Tetrahydroberberine pharmaceutical salts/cocrystals with dicarboxylic acids: Charge-assisted hydrogen bond recognitions and solubility regulation

Abstract With our consistent aim to further expand the solid-state landscape via molecular recognition and regulate solubility of tetrahydroberberine (THB), charge-assisted hydrogen bond (CAHB) recognitions and solubility regulation of pharmaceutical salts/cocrystals of THB are comprehensively investigated through exploring four pharmaceutical salts/cocrystals of THB. Four pharmaceutical salts/cocrystals of THB with oxalic acid, malonic acid, maleic acid and fumaric acid were obtained with solution evaporation approach. Comprehensive crystal structures and Hirshfeld surface analyses reveal CAHB recognitions between THBs and coformers are dominant intermolecular interactions to stabilize crystal packing. As expected, solubilities of four pharmaceutical salts/cocrystals of THB have been improved by dicarboxylic acids. Importantly, the dicarboxylic acid with higher solubility can modulate solubility of THB to become higher. The enthalpy of hydration for four pharmaceutical salts/cocrystals is greater than that for neutral pure THB when CAHBs (with electrostatic interactions) exist, which effectively improve solubility of THB. Solvent molecules can disrupt interactions of pharmaceutical salts/cocrystals by solvent···solute interactions when dicarboxylic acids are highly soluble thereby leading to enhancement of dissolution. Research results inspirationally enlightens that the solubility of insoluble APIs could be effectively regulated by utilizing gradient solubility coformers with simultaneously forming CAHBs between active pharmaceutical ingredients and coformers.