Christelle Herman

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(®). 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 °C. Our findings confirm that both polymorphs are racemic compounds, which is also confirmed by XRPD analysis.

A new approach for the estimation of the melting enthalpy of metastable crystalline compounds using differential scanning calorimetry: Application to the two crystallographic forms of Etiracetam

This article focuses on the development of an innovative method, based on thermodynamic considerations and with the use of Differential Scanning Calorimetry (DSC), for the estimation of the melting enthalpy of crystalline compounds which are metastable near their melting temperature. The curves obtained, at various heating rates, are analysed in two steps. In the first step, the area of a zone generated by the melting endothermic peak is calculated following a specific method. In the second step, the melting enthalpy is extracted from this area through an enthalpy balance. This method is applied to both identified crystallographic forms, named form I and form II, respectively, of Etiracetam (UCB Pharma). The results show that the melting enthalpy of the stable form II compare well with the ones obtained using conventional methods. The curves of the metastable form I present thermal instabilities (partial solid–solid polymorphic transition and beta-recrystallization) near the form I melting peak leading to difficulties for a direct determination of the melting enthalpy by conventional methods. The proposed method is therefore very useful for the estimation of the form I melting enthalpy.

The importance of screening solid-state phases of a racemic modification of a chiral drug: thermodynamic and structural characterization of solid-state phases of etiracetam

In this contribution different solid-state forms of the racemic compound (RS)-2-(2-oxo-pyrrolidin-1yl)-butyramide are studied from a structural and thermal point of view. Three different solid-state phases were identified, including two polymorphs and one hydrate phase. Comparison is made with the structure of the (S)-enantiomer, for which only one solid-state phase is known. The basic structural motif found in both polymorphs of the racemic compound is similar, but the basic motif observed for the hydrate differs. These synthons could in principle be used in future polymorph prediction studies to screen for possible alternative forms of the enantiopure compound. Based on the structure of the hydrate, further efforts should therefore be made in order to identify a hydrate structure of the enantiopure compound. Studying the different phases of a racemic compound can therefore help to guide polymorphic screening of an enantiopure compound.

Computational and experimental methods for the on-line measurement of the apparent viscosity of a crystal suspension

This paper proposes an experimental method, based on the Metzner and Otto concept, for the on-line measurement of the apparent viscosity of a crystal slurry during a crystallization process. The first step of this procedure consists of the determination of the N p-Re-Fr relation for Newtonian liquids, for two impeller-tank configurations, chosen such that this relation is a bijective one. This is achieved both experimentally and numerically, using Computational Fluid Dynamics. In the second step of the procedure, the same impeller-tank configurations are used for the determination of the evolution of the apparent viscosity of the crystal slurry (non-Newtonian liquid) during a reference pharmaceutical crystallization process (Etiracetam - UCB). The paper concludes on the influence of the Particle Size Distribution of the crystals on the apparent viscosity of the suspension. For a given crystal mass fraction, the bigger the crystals are - and then the less abundant they are - and the smaller the span is, the smaller the apparent viscosity of the suspension is.