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Use of in situ Raman, FBRM, and ATR-FTIR probes for the understanding of the solvent-mediated polymorphic transformation of II-I etiracetam in methanol

par Herman, Christelle ;Haut, Benoît ;Douieb, Selim ;Larcy, Aurélie ;Vermylen, Valérie;Leyssens, Tom
Référence Organic process research & development, 16, 1, page (49-56)
Publication Publié, 2012-01

Article révisé par les pairs

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Résumé :

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. © 2011 American Chemical Society.