Abstract
Understanding of solid-to-solid phase transition mechanisms in polymorphic systems is of critical importance for rigorous control over polymorph purity in the pharmaceutical industry to achieve the desired bioavailability and efficacy of drugs. Ubiquitous defects in crystals may play an important role in the pathways of phase transitions. However, such effects remain poorly understood. Here, the effects of crystal defects on the solid-to-solid phase transformations between dl-me-thio-nine polymorphs α and β are investigated by means of experimental and computational approaches. Thermal analyses of polycrystalline powders show two endothermic peaks in the α-to-β phase transition (and two exothermic peaks for the reverse transition), in contrast with one thermal event observed for single crystals. Variable-temperature 1D and 2D Raman spectra, as well as powder X-ray diffraction patterns, reveal the appearance of two peaks that can attributed to a two-step phase transition, and the extent of the second-step phase transition increases with milling time (or defect density). Quantification of transition kinetics unveils a remarkably higher energy barrier in the second-step phase transition than in the first, proceeding by the cooperative molecular motion pathway. The good linear fitting on the kinetic data by the Jeziorny model suggests that the second-step transition follows the nucleation and growth mechanism. Molecular dynamics simulations were also conducted to understand the role of crystal defects in the solid-state phase transition by tracking the atomic distribution and hydrogen bond lifetime during the transition. It was found that the increasing defect density hinders the propagation of cooperative molecular motion, leading to a combined transition mechanism involving both cooperative motion and nucleation and growth. This study highlights the significant impact of crystal defects on solid-state phase transitions, and the two-step transition mechanism postulated may be universal given the ubiquitous presence of defects in crystalline materials.
Highlights
Polymorphs of crystal structures often display distinct physical properties such as solubility (Williams et al, 2013), dissolution rate (Blagden et al, 2007) and elastic modulus (Bernstein, 2010) which are of significant importance for the manufacturing of pharmaceuticals and drug efficacy (Bauer et al, 2001; Singhal & Curatolo, 2004)
Single crystals of the dl-methionine polymorph were prepared by evaporative crystallization and further confirmed by Powder X-ray diffraction (PXRD)
This work combines thermal analyses, in situ Raman spectroscopy and molecular dynamics (MD) simulations to explore the role of crystal defects on the solid-to-solid dl-methionine polymorphic phase transition
Summary
Polymorphs of crystal structures often display distinct physical properties such as solubility (Williams et al, 2013), dissolution rate (Blagden et al, 2007) and elastic modulus (Bernstein, 2010) which are of significant importance for the manufacturing of pharmaceuticals and drug efficacy (Bauer et al, 2001; Singhal & Curatolo, 2004). It was suggested that the strain produced during the cooperative single-crystal-to-single-crystal phase transition may be dissipated at the defect sites, reducing the accumulation of energy for cooperative molecular displacement (Naumov et al, 2015) By this action, defects will interrupt the propagation of a new phase in the crystal layers (Smets et al, 2015). Crystal quality was postulated as a contributing factor to the transition barrier in polycrystalline powders, but details of the effects such as macroscopic size and crystal quality as well as microscopic crystal defects on phase transitions between polymorphs have not been resolved In this contribution, we study how the presence of crystal defects plays a dual role in both cooperative molecular motion and distinct nucleation and growth transition pathways
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