Pharmaceutical Salts of Carvedilol with Increased Solubility as an Approach for Enhancing the Drug Action

Abstract

Carvedilol (CVD) is a β-blocker antihypertensive drug commonly used to treat cardiovascular disorders. Since the poor oral bioavailability of CVD can be improved directly by the enhancement of the active pharmaceutical ingredient solubility, we have focused on the development of more soluble multicomponent crystals (MCCs), i.e., by employing anhydrous and hydrated salts, of CVD. Using solvent evaporation and anion exchange as crystallization methods, eight MCCs containing CVD and salt formers recognized as safe and often used in pharmaceutical routines were successfully prepared. An in-depth crystallographic description of these MCCs was conducted through X-ray diffraction (single-crystal X-ray diffraction, PXRD) and thermal (differential scanning calorimetry, thermogravimetric analyses) techniques. Structurally, the inclusion of polar counterions and water molecules in the crystal structures generates ionic 3D arrangements with the sets of CVD+/anion/(n)H2O or CVD+/anion H-bonded to each other in meticulous assemblies. From the equilibrium solubility study in conditions that resemble physiological ones, it was verified that all CVD salts had substantial enhancements in API solubility (up to 25-fold) compared to pure CVD. These outcomes reinforce the potential of the MCCs synthesized herein to optimize the low oral bioavailability of CVD.