Deracemization in a Complex Quaternary System with a Second‐Order Asymmetric Transformation by Using Phase Diagram Studies

Inspired by deracemization via temperature cycles, which enables the collection of crystals of the desired enantiomer from an initially racemic mixture, we focus in this work on an alternative batch process, namely crystallization-induced deracemization. This process starts with a suspension of enantiomerically pure crystals, which undergoes a simple cooling crystallization, coupled with liquid-phase racemization. The experimental and model-based analysis of such a process, carried out here, revealed that: (i) deracemization via temperature cycles is a safe choice to operate with high enantiomeric purity, although its throughput is limited by the suspension density; (ii) if the distomer is less prone to nucleation, crystallization-induced deracemization is a simple process; however, its performance is strongly limited by the solubility; (iii) the purity achieved with crystallization-induced deracemization can be increased by utilizing large seed mass and by optimizing the cooling profile or catalyst concentration. Alternatively, the purity increases via partial dissolution of the seeds, which resembles the heating part of the deracemization process via temperature cycles.

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Crystallization-Induced Deracemization: Experiments and Modeling

Bodák

Breveglieri

Mazzotti

2022

Crystal Growth & Design

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Multicomponent Chiral Quantification with Ultraviolet Circular Dichroism Spectroscopy: Ternary and Quaternary Phase Diagrams of Levetiracetam

et al. 2022

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Chiral molecules are challenging for the pharmaceutical industry because although physical properties of the enantiomers are the same in achiral systems, they exhibit different effects in chiral systems, such as the human body. The separation of enantiomers is desired but complex, as enantiomers crystallize most often as racemic compounds. A technique to enable the chiral separation of racemic compounds is to create an asymmetry in the thermodynamic system by generating chiral cocrystal(s) using a chiral coformer and using the solubility differences to enable separation through crystallization from solution. However, such quaternary systems are complex and require analytical methods to quantify different chiral molecules in solution. Here, we develop a new chiral quantification method using ultraviolet-circular dichroism spectroscopy and multivariate partial least squares calibration models, to build multicomponent chiral phase diagrams. Working on the quaternary system of (R)- and (S)-2-(2-oxopyrrolidin-1-yl)butanamide enantiomers with (S)-mandelic acid in acetonitrile, we measure accurately the full quaternary phase diagram for the first time. By understanding the phase stabilities of the racemic compound and the enantiospecific cocrystal, the chiral resolution of levetiracetam could be designed due to a large asymmetry in overall solubility between both sides of the racemic composition. This new method offers improvements for chiral molecule quantification in complex multicomponent chiral systems and can be applied to other chiral spectroscopy techniques.

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Deracemization in a Complex Quaternary System with a Second‐Order Asymmetric Transformation by Using Phase Diagram Studies

Cited by 2 publications

References 33 publications

Crystallization-Induced Deracemization: Experiments and Modeling

Crystallization-Induced Deracemization: Experiments and Modeling

Multicomponent Chiral Quantification with Ultraviolet Circular Dichroism Spectroscopy: Ternary and Quaternary Phase Diagrams of Levetiracetam

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