The isolation of a metastable conglomerate using a combined computational and controlled crystallization approach

Davey, Roger J.; Sadiq, Ghazala; Back, Kevin; Wilkinson, Laura L.; Seaton, Colin C.

doi:10.1039/c1cc16173c

Cited by 13 publications

(16 citation statements)

References 10 publications

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“…Understanding the interconversion and stability relationships between racemic and conglomerate forms is an important step in the crystallization of an API. − In this context, we have examined the crystallization behavior of 3-methyl-2-phenylbutyramide, 1 , an antimitotic compound that displays racemic and conglomerate forms, Figure . Notably, the solid-state properties of 1 have not been described previously.…”

Section: Introductionmentioning

confidence: 99%

Exploring the Crystal Landscape of 3-Methyl-2-phenylbutyramide: Crystallization of Metastable Racemic Forms from the Stable Conglomerate

Khandavilli

Gavin

Maguire

et al. 2018

Crystal Growth & Design

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In the solid state, (±)-3-methyl-2-phenylbutyramide 1 spontaneously resolves into a conglomerate (Form I) that crystallizes in a racemic form (Form II) upon melting followed by vapor crystallization, a rarely reported phenomenon. An additional racemic polymorph, Form III, has been characterized, and the thermodynamic relationship between the three forms established by a variety of computational and experimental methods including grinding, slurry crystallization, and seeding techniques. Both racemic Forms II and III are metastable and readily convert to the more stable conglomerate, Form I. Density functional theory calculations of the different polymorphs of 1 show that the enantiomers of 1 (R & S) are more stable than both racemic forms.

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Section: Introductionmentioning

confidence: 99%

Exploring the Crystal Landscape of 3-Methyl-2-phenylbutyramide: Crystallization of Metastable Racemic Forms from the Stable Conglomerate

Khandavilli

Gavin

Maguire

et al. 2018

Crystal Growth & Design

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“…Fortunately, the case of solid solutions (Figure c), where crystals can contain any composition of R and S enantiomers and which are hardest to separate, is rarely encountered for organic molecules. Apart from the ideal cases shown in Figure , there are numerous (combinations of) nonidealities possible, for example, the presence of a metastable conglomerate in racemic compound forming systems, partial solid solutions, the presence of liquid‐liquid equilibria, and the presence of (metastable) polymorphs …”

Section: Introductionmentioning

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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“…This is a method to remove the probabilistic nature of conglomerate formation and allow for more control over which substrates display this behaviour. The use of crystal engineering can be used to formulate co-crystallisation conditions which lead to conglomerate crystal structures (HEGGAD, [63,64] NUMZUT, [65] UHUCEH, [66] and others [67][68][69][70] ), while retaining favourable biophysical properties. For better or worse, this may also offer a means to evergreen patents on existing pharmaceuticals if a synthetic route is altered The choice of solvent has also been shown to control the formation of a conglomerate crystallisation over a racemic crystal.…”

Section: Resultsmentioning

confidence: 99%

A Potentially Limitless Chiral Pool via Conglomerate Crystallisation: Unidentified Spontaneous Resolution in the CSD.

Walsh

Barclay

Begg

et al. 2022

Preprint

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Conglomerate crystallisation is the behaviour responsible for spontaneous resolution and the discovery of molecular chirality by Pasteur. The phenomenon of conglomerate crystallisation of chiral organic molecules has been left largely undocumented and offers synthetic chemists a potential new chiral pool not reliant on biological systems to supply stereochemical information. While other crystallographic behaviours can be interrogated by automated searching, conglomerate crystallisations are not identified within the Cambridge Structural Database (CSD) and are therefore not accessible by conventional means. By conducting a manual search of the CSD, a list of over 1,700 chiral species capable of conglomerate crystallisation was curated by inspection of the synthetic routes described in each publication. The majority of these are produced by synthetic chemists who seldom note and rarely exploit the implications this phenomenon can have on the enantioenrichment of their crystalline materials. We propose that this list represents a limitless chiral pool which will continually grow in size as more conglomerate crystals are synthesised and recorded.

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The isolation of a metastable conglomerate using a combined computational and controlled crystallization approach

Cited by 13 publications

References 10 publications

Exploring the Crystal Landscape of 3-Methyl-2-phenylbutyramide: Crystallization of Metastable Racemic Forms from the Stable Conglomerate

Exploring the Crystal Landscape of 3-Methyl-2-phenylbutyramide: Crystallization of Metastable Racemic Forms from the Stable Conglomerate

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

A Potentially Limitless Chiral Pool via Conglomerate Crystallisation: Unidentified Spontaneous Resolution in the CSD.

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