Measuring Free-Energy Difference between Crystal Polymorphs through Eutectic Melting

Abstract

We describe a method to measure the free-energy difference, ΔG, between crystal polymorphs from their calorimetric data of eutectic melting with a common additive. The use of different additives yields ΔG as a function of temperature. The method is suitable for crystals that chemically decompose or physically transform before melting. It applies to not only true polymorphs but also pairs of racemate and conglomerate of resolvable enantiomers. We illustrate the method with the polymorphs of glycine, d-mannitol, and tazofelone and report a new value (123 °C) for the enantiotropic transition temperature of α and γ glycine. We show how different additives (including a liquid additive, water) can be used for different compounds. The ΔG data thus obtained are important for structure-stability studies and controlling crystallization in polymorphic systems.