Linear Deracemization Kinetics during Viedma Ripening: Autocatalysis Overruled by Chiral Additives

Steendam, René R. E.; Dickhout, Janneke; Enckevort, W.J.P. van; Meekes, Hugo; Raap, J.; Rutjes, Floris P. J. T.; Vlieg, Elias

doi:10.1021/acs.cgd.5b00127

Cited by 36 publications

(49 citation statements)

References 28 publications

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“…!,! ) > 0, growth occurs, while the case of Similarly to previous models 18,39,51,52 , due to the Gibbs-Thomson effect, the cluster solubility ! "…”

Section: Growth and Dissolutionmentioning

confidence: 76%

“…amino acids [4][5][6][7] and pharmaceuticals [8][9][10] that crystallize as conglomerate crystals by incorporating a fast racemization reaction. The outcome of the deracemization process depends on the initial conditions 11,12 : mass or crystal size distribution (CSD) imbalance between the enantiomers 1,[13][14][15] , presence of chiral impurities 16 or additives [17][18][19] or circularly polarized light 20 . In addition, the total time to enantiopurity varies drastically for different compounds, sometimes leading to very long processing times.…”

Section: Introductionmentioning

confidence: 99%

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Coupling Viedma Ripening with Racemic Crystal Transformations: Mechanism of Deracemization

Xiouras

Horst

Gerven

et al. 2017

Crystal Growth & Design

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It has been recently observed that coupling Viedma ripening with a seeded in-situ metastable racemic crystal to conglomerate transformation leads to accelerated and complete deracemization: crystal transformation-enhanced deracemization. By means of a simple kinetic model, we show that the mechanistic pathway of this new process depends profoundly on the interplay between the crystal transformation and racemization processes, which in turn influence the nucleation process of the counter enantiomer. If the nucleation of the counter enantiomer is suppressed (e.g. by sufficiently fast racemization, low amount of racemic compound or gradual feed, low relative solubility between racemic compound and conglomerate), deracemization proceeds via a second order asymmetric transformation (SOAT) and is limited primarily by the dissolution rate of the racemic crystals and the growth rate of the preferred enantiomer crystals. Breakage and agglomeration accelerate the process, but contrary to conventional Viedma ripening, they are not essential ingredients to explain the observed enantiomeric enrichment. If the nucleation process of the counter enantiomer is not sufficiently suppressed, deracemization is initially controlled by the dissolution rate of the racemic crystals, but Viedma ripening is subsequently required to convert the conglomerate crystals of the counter enantiomer formed by nucleation, resulting in slower deracemization kinetics. In both cases, the combined process leads to faster deracemization kinetics compared to conventional Viedma ripening, while it autocorrects for the main disadvantage of SOAT, i.e. the accidental nucleation of the counter enantiomer. In addition, crystal transformation-enhanced deracemization extends the range of applicability of solid-state deracemization processes to compounds that form metastable racemic crystals. interplay between the crystal transformation and racemization processes, which in turn influence the nucleation process of the counter enantiomer. If the nucleation of the counter enantiomer is 3 suppressed (e.g. by sufficiently fast racemization, low amount of racemic compound or gradual feed, low relative solubility between racemic compound and conglomerate), deracemization proceeds via a second order asymmetric transformation (SOAT) and is limited primarily by the dissolution rate of the racemic crystals and the growth rate of the preferred enantiomer crystals.Breakage and agglomeration accelerate the process, but contrary to conventional Viedma ripening, they are not essential ingredients to explain the observed enantiomeric enrichment. If the nucleation process of the counter enantiomer is not sufficiently suppressed, deracemization is initially controlled by the dissolution rate of the racemic crystals, but Viedma ripening is subsequently required to convert the conglomerate crystals of the counter enantiomer formed by nucleation, resulting in slower deracemization kinetics. In both cases, the combined process leads to faster deracemization kinetics compared ...

