Crystallization from Solutions Containing Multiple Conformers. 2. Experimental Study and Model Validation

Derdour, L.; Sivakumar, C.; Skliar, Dimitri; Pack, Sven; Lai, Chuan; Vernille, J. P.; Kiang, San

doi:10.1021/cg300975s

Cited by 14 publications

(20 citation statements)

References 28 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nowadays, in-process data mostly uses FBRM instrumentation [19][20][21] which measures only the chord length distribution which can be challenging to extract 'first-principles' face-specific kinetics [45].…”

Section: Overall Linear Growth Ratementioning

confidence: 99%

Precision measurement of the growth rate and mechanism of ibuprofen {001} and {011} as a function of crystallization environment

et al. 2014

View full text Add to dashboard Cite

Article:Nguyen, TTH, Hammond, RB, Roberts, KJ et al. (2 more authors) (2014) Precision measurement of the growth rate and mechanism of ibuprofen {001} and {011} as a function of crystallization environment. CrystEngComm, 16 (21). 4568 -4586. ISSN 1466-8033 https://doi.org/10.1039/c4ce00097h eprints@whiterose.ac.uk https://eprints.whiterose.ac.uk/ Reuse Unless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version -refer to the White Rose Research Online record for this item. Where records identify the publisher as the copyright holder, users can verify any specific terms of use on the publisher's website. TakedownIf you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request. acetonitrile. The crystal growth rates of the {001} and {011} faces of spontaneously nucleated crystals are precisely measured in-situ using optical microscopy revealing that their respective growth rates increase with increasing supersaturation to different extents, depending on the solvent type, with concomitant impact on the crystal habit. The measured aspect ratios, as a function of supersaturation, are generally higher at the 15 mL than the 0.5 mL scale size.Analysis of the growth rates versus supersaturation is consistent with a 2-D surface nucleation (Birth and Spread) model for both faces and at both scale sizes. The growth rates of the {001} and {011} faces exhibit much less growth rate dispersion when compared to literature data for a stirred batch crystallizer. 2The data is rationalized by examining the surface chemistry of the growing faces revealing, e.g. that polar protic solvents inhibit the growth rate of faces containing available binding sites for hydrogen bonding formation, such as carboxylic acid groups.

show abstract

Section: Overall Linear Growth Ratementioning

confidence: 99%

Precision measurement of the growth rate and mechanism of ibuprofen {001} and {011} as a function of crystallization environment

et al. 2014

View full text Add to dashboard Cite

show abstract

“…For example, in some cases, nucleation yields that polymorph in which the molecules retain their predominant solution phase conformation. [24][25][26] However, the dominant conformation in solution may also differ from conformations within the resulting polymorph. 27,28 Additionally, low concentration solvent additives can serve as molecular templates to promote nucleation and influence polymorph selection.…”

Section: Introductionmentioning

confidence: 99%

Salting out the polar polymorph: Analysis by alchemical solvent transformation

Duff

Dahal

Schmit

et al. 2014

The Journal of Chemical Physics

View full text Add to dashboard Cite

We computationally examine how adding NaCl to an aqueous solution with α- and γ-glycine nuclei alters the structure and interfacial energy of the nuclei. The polar γ-glycine nucleus in pure aqueous solution develops a melted layer of amorphous glycine around the nucleus. When NaCl is added, a double layer is formed that stabilizes the polar glycine polymorph and eliminates the surface melted layer. In contrast, the non-polar α-glycine nucleus is largely unaffected by the addition of NaCl. To quantify the stabilizing effect of NaCl on γ-glycine nuclei, we alchemically transform the aqueous glycine solution into a brine solution of glycine. The alchemical transformation is performed both with and without a nucleus in solution and for nuclei of α-glycine and γ-glycine polymorphs. The calculations show that adding 80 mg/ml NaCl reduces the interfacial free energy of a γ-glycine nucleus by 7.7 mJ/m(2) and increases the interfacial free energy of an α-glycine nucleus by 3.1 mJ/m(2). Both results are consistent with experimental reports on nucleation rates which suggest: J(α, brine) < J(γ, brine) < J(α, water). For γ-glycine nuclei, Debye-Hückel theory qualitatively, but not quantitatively, captures the effect of salt addition. Only the alchemical solvent transformation approach can predict the results for both polar and non-polar polymorphs. The results suggest a general "salting out" strategy for obtaining polar polymorphs and also a general approach to computationally estimate the effects of solvent additives on interfacial free energies for nucleation.

