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

Abstract

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.

Conformational Preference and Spectroscopical Characteristics of the Active Pharmaceutical Ingredient Levetiracetam

“…Neither the hydrated form of etiracetam shows any IMHB in solid state; for this solid state structure, the carboxamide group forms intermolecular hydrogen bonds with its neighbors and carbonyl group with the water molecules. 4 It is important to note that the structures of the most stable conformer (5) in water and ethanol are almost identical to the X-ray geometry of solid state LEV, both in its conformation and geometrical parameters (see Supplementary Figs. SI.3a and SI.3b). 25 The RMSD between the (5) in water and X-ray structure is 0.1742 Å, and the largest difference between them is observed in the conformation of the oxopyrrolidin ring.…”

“…55 As starting geometries, we used the solid-state structures reported for LEV 25 as well as the LEV's geometries found in the anhydrous polymorphic forms and hydrate phase of etiracetam. 4 The identified stable conformers have been further optimized in vacuum, water, and ethanol, based on density functional theory (DFT) quantum chemical calculations. The solvent effects have been considered by using the implicit Polarizable Continuum Model.…”

“…Therefore, it would be of high interest to compare the solid and liquid structures of LEV. Thus, our first aim for this study was to describe the differences between the known solid-state geometries of LEV 4,25 and its liquid (and gas) phase structures. The conformational landscape of LEV was initially obtained based on MM calculations in gas phase using the Tinker software, with the MMFF94 molecular mechanics force field.…”

“…9,11,23,24 For a better understanding of the pharmacodynamics of LEV, the characterization of its structure in solid and liquid state is crucial. Recently reported X-ray data show that etiracetam, the racemic mixture of R-and S-enantiomers, crystallizes in 3 different solid phases, that is, 2 polymorphs with monoclinic P2 1 /c symmetry and 1 hydrate phase of orthorhombic P1 symmetry, 4 whereas LEV crystallizes in a crystallographic form with monoclinic P2 1 symmetry. 25 It is important to emphasize that in both solid and liquid states, the spectroscopic response of drugs can be significantly affected by hydrogen bonding interactions.…”

“…Various methods of experimental and computational spectroscopy are synergistically applied nowadays for structure determination of active pharmaceutical ingredients, as well as for revealing subtle transformations between their solid and liquid phases. [1][2][3][4][5][6] In this study, we were interested in the molecular structure and properties of levetiracetam (LEV) ((S)-2-(2-oxopyrrolidin-1-yl) butanamide) (see Fig. 1), the biologically active S-enantiomer of etiracetam.…”