Preparation and characterization of novel mirabegron salts for sustaining dissolution and improving diffusion/permeability

Abstract

Overactive bladder (OAB) is a disturbing and distressing condition associated with severe adverse consequences, such as depression, social isolation and participation restriction. Mirabegron (Mira.), used for the treatment of OAB is a BCS class-III drug that displays inconsistent bioavailability upon oral administration depending on dose, gender, and food intake. The present investigation aimed to synthesize sustained release/slow dissolving salts of Mira. to overcome its food intake dependent erratic bioavailability and to improve its permeability. The solvent evaporation method was used to prepare novel slow dissolving salts of Mira. by reacting it with various long-chain fatty acids (stearic acid, palmitic acid, myristic acid, and lauric acid). The differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies suggested the genesis of a new crystalline phase due to a reaction between Mira. and fatty acids. Fourier-transform infrared spectroscopy (FTIR) and 1H Nuclear magnetic resonance (NMR) studies confirmed the transfer of proton between the primary amine group (-NH2) of Mira. and carboxylic acid group (-COOH) of fatty acids and thus the formation of salts. The prepared salts have significantly slower dissolution than Mira. in 6.8 pH phosphate buffer. The equilibrium solubility of prepared salts were lower than Mira in 6.8 pH phosphate buffer and water. The in-vitro diffusion study using the Franz diffusion cell proved better permeability of the prepared salts compared to Mira.