Towards an accurate and precise determination of the solid–solid transition temperature of enantiotropic systems

This paper presents two distinct methods for the determination of the solid–solid transition temperature (Ttr) separating the temperature ranges of stability of two crystallographic forms, hereafter called morphs, of a same substance. The first method, based on thermodynamic calculations, consists in determining Ttr as the temperature at which the Gibbs free energies of the two morphs are equal to each other. For this purpose, some thermodynamic characteristics of both morphs are required, such as the specific heat capacities, the melting temperatures and the melting enthalpies. These are obtained using the Differential Scanning Calorimetry (DSC). In the second method, Ttr is determined directly by an experimental study of the temperature ranges of stability of each morph. The three main originalities of the method developed are (i) to prepare samples composed by an isomassic mixture of crystals of both morphs, (ii) to set them in a thermostated and agitated suspension, and (iii) to use an in situ Raman spectroscopic probe for the determination of the crystallographic form of the crystals in suspension at equilibrium. Both methods are applied to determine the solid–solid transition temperature of the enantiotropic system of Etiracetam, and both of its two crystallographic forms so far identified, named morph I and morph II. The first method is shown to be very sensitive to the experimental data obtained by DSC while the second experimental method is a more accurate, precise, time- and effort-friendly method for the determination of Ttr. The solid–solid transition temperature of the Etiracetam system, determined with the second method, using three different solvents, is found to be equal to 303.65 K ± 0.5 K.

Research highlights
► We test two methods to obtain the solid–solid transition temperature of Etiracetam system, showing two enantiotropically related polymorphs.
► The first method, based on a thermodynamic development, is sensitive to the correctness of the data required.
► The second method is an experimental study of the stability thermal range of each morph.
► We identify the nature of crystals in suspension at equilibrium through Raman analysis.
► The solid-solid transition temperature is found equal to 303.65 K ± 0.5 K.