Thermal Analysis of Crystal Polymorphs: Free-Energy Difference between Polymorphs from Melting and Eutectic Melting Data

摘要

The relative stability of crystal polymorphs is an essential data for selecting correct solid forms for commercial development, for optimizing crystallization processes, and for elucidating structurestability relations in pharmaceutical solids. At constant pressure, the relative stability of two polymorphs is given by their free-energy difference, ΔG. We have used the DSC data of crystal melting to determine ΔG and its temperature slope and hence to predict the stability relations between polymorphs. In particular, this analysis yielded whether two polymorphs are related monotropically (one being more stable than the other at any temperature) or enantiotropically (one stable at low temperature and the other more stable at high temperature) and the enantiotropic transition temperature. We found good agreement between the predictions from melting data and from other data, such as solubility measured near the ambient temperature (Figure 1). We extended this technique to lower temperature by including the DSC data of eutectic melting of polymorphs with a common additive. By varying the additive, we determined ΔG as a function of temperature (Figure 2) and in turn, the enthalpy and entropy differences between polymorphs (ΔH and ΔS). These techniques are applicable to both single- and multi-component polymorphic systems. A two-component polymorphism important to chiral resolution is that of a racemic compound and a racemic conglomerate. We illustrate how the thermodynamic analysis of polymorphs can be combined with molecular studies to advance the understanding and engineering of pharmaceutical solids. References: J. Pharm. Sci. 1995, 84, 966; J. Am. Chem. Soc. 2000, 122, 585.