文摘
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. The experimental approach focuses on the use of solution calorimetry to measure the enthalpy difference between the amorphous and crystalline phases or between the polymorphs. A system composed of five polymorphs has been used to verify the methodology and its extension. The heat of fusion for the five polymorphs determined from the new methods are in good agreement with those from HyperDSC. A phase diagram using the heat of fusion determined from this study can be generated to rank the relative stability among the five polymorphs as a function of temperature.