Calorimetric Determination of Cocrystal Thermodynamic Stability: Sulfamethazine-Salicylic Acid Case Study

This work demonstrates how the thermodynamics of cocrystal formation from the pure, solid coformers can be directly determined from experimentally obtained calorimetric data, without involving solubility data or approximations of ideal solution. For the 1:1 cocrystal between the drug API sulfamethazine and salicylic acid, the melting temperatures and associated enthalpies of fusion have been determined for the coformers in their respective pure solid state and as an equimolar physical mixture and for the cocrystal, using differential scanning calorimetry. Heat capacities have been determined for the respective solid forms and their supercooled melts. The Gibbs energy for cocrystal formation and the enthalpic and entropic components have been determined as functions of temperature through a thermodynamic cycle. The Gibbs energy, enthalpy, and entropy of mixing have been estimated from the thermodynamic functions for cocrystal formation and fusion of the solid phases. The results show that the Gibbs energy for cocrystal formation is negative, i.e. the cocrystal is the stable solid phase in relation to a 1:1 mixture of the coformers throughout the temperature interval from room temperature to the cocrystal melting point, and becomes increasingly negative with increasing temperature. Cocrystal formation is an endothermic process, driven by the favorable entropy increase, and is accompanied by a 6% increase in molecular volume. At room temperature, liquid mixing of coformers is found to be weakly exothermic. The results qualitatively align with a previously reported analysis based on solubility data.