Energy barriers and mechanisms in solid–solid polymorphic transitions exhibiting cooperative motion

Ende, Joost A. van den; Ensing, Bernd; Cuppen, H. M.

doi:10.1039/c5ce02550h

Cited by 21 publications

(19 citation statements)

References 31 publications

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“…A barrier of 35 meV seems very small, and if indeed true, this would mean that the transition between form I and III would readily occur in an experimental setting. The transition, however, involves a cooperative motion and as we have shown earlier for dl -norleucine, 14 the barrier of this process scales linearly with the number of molecules involved in the movement. The barrier of 35 meV hence corresponds to the free energy barrier involved in sliding a 29 Å by 28 Å area from a F-I to a F-III orientation or the other way around ( Figure 10 ).…”

Section: Simulations Of F-iii To F-i Transitionsupporting

confidence: 60%

The Rich Solid-State Phase Behavior of l-Phenylalanine: Disappearing Polymorphs and High Temperature Forms

Cuppen

Smets

Krieger

et al. 2019

Crystal Growth & Design

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After years of controversy over the solid state structure of the essential amino acid l-phenylalanine, four different polymorphic forms were published recently. The common form I has symmetry P21 with four molecules in the asymmetric unit (Z′ = 4), similar to form III, but with a different arrangement of molecular bilayers. Form II, obtained from the hydrate at very low humidity, is unrelated to forms I and III, as is the high-density form IV. The present investigation demonstrates that this prototype aromatic amino acid has two additional high-temperature phases Ih and IIIh obtained from form I and form III above 458 and 440 K, respectively, when flipping between two alternative side-chain conformations becomes dynamic and causes pairs of molecules, initially crystallographically independent, to become equivalent above a sharp transition temperature. These abrupt and reversible phase changes occur with a reduction of Z′ from 4 (low T) to 2 (high T) and modified crystal symmetry. We furthermore experienced an example of disappearing polymorph for form I which after growing form III in one of our laboratories could no longer be crystallized at room temperature. In contrast, form III crystals may be irreversibly converted to form I crystals as a result of sliding of molecular bilayers in the crystal at elevated temperature. No conversions between the high-temperature forms Ih and IIIh were found. The remarkable crystallographic results are here corroborated by Molecular Dynamics and metadynamics simulations of the form I – form III system.

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Section: Simulations Of F-iii To F-i Transitionsupporting

confidence: 60%

The Rich Solid-State Phase Behavior of l-Phenylalanine: Disappearing Polymorphs and High Temperature Forms

Cuppen

Smets

Krieger

et al. 2019

Crystal Growth & Design

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“…For molecular crystals, mechanistic insight into martensitic-type transformations has come from simulations of phase transitions in crystals of DL-norleucine [111,[127][128][129][130] and terephthalic acid [131]. The three known forms of DL-norleucine consist of stacked, hydrogen-bonded bilayers, separated by a van der Waals surface.…”

Section: Displacive/martensitic Transformationsmentioning

confidence: 99%

Polymorphic phase transitions: Macroscopic theory and molecular simulation

Anwar

Zahn

2017

Advanced Drug Delivery Reviews

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Transformations in the solid state are of considerable interest, both for fundamental reasons and because they underpin important technological applications. The interest spans a wide spectrum of disciplines and application domains. For pharmaceuticals, a common issue is unexpected polymorphic transformation of the drug or excipient during processing or on storage, which can result in product failure. A more ambitious goal is that of exploiting the advantages of metastable polymorphs (e.g. higher solubility and dissolution rate) while ensuring their stability with respect to solid state transformation. To address these issues and to advance technology, there is an urgent need for significant insights that can only come from a detailed molecular level understanding of the involved processes. Whilst experimental approaches at best yield time- and space-averaged structural information, molecular simulation offers unprecedented, time-resolved molecular-level resolution of the processes taking place. This review aims to provide a comprehensive and critical account of state-of-the-art methods for modelling polymorph stability and transitions between solid phases. This is flanked by revisiting the associated macroscopic theoretical framework for phase transitions, including their classification, proposed molecular mechanisms, and kinetics. The simulation methods are presented in tutorial form, focusing on their application to phase transition phenomena. We describe molecular simulation studies for crystal structure prediction and polymorph screening, phase coexistence and phase diagrams, simulations of crystal-crystal transitions of various types (displacive/martensitic, reconstructive and diffusive), effects of defects, and phase stability and transitions at the nanoscale. Our selection of literature is intended to illustrate significant insights, concepts and understanding, as well as the current scope of using molecular simulations for understanding polymorphic transitions in an accessible way, rather than claiming completeness. With exciting prospects in both simulation methods development and enhancements in computer hardware, we are on the verge of accessing an unprecedented capability for designing and developing dosage forms and drug delivery systems in silico, including tackling challenges in polymorph control on a rational basis.

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“…Although the layers move in a concerted fashion, the results further indicate that local fluctuations in the conformations of the aliphatic chains play a crucial role in keeping the cooperative mechanism sustainable at large length scales (see figure). The results suggest a mechanism where formation of a nucleus of the new phase occurs through cooperative motion, which then grows through propagation in a wave-like manner through the crystal [3]. At the length scale of theinitial size of the cluster, classical nucleation theory and the cooperative mechanism could naturally come together.…”

mentioning

confidence: 82%

Coordination frameworks of tetrakis[meso-(3,5-biscarboxyphenyl)]-metalloprphyrins with polynuclear metallic nodes

Goldberg¹,

Tripuramallu²

2016

Acta Cryst Sect A

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Energy barriers and mechanisms in solid–solid polymorphic transitions exhibiting cooperative motion

Cited by 21 publications

References 31 publications

The Rich Solid-State Phase Behavior of l-Phenylalanine: Disappearing Polymorphs and High Temperature Forms

The Rich Solid-State Phase Behavior of l-Phenylalanine: Disappearing Polymorphs and High Temperature Forms

Polymorphic phase transitions: Macroscopic theory and molecular simulation

Coordination frameworks of tetrakis[meso-(3,5-biscarboxyphenyl)]-metalloprphyrins with polynuclear metallic nodes

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