Synthesis And Properties Of Pharmaceutical Cocrystals Of Tetrahydropalmatine

Objective Pharmaceutical cocrystals of tetrahydropalmatine（THP）have been designed and synthesized based on pharmaceutical cocrystal technology to improve the physicochemical properties of THP,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 tetrahydropalmatine cocrystals.Methods Three representative Pharmaceutical cocrystals of THP have been synthesized through solvent evaporation method,then characterized and analyzed by single-crystal X-ray diffraction,NMR,XRPD,IR,TGA and Crystalexplorer software.The solubilities of THP 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 THP pharmaceutical cocrystals were determined by the disk diffusion method.Results Three types unreported THP pharmaceutical cocrystals were synthesized by solvent evaporation method:pharmaceutical cocrystals of tetrahydroberberine with dicarboxylic acids C₂₁H₂₅O₄N·C₄H₄O₄（THP-MAL）and C₂₁H₂₅O₄N·C₄H₄O₄（THP-FUM）,with simple sulfonic acid 2C₂₁H₂₆O₄N·2CH₃O₃S·H₂O（THP-MAS）,C₂₁H₂₅O₄N·H₃NO₃S（THP-SA）and C₂₁H₂₅O₄N·C₁₀H₁₈O₄S（THP-CSA）,andwithbenzenesulfonicacid2C₂₁H₂₆O₄N·2C₇H₅O₆S·C₇H₈O₂（THP-SSA）and C₂₁H₂₅O₄N·C₆H₇NO₃S（THP-ABA）.The cocrystal structure was analyzed qualitatively and quantitatively by CrystalExplorer software.The structure analysis showed that the CCF could provide hydrogen bond acceptor and give hydrogen protons.This will help molecular recognition to form cocrystal of THP.The dissolution rate and solubility of these pharmaceutical cocrystals were significantly improved compared to parent compound THP.Notably,the cocrystal THP-SSA not only improved the dissolution rate and solubility but also does not leaded to hygroscopicity.THP-MAL,THP-FUM,THP-CSA and THP-ABA showed better antibacterial effect in vitro than one or more against S.albus,S.aureus and E.coli,compared with THP.Conclusions Pharmaceutical cocrystals of THP were been synthesized by solvent evaporation method,which can effectively solve the problem of low water solubility.In the design and synthesis of the cocrystal of tetrahydropalmatine,it is necessary to consider the isoquinoline structure in the THP molecule,which leads to the weak alkalinity of THP due to the existence of isoquinoline structure.Secondly,the CCF with strong acidity should be choosen,the charge-assisted hydrogen bond with THP is formed to promote the formation of cocrystal of THP.