Continuous Crystallization and Polymorph Dynamics in the <scp>l</scp>-Glutamic Acid System

Lai, Tsai-Ta C.; Ferguson, Steven; Palmer, Laura; Trout, Bernhardt L.; Myerson, Allan S.

doi:10.1021/op500171n

Cited by 67 publications

(105 citation statements)

References 22 publications

(28 reference statements)

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“…Interestingly the metastable polymorph became established even in circumstances where a large seed dose of the beta polymorph had been employed at the start of the continuous run. During a transient increase in supersaturation a small amount of the metastable alpha polymorph crystallised and thereafter persisted as the dominant solid phase present [53]. These results are entirely in keeping with the domain diagram developed here (Figure 3).…”

Section: Resultssupporting

confidence: 88%

Thermodynamic vs. Kinetic Basis for Polymorph Selection

Hodnett

Verma

2019

Processes

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Ratios of equilibrium solubilities rarely exceed two-fold for polymorph pairs. A model has been developed based on two intrinsic properties of polymorph pairs, namely the ratio of equilibrium solubilities of the individual pairs (C*me/C*st) and the ratio of interfacial energies (γst/γme) and one applied experimental condition, namely the supersaturation identifies which one of a pair of polymorphs nucleates first. A domain diagram has been developed, which identifies the point where the critical free energy of nucleation for the polymorph pair are identical. Essentially, for a system supersaturated with respect to both polymorphs, the model identifies that low supersaturation with respect to the stable polymorph (Sst) leads to an extremely small supersaturation with respect to the metastable polymorph (Sme), radically driving up the critical free energy with respect to the metastable polymorph. Generally, high supersaturations sometimes much higher than the upper limit of the metastable zone, are required to kinetically favour the metastable polymorph.

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Section: Resultssupporting

confidence: 88%

Thermodynamic vs. Kinetic Basis for Polymorph Selection

Hodnett

Verma

2019

Processes

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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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“…The mathematical modeling for single stage MSMPR system was described in detail in our previous work. 17 One dimension population balance model was introduced to describe the crystallization of p-aminobenzoic acid polymorphs in each stage. The governing equations are presented below.…”

Section: Dynamic Simulationmentioning

confidence: 99%

Control of Polymorphism in Continuous Crystallization via Mixed Suspension Mixed Product Removal Systems Cascade Design

Lai

Cornevin

Ferguson

et al. 2015

Crystal Growth & Design

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105

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Control of polymorphism of the enantiotropic p-aminobenzoic acid at either the α or β polymorph while maintaining high yield was achieved by mixed suspension mixed product removal (MSMPR) cascade design. A systematic approach was developed to identify the operational window of the process variables, stage temperature and residence time, in which the stringent polymorph purity criterion (>95 wt %) and high yield were met. The comprehensive understanding of the polymorphism of the model compound, p-aminobenzoic acid, was the key for the identification of the operational window. On the basis of single-stage MSMPR experiments, three temperature regimes thermodynamic control, energy barrier control, and kinetic competitionwere identified, and the interplay between the crystallization kinetics and the thermodynamics in each regime was elucidated. Experimental studies also demonstrated the first polymorph specific MSMPR for enantiotropic systems. Single-stage MSMPRs at low temperature, e.g., 5°C, were found to be β polymorph-specific at steady states across multiple operating conditions. Two-stage MSMPR was designed to alter the polymorphism at the 5°C stage from β polymorph-specific to α polymorph-specific. The first stage temperature was selected in the thermodynamic control regime (30°C) at which the steady state polymorphism was α-specific. Feeding continuously to the second stage, the α crystals generated at the first stage increased the total surface area and thereby the secondary nucleation and mass deposition rates of the α polymorph in the 5°C stage. This in turn increased the α polymorph from 0 wt % to at least 75 wt %, proving that it is feasible to control the polymorphism via design of the MSMPR cascade.

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Continuous Crystallization and Polymorph Dynamics in the l-Glutamic Acid System

Cited by 67 publications

References 22 publications

Thermodynamic vs. Kinetic Basis for Polymorph Selection

Thermodynamic vs. Kinetic Basis for Polymorph Selection

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

Control of Polymorphism in Continuous Crystallization via Mixed Suspension Mixed Product Removal Systems Cascade Design

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