Efficient separation of enantiomers by preferential crystallization in two coupled vessels

Elsner, M. P.; Ziomek, G.; Seidel‐Morgenstern, Andreas

doi:10.1002/aic.11719

Cited by 48 publications

(57 citation statements)

References 22 publications

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“…The coupled batch methodology used in this study is an extension of earlier coupled batch preferential crystallization experiments performed by Elsner et al and Levilain et al It is a technique based on adding homochiral seed crystals to a solution under conditions within the metastable limit. In this domain, both of the enantiomers have distinct driving forces as the liquid phase is thermodynamically unstable but kinetically constrained due to the different initial surface areas of the seed crystals …”

Section: Introductionmentioning

confidence: 99%

Diastereomeric salt crystallization of chiral moleculesvia sequential coupled‐Batch operation

et al. 2018

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A novel process, sequential coupled‐batch diastereomeric crystallization is presented for the resolution of racemic mixtures. This strategy utilized a preferential crystallization of diastereomeric salt followed by sequential coupled diastereomeric salt resolution of racemic ibuprofen with the resolving agent (S)‐lysine utilizing a novel small scale pneumatic liquid exchange design to couple two batch crystallizers. Results were compared to conventional sequential resolution via seeded isothermal batch crystallization. Diastereomeric salt resolution was developed using the ternary phase diagram of the isolated (R)‐ibuprofen‐(S)‐lysine and (S)‐ibuprofen‐(S)‐lysine salts and optimized empirically with the aid of process analytical technology. Sequential coupled‐batch crystallization was found to be capable of increasing the yield of both salts while maintaining purity. This gave an increase in both the productivity and yield (20.5% for (S)‐ibuprofen‐(S)‐lysine) compared to the equivalent sequential batch (17.7% for (S)‐ibuprofen‐(S)‐lysine) crystallization methodology. Single crystals of the (S)‐ibuprofen‐(S)‐lysine were isolated, and its single crystal structure determined. © 2018 American Institute of Chemical Engineers AIChE J, 65: 604–616, 2019

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Section: Introductionmentioning

confidence: 99%

Diastereomeric salt crystallization of chiral moleculesvia sequential coupled‐Batch operation

et al. 2018

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“…In a follow‐up paper, a flow sheet with two coupled crystallizers, which were seeded using opposite enantiomers and which were connected through liquid‐phase exchange pipes, was presented . This concept was previously successfully demonstrated—both theoretically and experimentally—for two coupled batch crystallizers . As in the case of the two batch crystallizers, the continuous process allowed obtaining both enantiomers in pure form.…”

Section: The Flow Sheet and Its Rationalementioning

confidence: 99%

Separation of conglomerate forming enantiomers using a novel continuous preferential crystallization process

2015

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in Wiley Online Library (wileyonlinelibrary.com) Providing enantiomerically pure products is of key importance in the fine chemicals, food, and pharmaceutical industries. A continuous preferential crystallization process is presented that allows the separation of conglomerate forming enantiomers in a stable, robust, and flexible way. This is achieved by coupling two continuous crystallizers by exchanging their clear liquid phases. Each crystallizer is connected to a suspension mill responsible for in situ seed generation through particle breakage. The dynamic and steady-state behavior of this process is extensively analyzed for racemic feed streams through process simulations, and parameter regions, which yield pure enantiomers in both crystallizers, are identified. For enriched feed streams, it is further shown when this novel flow sheet is capable of outperforming an ideal batch process in terms of solvent consumption per unit mass of desired enantiopure product produced.

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“…Many researchers have tried to circumvent this problem, for instance by using coupled batch crystallizers -crystallizing the preferred enantiomer in one crystallizer and the counter enantiomer in another crystallizer, with exchange of solution between the two crystallizers [13], coupled batch crystallizers with seeding of the preferred enantiomer in one crystallizer and allowing nucleation of the counter enantiomer in another crystallizer maintained at a different temperature [14,15], coupled batch crystallizers with a membrane between the crystallizers to prevent transport of crystals from one crystallizer to another [16], and racemization of the solute species to equalize the concentrations of the preferred and counter enantiomer [17,18], Another way to circumvent the crystallization of the counter enantiomer is to use tailor made additives to inhibit the nucleation and growth of the counter enantiomer. This will be convenient if the scale of the resolution is such that a fully batch system is most suitable and crystallization or recycling of the counter enantiomer is not required.…”

Section: Introductionmentioning

confidence: 99%

Effect of additives on the preferential crystallization of L-asparagine monohydrate

Kongsamai

Maneedaeng

Flood

et al. 2017

Eur. Phys. J. Spec. Top.

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Preferential Crystallization (PC) is a popular process to separate enantiomers, however the nucleation and growth of the counter enantiomer during the process can compromise the enantiopurity of the final crystalline product. This research investigates the use of additives to inhibit the nucleation and growth of the counter enantiomer. In this study, we use Lasparagine monohydrate (L-Asn•H2O) as the preferred enantiomer in crystallization from DLAsn•H2O solutions. Additives include both pure enantiomers of several related amino acid species. This allows investigation of differences in inhibition caused by additives that are of the same chirality and different chirality as the preferred enantiomer. The additives had no discernible effect on the solubility but had a small effect on the metastable limit, with additives tending to slightly widen the metastable zone but also make the zone widths more

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Efficient separation of enantiomers by preferential crystallization in two coupled vessels

Cited by 48 publications

References 22 publications

Diastereomeric salt crystallization of chiral moleculesvia sequential coupled‐Batch operation

Diastereomeric salt crystallization of chiral moleculesvia sequential coupled‐Batch operation

Separation of conglomerate forming enantiomers using a novel continuous preferential crystallization process

Effect of additives on the preferential crystallization of L-asparagine monohydrate

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