Speciation of Substituted Benzoic Acids in Solution: Evaluation of Spectroscopic and Computational Methods for the Identification of Associates and Their Role in Crystallization

Be̅rziņš, Agris; Semjonova, Aina; Actiņš, Andris; Salvalaglio, Matteo

doi:10.1021/acs.cgd.0c01605

Cited by 11 publications

(7 citation statements)

References 82 publications

(147 reference statements)

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“…Second, we selected this compound to try to find an approach for additive crystallization that would allow a reliable preparation procedure for the disappearing polymorphs. Our previous study [47] has already confirmed that polymorphs II and III can be obtained by varying the crystallization conditions. In this study, we additionally characterized forms I and III, performed screening of additives allowing control of the polymorphic outcome in the crystallization, explored the most promising additives for the crystallization control, and explored the effect of additives on phase transitions.…”

Section: Introductionmentioning

confidence: 52%

Controlling the Polymorphic Outcome of 2,6-Dimethoxybenzoic Acid Crystallization Using Additives

Semjonova

Be̅rziņš

2022

Crystals

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In this study, 2,6-dimethoxybenzoic acid (2,6MeOBA) was used as a model substance to investigate the use of additives to control the polymorphic outcome of crystallization. 2,6MeOBA exists as three polymorphs. Two of the 2,6MeOBA polymorphs, I and III, obtained in most of the crystallization experiments, were characterized by thermal analysis, and their relative thermodynamic stability was determined. Forms I and III are enantiotropically related, where form III is the high-temperature form. Pure form II was very difficult to obtain. Crystallization of 2,6MeOBA was explored under different conditions by performing evaporation and cooling crystallization from different solvents. Surfactants, polymers, and different molecular compounds with diverse possibilities for the formation of intermolecular interactions were tested as additives. The additives facilitating the crystallization of the metastable forms were additionally studied under different crystallization conditions. The effect of additives polyethylene glycol (PEG) and hydroxypropyl cellulose (HPC) on the thermodynamic stability and solvent-mediated phase transition (SMPT) kinetics was evaluated. HPC and PEG showed the potential to favor the formation of form III in crystallization from water.

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Section: Introductionmentioning

confidence: 52%

Controlling the Polymorphic Outcome of 2,6-Dimethoxybenzoic Acid Crystallization Using Additives

Semjonova

Be̅rziņš

2022

Crystals

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“…It was hypothesized that the structural motifs of API dimers in solution encode the polymorphic outcomes of crystal nucleation. As such, MD simulations of organic molecules in solutions have focused on the association of monomer building blocks to support experimental studies 127–131 . In simple 2D models of flexible chiral molecules, Carpenter and Grünwald 132 recently demonstrated how bulk crystal structures are related to the organization of building blocks prior to nucleation and the importance of kinetics in predicting polymorphism.…”

Section: Modeling Approaches To Simulate Nucleation From Solutionmentioning

confidence: 99%

Molecular simulation approaches to study crystal nucleation from solutions: Theoretical considerations and computational challenges

Finney,

Salvalaglio

2023

WIREs Comput Mol Sci

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Nucleation is the initial step in the formation of crystalline materials from solutions. Various factors, such as environmental conditions, composition, and external fields, can influence its outcomes and rates. Indeed, controlling this rate‐determining step toward phase separation is critical, as it can significantly impact the resulting material's structure and properties. Atomistic simulations can be exploited to gain insight into nucleation mechanisms—an aspect difficult to ascertain in experiments—and estimate nucleation rates. However, the microscopic nature of simulations can influence the phase behavior of nucleating solutions when compared to macroscale counterparts. An additional challenge arises from the inadequate timescales accessible to standard molecular simulations to simulate nucleation directly; this is due to the inherent rareness of nucleation events, which may be apparent in silico at even high supersaturations. In recent decades, molecular simulation methods have emerged to circumvent length‐ and timescale limitations. However, it is not always clear which simulation method is most suitable to study crystal nucleation from solution. This review surveys recent advances in this field, shedding light on typical nucleation mechanisms and the appropriateness of various simulation techniques for their study. Our goal is to provide a deeper understanding of the complexities associated with modeling crystal nucleation from solution and identify areas for further research. This review targets researchers across various scientific domains, including materials science, chemistry, physics and engineering, and aims to foster collaborative efforts to develop new strategies to understand and control nucleation.This article is categorized under: Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods Molecular and Statistical Mechanics > Free Energy Methods Theoretical and Physical Chemistry > Statistical Mechanics

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“…As such, MD simulations of organic molecules in solutions have focused on the association of monomer building blocks to support experimental studies. [131,132,133,134,135] In simple 2D models of flexible chiral molecules, Carpenter and Grünwald [136] recently demonstrated how bulk crystal structures are related to the organisation of building blocks prior to nucleation and the importance of kinetics in predicting polymorphism.…”

Section: Prenucleation Speciesmentioning

confidence: 99%

Theoretical and computational approaches to study crystal nucleation from solution

Finney

Salvalaglio

2023

Preprint

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Nucleation is the initial step towards the formation of crystalline materials from solutions. Various factors, such as environmental conditions, additives, and external forces, can influence its outcomes and rates. Indeed, controlling this rate-determining step towards phase separation can affect the material structure and properties, and it is crucial in a range of scientific fields. In this regard, atomistic simulation methods can be exploited to gain insight into nucleation mechanisms - an aspect difficult to ascertain in experiments - and estimate nucleation rates. However, the microscopic nature of simulations affects the phase behaviour of nucleating solutions when compared to macroscopic systems. Additionally, a challenge in modelling nucleation from solution is associated with the inadequacy of standard molecular simulations to access the timescales necessary to observe crystal nucleation due to the inherent rareness of these events. In recent decades, simulation methods have emerged to circumvent length- and timescale limitations. However, which simulation method is most suitable for studying crystal nucleation from solution is not always obvious. This review summarises the recent advances in this field, providing an overview of the typical nucleation mechanisms and the suitability of different simulation methods to study them. By doing so, we aim to provide a deeper understanding of the complexities associated with modelling crystal nucleation from solution and identify areas for further research. Our review targets researchers across various scientific fields, including materials science, chemistry, physics and engineering, and will hopefully contribute to developing new strategies for understanding and controlling nucleation.

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Speciation of Substituted Benzoic Acids in Solution: Evaluation of Spectroscopic and Computational Methods for the Identification of Associates and Their Role in Crystallization

Cited by 11 publications

References 82 publications

Controlling the Polymorphic Outcome of 2,6-Dimethoxybenzoic Acid Crystallization Using Additives

Controlling the Polymorphic Outcome of 2,6-Dimethoxybenzoic Acid Crystallization Using Additives

Molecular simulation approaches to study crystal nucleation from solutions: Theoretical considerations and computational challenges

Theoretical and computational approaches to study crystal nucleation from solution

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