Design and Performance Assessment of Continuous Crystallization Processes Resolving Racemic Conglomerates

Köllges, Till; Vetter, Thomas

doi:10.1021/acs.cgd.7b01618

Cited by 20 publications

(35 citation statements)

References 41 publications

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“…Traditionally, this may have been difficult to implement industrially in the pharmaceutical industry which has almost exclusively utilized standard batch equipment. However, the past decade has seen a significant uptake of crystallizer technologies for use in next generation continuous pharmaceutical platforms with ability to separate enantiomers in a continuous manner as well as access to a wider ranges of particle sizes, improved polymorph control, and increased purity …”

Section: Introductionmentioning

confidence: 99%

Diastereomeric salt crystallization of chiral molecules via 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 molecules via sequential coupled‐Batch operation

et al. 2018

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“…, describing the number of fragments of size L formed when breaking a particle of size λ was chosen as: [50][51][52][53]…”

Section: Process Modelmentioning

confidence: 99%

Polymorph Selection and Process Intensification in a Continuous Crystallization–Milling Process: A Case Study on l-Glutamic Acid Crystallized from Water

Köllges

Vetter

2019

Org. Process Res. Dev.

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The continuous crystallization of L-glutamic acid from water is studied in a single stage mixed suspension mixed product removal crystallizer that is coupled to a milling loop. We show that the stable β polymorph can be obtained in the presence of milling at operating conditions that would lead to the metastable α polymorph without milling. The effect is first shown through a series of experiments carried out at different residence times, feed concentrations and in the absence/presence of milling. The experimental observations are rationalized through the use of a population balance equation model. We conclude that the observed effects result from fines generation and the corresponding increase in crystal surface area. Using the model, we obtain a map of polymorphic outcomes and process productivity in dependence of operating conditions. It is shown that the combined milling/crystallization process exhibits higher productivity and an enlarged region of operating conditions where the stable polymorph of L-glutamic acid can be reliably obtained in comparison to a conventional crystallization process.

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“…Therefore, chiral resolution, the separation of a racemic (equimolar) mixture into its enantiomers, is the most widely used approach to produce preferred enantiomers. Many of the available resolution techniques such as chromatography [4][5][6][7] and membrane separation [8][9][10], typically deliver the product in diluted form in the liquid phase often requiring a crystallization step for producing the desired solid product [11]. In contrast, preferential crystallization can be directly used as an attractive and efficient means to separate the racemic mixtures due to its ability to provide high purity solid products.…”

Section: Introductionmentioning

confidence: 99%

Modeling and Simulation Studies of a Novel Coupled Plug Flow Crystallizer for the Continuous Separation of Conglomerate-Forming Enantiomers

Majumder

2018

Processes

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Separation of enantiomers is a major concern in pharmaceutical industries due to the different therapeutic activities exhibited by the enantiomers. Preferential crystallization is an attractive means to separate the conglomerate-forming enantiomers. In this work, a simulation study is presented for a proposed novel preferential crystallization configuration that involves coupled plug flow crystallizers (PFCs). The PFCs are coupled through liquid phase exchange which helps the enrichment of the preferred enantiomer in the liquid phase. A set of coupled population balance equations (PBEs) are used to describe the evolution of the crystal size distribution (CSD) in the PFCs. The PBEs and the relevant mass balance equations are solved using the high-resolution finite-volume method. The simulation results predict that the proposed configuration has higher productivity compared to the currently used crystallization configurations while maintaining the same level of purity. Moreover, the effect of process variables, such as the extent of liquid phase change and the location of the PFC where liquid phase exchange occurs, are studied. The insights obtained from this simulation study will be useful in design, development, and optimization of such novel crystallization platforms.

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Design and Performance Assessment of Continuous Crystallization Processes Resolving Racemic Conglomerates

Cited by 20 publications

References 41 publications

Diastereomeric salt crystallization of chiral molecules via sequential coupled‐Batch operation

Diastereomeric salt crystallization of chiral molecules via sequential coupled‐Batch operation

Polymorph Selection and Process Intensification in a Continuous Crystallization–Milling Process: A Case Study on l-Glutamic Acid Crystallized from Water

Modeling and Simulation Studies of a Novel Coupled Plug Flow Crystallizer for the Continuous Separation of Conglomerate-Forming Enantiomers

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