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.

The objective of the present paper is to show the utility of combining distinct online and in situ probes, tracking both the solid and the liquid phases, to come to a full understanding of the mechanism underlying polymorphic transformations. The study focuses on the batch crystallization process of etiracetam (racemic intermediate to the synthesis of levetiracetam [Keppra, UCB Pharma], presenting two enantiotropically related crystallographic forms) in methanol, as this process relies on a polymorphic transformation in solution prior to the isolation of the final compound. The polymorphic transformation is shown to follow a solvent-mediated polymorphic transformation mechanism, which is characterized by three successive phases. Identification and understanding of each of these phases requires the knowledge on the nature of the crystallographic form (Raman probe), the variations in particle size distributions (FBRM probe) as well as the solute concentration in solution (ATR-FTIR probe), showing the necessity of combining these different online analyzers.

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