Azilsartan piperazine salt solvate and monohydrate: preparation, crystal structure, enhanced solubility and oral bioavailablity

Two azilsartan-piperazine salt solvates with methanol (Az-Pz·MeOH) and ethanol (Az-Pz·EtOH) and a hydrate (Az-Pz·H2O) have been prepared and exhaustively characterized by physicochemical methods. The crystal structures suggest that one azilsartan transfers one proton from carboxylic group to piperazine to form 2-D corrugation-like structures in Az-Pz·MeOH and Az-Pz·EtOH, and transfers two protons from carboxylic and oxadiazolyl groups to piperazine to form 1-D chain structure in Az-Pz·H2O. The salt solvates and hydrate are very stable after 24 h slurry experiments in distilled water at 37 oC, and improve the azilsartan solubility approximately a 322-fold increase for Az-Pz·H2O and a 140-fold increase for Az-Pz·MeOH and Az-Pz·EtOH over that of the free Az form. The pharmacokinetic experiments show that Az-Pz·EtOH and Az-Pz·H2O improves plasma azilsartan concentration Cmax and AUC (P 0.05). The research demonstrates that the pharmaceutical salt is a promising approach in increasing solubility and enhancing oral bioavailability of low-solubility azilsartan.