Combining Solid-State and Solution Calorimetry for the Gibbs Free Energy Calculation of Polymorphs To Determine the Relative Stability and Solubility

Abstract

A novel pure component approach using HyperDSC for the relative stability determination was reported in 2012 (Hsieh et al. Cryst. Growth Des. 2012, 12, 5481). The accuracy of this approach depends upon the accurate physical properties of the amorphous and crystalline phases, including heat capacity and heat of fusion. However, it has been encountered that the heat of fusion for some pharmaceutical compounds cannot be accurately determined due to thermal decomposition or recrystallization upon melting even at very high heating rate. Hence, we report here two new methods for accurate heat of fusion determination using a combination of solid-state and solution calorimetry, determining the heat of solution at temperatures much lower than the melting point, thus avoiding decomposition or recrystallization. The theoretical derivation and experimental procedure for these two methods are reported in this study. The theoretical derivation of thermodynamic equations relates the solid-state and solution approaches. ...