Alhadid, A., Kefalianakis, L., Wendler, A., Nasrallah, S., Jandl, C., Kronawitter, S.M., Kieslich, G. and Minceva, M., 2024. Thermodynamic Approach for Estimating the Melting Enthalpy of Cocrystals. Crystal Growth & Design. https://doi.org/10.1021/acs.cgd.4c00393

Abstract

The synthesis of cocrystals is an established and efficient method for tuning the solubility of pharmaceutical andindustrially relevant compounds. Predicting the cocrystal solubility prerequisites knowledge about the melting properties and thestoichiometry of the cocrystal along with the activity coefficients of individual constituents in the liquid solution. Reliablethermodynamic models can estimate the activity coefficients of components in the liquid phase; on the other hand, predicting thecocrystal melting properties and stoichiometry remains a key challenge. In this work, we propose an approach for estimating themelting enthalpy of cocrystals, where the melting enthalpy of the cocrystal is calculated using the melting properties of its pureconstituents, the cocrystal stoichiometry and melting temperature, and the enthalpy of mixing the constituents in the liquid solution.For selected model systems, we show that by using our approach, the calculated melting enthalpy allowed for predicting the cocrystalliquidus line equally well and, in some cases, better than when using the experimental melting enthalpy values. Furthermore, weapply our approach to accurately predict the complete phase diagram of binary eutectic systems with cocrystal formation, in whichthe properties of the cocrystals have not been reported before. The advantage of our approach is the ability to model the solid−liquid phase diagram of eutectic systems with cocrystal formation without requiring extensive investigations of the cocrystalstoichiometry and melting properties. Therefore, the approach has the capacity to fill gaps of experimental uncertainties indetermining the cocrystal melting enthalpy when isolating the cocrystal is challenging. By streamlining the prediction of cocrystalmelting enthalpy, our proposed approach could accelerate the identification and design of pharmaceutically active cocrystals, offeringa potent tool for expediting drug development processes.

Read the paper here.