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“…!,! ) > 0, growth occurs, while the case of Similarly to previous models 18,39,51,52 , due to the Gibbs-Thomson effect, the cluster solubility ! "…”

Section: Growth and Dissolutionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Coupling Viedma Ripening with Racemic Crystal Transformations: Mechanism of Deracemization

Xiouras

Horst

Gerven

et al. 2017

Crystal Growth & Design

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show abstract

“…In their study though, a heating plate was used to create a strong temperature gradient, which according to the author's interpretation enhanced crystal dissolution in hot zones and crystal growth in cold zones, effectively leading to deracemization 26 . Temporal temperature variations have also been shown to induce enantiomeric enrichment in a similar manner 28,29,44 . However, such effects can be excluded in the present study, since a heating jacket was used to create a homogeneous and controlled temperature profile in the reactor, which remained essentially constant for the entire duration of the experiments.…”

Section: Resultsmentioning

confidence: 94%

Towards Deracemization in the Absence of Grinding through Crystal Transformation, Ripening, and Racemization

Xiouras

Cleemput

Kumpen

et al. 2016

Crystal Growth & Design

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New insights into the obscure mechanisms of solid-state deracemization phenomena are obtained by crystal ripening experiments that, contrary to standard techniques, exclude attrition enhancement (grinding). The results point out that small particles and an initial size imbalance between the two enantiomeric crystal populations can intensify the rate of solid-state enantiomeric enrichment even in the absence of intermediate actions (e.g. grinding or thermal cycling). On this ground, a new process that creates such initial conditions is designed and exemplified for the proteinogenic glutamic acid. As a first step, racemic compound solvate (DL-glutamic acid monohydrate) crystals are completely converted to small-sized conglomerate anhydrate crystals, in the presence of larger seeds of a single chirality. After the transformation is complete and the racemization catalyst is added, the suspension contains an equal number of small-sized conglomerate crystals of both enantiomers together with the larger seeds of the preferred enantiomer. Over time, the large crystals of the preferred enantiomer tend to grow at the expense of smaller ones, which dissolve. This, combined with the fast racemization, leads to enantiomeric enrichment. The possible occurrence of enantioselective agglomeration between small and seed crystals speeds up this process by removing small crystals of the preferred enantiomer. Since most amino acids and several other pharmaceutical compounds are known to form metastable racemic hydrate crystals, it is expected that this new method is readily applicable to a variety of compounds. In addition, the process provides a technically simpler and more scalable route to enantiomeric enrichment compared to attrition-enhanced deracemization and its applicability extends to the wider pool of compounds that crystallize as racemic crystals.

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“…Viedma ripening (VR) and temperature cycle‐induced deracemization (TCID) are key approaches to deracemization and are being actively studied. We recently reported that second‐order asymmetric transformation (SOAT), a combination of preferential crystallization (PC) and racemization, could achieve relatively high process productivity compared with TCID due to the short processing time.…”

Section: Introductionmentioning

confidence: 99%

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

Oketani

Marin

Tinnemans³

et al. 2019

Chemistry A European J

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A productive deracemization process based on a quaternary phase diagram study of a naphthamide derivative is reported. New racemic compounds of an atropisomeric naphthamide derivative have been discovered, and a quaternary phase diagram has been constructed that indicated that four solids are stable in a methanol/H2O solution. Based on the results of a heterogeneous equilibria study showing the stable domain of the conglomerate, a second‐order asymmetric transformation was achieved with up to 97 % ee. Furthermore, this methodology showcases the chiral separation of a stable racemic compound forming system and does not suffer from any of the typical limitations of deracemization, although application is still limited to conglomerate‐forming systems. We anticipate that this present study will serve as a fundamental model for the design of sophisticated chiral separation processes.

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Linear Deracemization Kinetics during Viedma Ripening: Autocatalysis Overruled by Chiral Additives

Cited by 36 publications

References 28 publications

Coupling Viedma Ripening with Racemic Crystal Transformations: Mechanism of Deracemization

Coupling Viedma Ripening with Racemic Crystal Transformations: Mechanism of Deracemization

Towards Deracemization in the Absence of Grinding through Crystal Transformation, Ripening, and Racemization

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

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