Synthesis And Properties Of Pharmaceutical Cocrystals Of Tetrahydroberberine

Objective Pharmaceutical cocrystals of tetrahydroberberine（THB）have been designed and synthesized based on pharmaceutical cocrystal technology to improve the physicochemical properties of THB,improve bioavailability,systematically explore its synthesis conditions and rules,and in-depth analyze of the relationship between structure and properties,which may provide theoretical guidance and basis for rationally designing target structure with ideal properties of protoberberine cocrystals.Methods Four representative Pharmaceutical cocrystals of THB have been synthesized through solvothermal method and solvent evaporation method,and structurally characterized by single-crystal X-ray diffraction,powder X-ray diffraction analysis（XRPD）,infrared spectroscopy（IR）and thermogravimetric analysis（TGA）.Hirshfeld surface maps and 2D fingerprint plots of these pharmaceutical cocrystals were generated by CrystalExplorer software to explore the molecular self-assembly mechanism.The solubilities of THB pharmaceutical cocrystals were further investigated by using the basket method or paddle method undertook in the aqueous media.The hygroscopic stabilities of cocrystals were carried out by accelerated experiments.The antibacterial activities in vitro of THB pharmaceutical cocrystals were determined by the disk diffusion method.The antitumor activities in vitro of these pharmaceutical cocrystals were investigated by the SRB method,and the IC₅₀ were calculated.Results Three types unreported THB pharmaceutical cocrystals were synthesized by solvothermal method and solvent evaporation method:pharmaceutical cocrystals of tetrahydroberberine with polyoxometalate(（THB）₃(H₅PMo₁₂O₄₀)（1）,（THB）₃(H₃PW₁₂O₄₀)（2）and（THB）₄·(H₄SiW₁₂O₄₀)（3）),with hydrochloride（[HTHB]Cl（4）,[HTHB]Cl·CH₃OH（5）and[HTHB]Cl·CH₃COOH（6））and with dicarboxylic acids(C₂₀H₂₂NO₄·C₂H₁O₄·H₂O（7）,C₂₀H₂₂NO₄·C₃H₃O₄（8）,C₂₀H₂₂NO₄·C₄H₃O₄（9）and C₂₀H₂₂NO₄·C₄H₄O₄·0.5C₄H₂O₄（10）).Hirshfeld surface qualitatively and quantitatively analyzed the intermolecular interaction forces（hydrogen bonds andπ···π/C-H···π）to explore the formation and recognition mechanisms of these pharmaceutical cocrystals.The dissolution rate and solubility of 4¹0 were significantly improved compared to parent compound THB.Notably,the cocrystals 5¹0 not only improved the dissolution rate and solubility but also does not leaded to hygroscopicity.The cocrystals1¹0 exhibit superior in vitro antibacterial activities on S.aureus and E.coli compared with their parent compounds.Additionally,the cocrystals 1⁶ showed better anti-tumor activities against human hepatoma HepG2 cells than parent compounds.Conclusions Pharmaceutical cocrystal of tetrahydroberberine were been synthesized by solvothermal method and solvent evaporation method.Structural analysis indicates that hydrogen bond acceptors and hydrogen protons provided by cocrystal formers will facilitate molecular recognition to form tetrahydroberberine pharmaceutical cocrystal.The cocrystal technology can effectively improve the water solubility of tetrahydroberberine without causing the problem of moisture stability,thereby improving the antibacterial and antitumor activity of tetrahydroberberine.