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

Abstract

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.

Solution‐mediated polymorphic transformation of amorphous form to Form I of olmesartan medoxomil in methanol‐water mixture solvents

“…SMPTs are composed of three stages: dissolution of the metastable polymorph, nucleation of the stable form, and growth of the stable form. Each stage could be the rate determining step, therefore it is necessary to monitor the solution concentration as well as the solid‐state composition during the transformation for understanding which stage dominate the kinetics of the process.…”

Raman, UV, NIR, and Mid‐IR Spectroscopy with Focused Beam Reflectance Measurement in Monitoring Polymorphic Transformations

“…Mid-IR Discrimination between polymorphic forms of solids [11,12] ATR-UV/Vis Solvent-mediated polymorphic transformation monitoring in batch crystallization (changes in solute concentration) [13][14][15][16] NIR Determination of the polymorphic ratio of solid mixtures [17][18][19] NIR Solvent-mediated polymorphic transformation monitoring [18,20] Raman Determination of the polymorphic ratio of solid mixtures [21][22][23][24][25] FT-Raman, FTIR Comparison between the two techniques in determining the polymorphic ratio of solid mixtures [26,27] Raman Cocrystallization of carbamazepine and nicotinamide monitoring [28] Raman Solvent-mediated polymorphic transformation monitoring [29,30] Raman, FBRM, PVM Study on the impact of operating parameters on polymorphic transformation of D-mannitol [31] Raman Measurement of the total solid concentration in a polymorphic system [32,33] Raman Measurement of solute concentration in a polymorphic system [34,35] FBRM Solvent-mediated polymorphic transformation monitoring [36][37][38][39][40] Raman, NIR, UV/Vis Solvent-mediated polymorphic transformation monitoring [41,42] Raman Feedback strategies to control polymorphs of carvedilol [43,44] Raman, NIR Application of quantitative Raman spectroscopy using a good calibration practice (GCP) procedure [45] a) b) Crystallization Process Informatics System (Cry-PRINS) software. CryPRINS provides a communication interface via file transfer, OPC (Object linking and embedding ...…”

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

“…Single FII crystals (stable above 303.5 K) can be obtained leaving single crystals of FI in suspension in MeOH at 313 K for 48 h. A solvent-mediated polymorphic transformation occurs, with dissolution of FI, combined with nucleation and crystal growth of FII crystals. The solvent mediated transition is described elsewhere for the etiracetam compound Herman, Haut, Douieb et al, 2012;Herman, Leyssens, Debaste & Haut, 2012;.…”

“…The racemic modification of 2-(2-oxo-pyrrolidin-1-yl)butyramide, also called etiracetam, presents itself as a racemic compound Herman, Haut, Douieb et al, 2012;Herman, Leyssens, Debaste & Haut, 2012;, 1 and can be encountered as a racemic intermediate during the synthesis of leviteracetam. Up to now, two distinct polymorphic forms of etiracetam, called form I (FI) and form II (FII), were identified and intensively studied elsewhere Herman, Haut, Douieb et al, 2012;Herman, Haut, Aerts & Leyssens, 2012;Herman, Leyssens, Debaste & Haut, 2012;. However, no structural characterization of these polymorphs was given.…”