Solid-liquid phase diagrams for the determination of the solid state nature of both polymorphs of (RS)-2-(2-oxo-pyrrolidin-1-yl)-butyramide

This work focuses on the determination of the solid state nature of (RS)-2-(2-oxo-pyrrolidin-1-yl)butyramide (Etiracetam), the racemic intermediate of (S)-2-(2-oxo-pyrrolidin-1-yl)-butyramide, an Active Pharmaceutical Ingredient, marketed under the name Levetiracetam (R). It is show how this information can easily be extracted from solid-liquid phase diagrams of the racemic system. As two polymorphs of Etiracetam are known (Forms I and II), the analyses have been performed considering both polymorphs. The solid-liquid phase diagrams are determined experimentally, using Differential Scanning Calorimetry, and theoretically, using the Prigogine-Defay and Schroeder-Van Laar equations. Only the phase diagram involving the polymorph stable at higher temperatures (Form II) can be constructed experimentally. The theoretical phase diagram involving this polymorph compares well with the experimental one, thus allowing the use of theoretical equations for the prediction of the solid-liquid phase diagram involving Form I, which is meta-stable above 30.5 degrees C. Our findings confirm that both polymorphs are racemic compounds, which is also confirmed by XRPD analysis. (C) 2012 Elsevier B.V. All rights reserved.