show abstract

“…Computation was performed for an isothermal anti-solvent crystallization of a substance, hereafter denoted A, which is present as two main conformations in solution. The constant of equilibrium between conformers at different temperatures for A was reported in a previous study [71] and solute integration factor for same substance was reported in [73]. The corresponding reduced constants, KR, and kRF are calculated and reported here in Figure 8.…”

Section: Crystal Growth Inhibition By the Wrong Conformermentioning

confidence: 93%

“…Crystal growth inhibition due to integration of the WC, Θ RF , can be computed using Equation (22) at different temperatures, T 1 and T 2 . k F is expected to vary NLT 1 and the experimental measurement of k F at two temperatures is sufficient to extrapolate a trend in the typical temperature range for crystallization of organic substances from solution [73]. The activation energy for solute integration, E a , is expected to vary in the typical range for small organic molecules: 5 to 25 kcal/mol [128][129][130] and K R can be determined from solubility measurements and/or NMR analysis [50].…”

Section: Of 24mentioning

confidence: 99%

“…However, there is steady growing evidence that improved potency of specific conformers under physiological conditions led to an increase in the focus on relatively stable conformers, as evidenced by recent reports [51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68]. Since crystallization is the main purification and separation unit operation in the development of new medicines, studies about molecular flexibility and the effect of the presence of conformation stability and conversion in solution on nucleation, crystal growth and polymorphism has also been steadily increasing [50,[69][70][71][72][73][74][75][76][77][78][79][80][81][82].…”

mentioning

confidence: 99%

See 1 more Smart Citation

Review and Modeling of Crystal Growth of Atropisomers from Solutions

2019

View full text Add to dashboard Cite

In this paper, theories on anisotropic crystal growth and crystallization of atropisomers are reviewed and a model for anisotropic crystal growth from solution containing slow inter-converting conformers is presented. The model applies to systems with growth-dominated crystallization from solutions and assumes that only one conformation participates in the solute integration step and is present in the crystal lattice. Other conformers, defined as the wrong conformers, must convert to the right conformer before they can assemble to the crystal lattice. The model presents a simple implicit method for evaluating the growth inhibition effect by the wrong conformers. The crystal growth model applies to anisotropic growth in two main directions, namely a slow-growing face and a fast-growing face and requires the knowledge of solute crystal face integration coefficients in both directions. A parameter estimation algorithm was derived to extract those coefficients from data about temporal concentration and crystal size during crystallization and was designed to have a short run time, while providing a high-resolution estimation. The model predicts a size-dependent growth rate and simulations indicated that for a given seed size and solvent system and for an isothermal anti-solvent addition crystallization, the seed loading and the supersaturation at seeding are the main factors impacting the final aspect ratio. The model predicts a decrease of the growth inhibition effect by the wrong conformer with increasing temperature, likely due to faster equilibration between conformers and/or a decrease of the population of the wrong conformer, if of low energy, at elevated temperatures. Finally, the model predicts that solute surface integration becomes the rate-limiting mechanism for high solute integration activation energies, resulting in no impact of the WC on the overall crystal growth process.

show abstract

Crystallization from Solutions Containing Multiple Conformers. 2. Experimental Study and Model Validation

Cited by 14 publications

References 28 publications

Precision measurement of the growth rate and mechanism of ibuprofen {001} and {011} as a function of crystallization environment

Precision measurement of the growth rate and mechanism of ibuprofen {001} and {011} as a function of crystallization environment

Salting out the polar polymorph: Analysis by alchemical solvent transformation

Review and Modeling of Crystal Growth of Atropisomers from Solutions

Contact Info

Product

Resources

About