Polymorphic phase transitions: Macroscopic theory and molecular simulation

Abstract

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.

Mapping the polymorphic transformation gateway vibration in crystalline 1,2,4,5-tetrabromobenzene

“…Recent work has investigated the structural strain associated with the polymorph change that contributes to the thermosalient nature of TBB, and suggested that low-frequency vibrational modes near 43 cm –1 and 47 cm –1 are integral to the conversion 12. The importance of low-frequency vibrations for determining the properties of TBB crystals is consistent with the established relationship that exists between low-frequency lattice phonons and displacive/martensitic phase transformations as observed in other crystalline solids 23–25. In the current study, experimental low-frequency Raman spectral data (10–250 cm –1 ) was collected at various temperatures and combined with solid-state density functional theory (ss-DFT) simulations to provide clear assignments of the vibrational motions in this region.…”

Molecular Dynamics Simulations of the “Breathing” Phase Transformation of MOF Nanocrystallites

“…Note that such surface effects hindering the transformation for smaller crystallites have previously been found in MD simulations of the phase transformations of molecular crystals. [28][29][30] In order to investigate this behavior on a fundamental level, we chose here Zn 2 (bdc) 2 dabco (DMOF-1) as a model system. [31] The pcu topology allows for a displacive shear transformation, [14] and even though this particular system has not been observed in a closed pore (cp) state, our force field predicts a stable cp phase, making DMOF-1 a suitable, yet simple system for our investigations, serving as a demonstrator system to develop and benchmark the methodology of nanocrystallite simulations in general.…”

“…Clearly, such surface effects can only be considered in simulations beyond PBC. Note that such surface effects hindering the transformation for smaller crystallites have previously been found in MD simulations of the phase transformations of molecular crystals . In order to investigate this behavior on a fundamental level, we chose here Zn 2 (bdc) 2 dabco (DMOF‐1) as a model system .…”

Imaging of dehydration in particulate matter using Raman line-focus microscopy

“…Our findings are pointing towards mechanistic models based on combining information at different levels: spectroscopic imaging visualizing molecular level phenomena, such as solid-state diversity during dehydration in a single particle, combined with optical microscopy to visualize particle level phenomena, such as crack density related to this phase transformation. This can provide a basis for multiscale mechanistic models 49 and experimental validation of computer simulations. This approach would have similarities with the deep learning process in cancer diagnosis based on imaging of cellular samples 50 .…”