Solubility and thermodynamic analysis of famotidine polymorphs in pure solvents

The present study investigates the solubility of famotidine polymorphs forms A and B between 298.15 K and 348.15 K in a range of pure solvents: water, methanol, ethanol, isopropanol and acetonitrile. Empirical and semi-empirical models have been fitted to solubility data determined experimentally by a gravimetric method. The solid phases have been characterized by FTIR and Raman spectroscopy, SEM and PXRD. In addition, heat capacities and melting data determined by DSC have been used to estimate the fusion thermodynamics and the activity of the solid phases as a function of temperature. The relationship between the famotidine polymorphs is monotropic, with form A being the stable polymorph. For both polymorphs, in terms of mass ratio, the solubility in the studied solvents decreases in the order methanol > water > ethanol > acetonitrile > isopropanol. The activity coefficient at saturation in all the solutions exceeds unity, showing a positive deviation with respect to ideality, which translates into solubilities significantly lower than the ideal values. Among the alcohols, a consistent correlation is observed between the polarity and the order of solubility.The Hildebrand solubility parameter is also well correlated with the order of solubilities in the studied solvents, with a higher solubility in more polar solvents, revealing the importance of the hydrogen bonding of the sulfamoyl group oxygens.