Carvedilol Pharmaceutical Cocrystals: Preparation, Advanced Characterization and Dissolution Behavior

The work aims to improve the solubility and dissolution rate of the cardiovascular drug carvedilol (CVD) of II class BCS by a co-crystallization approach. The slurry method was used to preparation of CVD cocrystals. The existence of new solid phases was confirmed by PXRD, DSC, TGA, FTIR and UV-vis spectroscopy. The dissolution kinetics of two component systems in a model buffer solution was studied by the classical shake flask method. The process of CVD release from co-crystals tablets were studied in accordance with Pharmacopoeia standard using a dissolution tester. Pharmaceutical cocrystals of CVD with two coformers, 2-hydroxybenzamide (2OHBZA) and 4-hydroxybenzamide (4OHBZA) in molar ratio 1:1, have been obtained for the first time. Thermodynamic characteristics of the cocrystallization reaction of the active pharmaceutical ingredient with the selected coformers have been experimentally determined for the synthesized CVD/2OHBZA and CVD/4OHBZA cocrystals. It has been shown that the process of cocrystal formation is enthalpy-determined, which is typical for most two-component crystals. Kinetic solubility profiles of new solid phases have been determined in a buffer solution pH 7.4, simulating the pH of blood plasma. It was found that the equilibrium solubility of co-crystal forms of carvedilol significantly exceeds the solubility of original drug. In vitro study of the release of CVD from co-crystal tablets showed a improving of the drug release rate into solution to 67% for CVD/2OHBZA and 43% for CVD/4OHBZA, that by 2.6 and 1.7 times higher then the raw drug. Considering the significant enhancement of carvedilol solubility in two-component systems and their stability in aqueous medium, co-crystallization is a promising approach for the development of new dosage forms of this drug with improved bioavailability.