X-ray diffraction,XRD,IR,and NMR methods.The self-assembly mechanism of supramolecule of flavonoids pharmaceutical co-crystals has been investigated based on analyzing the Hirshfeld surface maps and 2D fingerprint plots of these pharmaceutical co-crystals generated by the software of CrystalExplorer v.3.1.The thermo-chemical properties of products were studied by thermal analysis（TG-DSC）.The dissolution of pharmaceutical co-crystals in vitro has been investigated by using basket method or paddle method undertook in 0.1 M HCl aqueous solution.The stability investigations of co-crystals were carried out by accelerated test.Antibacterial activities of pharmaceutical co-crystals have been studied by using disk diffusion method.SRB method was utilized to study the antitumor activities in vitro,and the IC50 were calculated.Results Nine kinds of unreported co-crystals of flavonoids have been synthesized by solvent evaporation method.C₁₅H₁₀O₆?1.5C₁₀H₈N₂（1）,C₁₅H₁₀O₆?C₁₀H₈N₂（2）,2C₁₅H₁₀O₆C₁₀H₈N₂?2H₂O（3）,C₁₅H₁₀O₇?1.5C₁₀H₈N₂（4）,C₁₅H₁₀O₈?2C₁₀H₈N₂·H₂O（5）,C₁₅H₁₀O₈?C₁₀H₈N₂?C2H6O（6）,C₁₅H₁₀O₅?C₁₀H₈N₂（7）,2C₁₅H₁₀O₇?3C₁₀H₈N₂（8）and C₁₅H₁₀O₆?3C₁₀H₈N₂（9）.The analytical results of Hirshfeld surface maps and 2D fingerprint plots showed that intermolecular H···N/O···H,π···π/C-H···π,O···H/H···C and O···H/H···O play a leading role in the self-assembly process of supramolecular synthons of co-crystals of flavonoids.Comparisons of solubility curves reveal that the dissolution rates of the pharmaceutical co-crystals（4,5,6,7 and 9）were better than that of the original drugs,respectively.The hygroscopicity of original drug active ingredients has been improved by forming co-crystals 4,7 and 8.The pharmaceutical co-crystals exhibit better in vitro antibacterial activities on Staphylococcus aureus（S.aureus）and Escherichia coli（E.coli）compared with their original drug active ingredients.Compared with their original drug active ingredients,the pharmaceutical co-crystals（2,3,4,6 and 8）exhibit more remarkable activities against human hepatoma HepG2 cells,cervical carcinoma Hela cells and Caco2 human colon tumor cell lines.Conclusions Pharmaceutical co-crystal of flavonoids with 4,4’-bipyridine can be synthesized by solvent evaporation method.The structures of pharmaceutical co-crystals were analyzed and compared.Intermolecular H···N/O···H,π···π/C-H···π,O···H/H···C and O···/H···O play a leading role in the self-assembly process of supramolecular synthons of cocrystals of flavonoids.The flavonoids co-crystals formed by the pharmaceutical co-crystals technology has improved the solubility and hygroscopicity,decreased meiting point,and strong antibacterial activity and anti-tumor activity compared with the active ingredients of active pharmaceutical ingredients.