Solubility of Two Polymorphs of Tolbutamide in n-Propanol: Comparison of Methods

The solid-liquid solubility of two polymorphs of the title compound has been measured in n-propanol over the temperature range (278 K-303 K) by an isothermal, gravimetric method and a low heating rate polythermal method. Due to marked differences in the settling behavior of crystals of the two polymorphs in the investigated solvent, it is found that the low heating rate polythermal method gives the overall best performance for this particular system. Systematic slurry conversion experiments show that FII is the stable polymorph over the investigated temperature range (268 K-308 K). Solubility data for both polymorphs is well correlated, and has been extrapolated to the melting point, by a previously proposed semi-empirical regression model based on solid-phase calorimetric data. The system exhibits a marked positive deviation from Raoult's law, with solute activity coefficients at equilibrium decreasing with increasing temperature.