m-Hydroxybenzoic acid: quantifying thermodynamic stability and influence of solvent on the nucleation of a polymorphic system

Nucleation of m-hydroxybenzoic acid crystals in different pure solvents has been investigated, and the thermodynamic interrelationship between two polymorphs was analyzed. The melting properties and specific heat capacities of both polymorphs have been determined by differential scanning calorimetry, and the solubility in several solvents at different temperatures was measured gravimetrically. Absolute values of the Gibbs free energy, enthalpy and entropy of fusion, and the activity of the polymorphs have been determined as functions of temperature. It is established that the polymorphs are monotropically related, with differences in enthalpy and Gibbs free energy of approximately 1 kJ/mol at room temperature. In a total of 539 nucleation experiments, in six solvents and with different cooling rates, the visible onset of nucleation was recorded and the nucleating polymorph was isolated. It is found that the degree of supersaturation required for nucleation and the polymorphic outcome depend strongly on the solvent. The metastable polymorph is kinetically favored under all evaluated experimental conditions, and for most of the conditions it is also statistically the most probable outcome. Nucleation of the stable polymorph is increasingly promoted in solvents of increasing solubility. It is shown how this can be rationalized by analysis of solubility and rate of supersaturation generation.