Towards continuous deracemization via racemic crystal transformation monitored by in-situ Raman spectroscopy

Christos Xiouras, Giuseppe Belletti, Raghunath Venkatramanan, Alison Nordon, Hugo Meekes, Elias Vlieg, Georgios D. Stefanidis, Joop H. Ter Horst

Research output: Contribution to journalArticle

Abstract

In this work, we demonstrate a semi-batch solid-state deracemization process for N-(2- chlorobenzylidene)-phenylglycine amide (NCPA), a complex chiral polymorphic system that involves three types of crystalline racemates (racemic compound and conglomerate forms I and II). In this process, gradually fed metastable racemic compound crystals are converted in situ to crystals of the preferred (seeded) enantiomer under grinding conditions through a series of solvent- mediated transformations in a racemizing solution. The phase diagram for this system shows that while conglomerate form II is stable at the conditions examined (acetonitrile at 21°C), form I crystals of a single enantiomer (used as seeds) are unstable at (nearly) racemic compositions and convert to the racemic compound upon addition of the racemization catalyst. Thus, care needs to be exercised in order to fully convert form I to form II before addition of the racemization catalyst in order to prevent the undesired crystallization of the racemic compound. This can be achieved by adding a small amount of water, which is found to enhance the nucleation and growth kinetics of the most stable conglomerate form II, eventually leading to complete deracemization. Importantly, we show that this special deracemization process can be easily monitored online by Raman spectroscopy, which gives access to the evolution of the solid phase composition. For the studied system, this information can in turn be used to directly estimate the solid-phase enantiomeric excess online throughout the process, as long as conglomerate crystals of the counter enantiomer do not form.
LanguageEnglish
Pages5858-5868
Number of pages11
JournalCrystal Growth and Design
Volume19
Issue number10
Early online date6 Sep 2019
DOIs
Publication statusPublished - 2 Oct 2019

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Enantiomers
Raman spectroscopy
enantiomers
Crystals
crystals
solid phases
catalysts
Catalysts
information systems
Growth kinetics
grinding
Crystallization
Acetonitrile
Amides
Phase composition
amides
Phase diagrams
acetonitrile
Seed
seeds

Keywords

  • deracemization
  • racemic crystal transformation
  • Raman spectroscopy

Cite this

Xiouras, Christos ; Belletti, Giuseppe ; Venkatramanan, Raghunath ; Nordon, Alison ; Meekes, Hugo ; Vlieg, Elias ; Stefanidis, Georgios D. ; Ter Horst, Joop H. / Towards continuous deracemization via racemic crystal transformation monitored by in-situ Raman spectroscopy. In: Crystal Growth and Design. 2019 ; Vol. 19, No. 10. pp. 5858-5868.
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Towards continuous deracemization via racemic crystal transformation monitored by in-situ Raman spectroscopy. / Xiouras, Christos; Belletti, Giuseppe; Venkatramanan, Raghunath; Nordon, Alison; Meekes, Hugo; Vlieg, Elias; Stefanidis, Georgios D.; Ter Horst, Joop H.

In: Crystal Growth and Design, Vol. 19, No. 10, 02.10.2019, p. 5858-5868.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Towards continuous deracemization via racemic crystal transformation monitored by in-situ Raman spectroscopy

AU - Xiouras, Christos

AU - Belletti, Giuseppe

AU - Venkatramanan, Raghunath

AU - Nordon, Alison

AU - Meekes, Hugo

AU - Vlieg, Elias

AU - Stefanidis, Georgios D.

AU - Ter Horst, Joop H.

PY - 2019/10/2

Y1 - 2019/10/2

N2 - In this work, we demonstrate a semi-batch solid-state deracemization process for N-(2- chlorobenzylidene)-phenylglycine amide (NCPA), a complex chiral polymorphic system that involves three types of crystalline racemates (racemic compound and conglomerate forms I and II). In this process, gradually fed metastable racemic compound crystals are converted in situ to crystals of the preferred (seeded) enantiomer under grinding conditions through a series of solvent- mediated transformations in a racemizing solution. The phase diagram for this system shows that while conglomerate form II is stable at the conditions examined (acetonitrile at 21°C), form I crystals of a single enantiomer (used as seeds) are unstable at (nearly) racemic compositions and convert to the racemic compound upon addition of the racemization catalyst. Thus, care needs to be exercised in order to fully convert form I to form II before addition of the racemization catalyst in order to prevent the undesired crystallization of the racemic compound. This can be achieved by adding a small amount of water, which is found to enhance the nucleation and growth kinetics of the most stable conglomerate form II, eventually leading to complete deracemization. Importantly, we show that this special deracemization process can be easily monitored online by Raman spectroscopy, which gives access to the evolution of the solid phase composition. For the studied system, this information can in turn be used to directly estimate the solid-phase enantiomeric excess online throughout the process, as long as conglomerate crystals of the counter enantiomer do not form.

AB - In this work, we demonstrate a semi-batch solid-state deracemization process for N-(2- chlorobenzylidene)-phenylglycine amide (NCPA), a complex chiral polymorphic system that involves three types of crystalline racemates (racemic compound and conglomerate forms I and II). In this process, gradually fed metastable racemic compound crystals are converted in situ to crystals of the preferred (seeded) enantiomer under grinding conditions through a series of solvent- mediated transformations in a racemizing solution. The phase diagram for this system shows that while conglomerate form II is stable at the conditions examined (acetonitrile at 21°C), form I crystals of a single enantiomer (used as seeds) are unstable at (nearly) racemic compositions and convert to the racemic compound upon addition of the racemization catalyst. Thus, care needs to be exercised in order to fully convert form I to form II before addition of the racemization catalyst in order to prevent the undesired crystallization of the racemic compound. This can be achieved by adding a small amount of water, which is found to enhance the nucleation and growth kinetics of the most stable conglomerate form II, eventually leading to complete deracemization. Importantly, we show that this special deracemization process can be easily monitored online by Raman spectroscopy, which gives access to the evolution of the solid phase composition. For the studied system, this information can in turn be used to directly estimate the solid-phase enantiomeric excess online throughout the process, as long as conglomerate crystals of the counter enantiomer do not form.

KW - deracemization

KW - racemic crystal transformation

KW - Raman spectroscopy

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DO - 10.1021/acs.cgd.9b00867

M3 - Article

VL - 19

SP - 5858

EP - 5868

JO - Crystal Growth and Design

T2 - Crystal Growth and Design

JF - Crystal Growth and Design

SN - 1528-7483

IS - 10

ER -