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-methionine 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.

Crystallization of chiral compounds is dictated by chiral recognition and molecular self-assembly in solution. However, their interplay remains elusive. The reason for the considerably reduced polymorphism in chiral molecules than that of nonchiral molecules remains unclear. Herein, we use a combination of experimental and computational techniques to show that excessive enantiomer functioning, as a native crystallization inhibitor, selectively suppresses the crystallization of racemic polymorphs, affording preferential crystallization of the metastable α polymorph of dl-methionine. Bulk crystallization assays show concomitant crystallization of the α and β polymorphs of racemic dl-methionine in the solution with no enantiomeric excess. However, when the solution contains excessive d-/l-methionine enantiomer, only the metastable α form can be crystallized. Crystal growth experiments, fluoresce confocal microscopy, and atomic force microscope surface topology measurements reveal the growth inhibition of both polymorphs with preferential suppression of the β form by excess native enantiomer. Binding energy calculations and molecular dynamic simulations further demonstrate the preferential adsorption of excessive enantiomers on the (0 0 2) facet of the β form over the α form. Overall, our results uncover a unique chiral self-positioning mechanism where the excess enantiomer solutes serve as a native growth inhibitor to disrupt the kinetics of racemic polymorphic crystallization, affording selective crystallization of only one polymorph of dl-methionine. Our results highlight the important effect of excess enantiomer in a solution on the polymorph occurrence of chiral molecules.

Developing multicomponent crystal forms, especially cocrystals and salts, is becoming a promising pathway to improve the solubility and bioavailability of drugs. Herein, new multicomponent crystals of SHR0302, a new generation of Janus Kinase (JAK) inhibitor that suffers from poor solubility, were developed based on a cooperative approach of computational and experimental coformer screenings. Virtual screening methods, including the conductor-like screening model for realistic solvents (COSMO-RS) and molecular complementary (MC) analysis, were employed to predict the binding affinity between SHR0302 and selected coformers. The developed screening method was capable of reducing the screening database to 30 coformers from a total of 42 proposed coformers. The proof-of-concept experimental screening study was performed to demonstrate the efficiency of computational screening, wherein three new multicomponent crystalline forms were found and fully characterized by powder X-ray diffraction, thermal analysis, and IR and 1H-NMR spectroscopy. Further, the measurements of the solubility property of these new multicomponent crystal forms reveal an apparent promotion compared with the drug alone. Finally, the receiver operator characteristic (ROC) curve was used to assess the prediction performance of the COSMO-RS model. It was found that the established screening model can effectively shorten the experimental screening time and efforts.