School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin University, Weijin Road, Tianjin 300072, People's Republic of China.
IUCrJ. 2023 Mar 1;10(Pt 2):164-176. doi: 10.1107/S2052252523000118.
Multicomponent crystals of a chiral drug with non-chiral components have attracted increasing attention in the application of enantiomer purification and regulation of the physicochemical properties of crystalline materials. Crystalline solid solutions provide opportunities for fine-tuning material properties because of continuously adjustable component stoichiometry ratios. The synthesis, crystal structure, thermodynamics and solid-state enantioselectivity of a series of multicomponent crystals of chiral dihydromyricetin (DMY) with caffeine (CAF) or theophylline (THE) were investigated and the results reveal how the subtle change of molecular structure of the coformer dictates the enantiomer selectivity in multicomponent cocrystals. A series of multicomponent cocrystal solvates of chiral DMY with CAF and THE were synthesized by the slurry cocrystallization method in acetonitrile. Although most racemic mixtures crystallize as racemic compounds or conglomerates, both DMY-CAF and DMY-THE crystallize as chiral solid solutions, unveiled by pseudo-binary melt phase diagrams and pseudo-ternary solution phase diagrams. Crystal structures of Rac-DMY-CAF, R,R-DMY-CAF, Rac-DMY-THE and R,R-DMY-THE are reported for the first time via single-crystal X-ray diffraction, displaying two distinct types of solid solution differing in mixing scale of enantiomers spanning several orders of magnitude. Surprisingly, this remarkable impact on enantiomer discrimination was simply achieved by the reduction of a methyl group of CAF to the THE coformer, which was further rationalized from their crystal structures and intermolecular interactions. Collectively, this work has demonstrated that a subtle change in the molecular structure of a coformer can regulate enantioselectivity in crystalline materials, guiding the purification of chiral racemic compounds via the cocrystallization method and the design of solid-solution crystalline materials.
手性药物与非手性成分的多组分晶体在对映体纯 化和调控晶体材料物理化学性质的应用中引起了越来越多的关注。由于组分化学计量比可连续可调，晶态固溶体为精细调控材料性质提供了机会。本研究考察了一系列手性二氢杨梅素（DMY）与咖啡因（CAF）或茶碱（THE）的多组分晶体的合成、晶体结构、热力学和固态对映体选择性，结果揭示了共晶形成分子结构的细微变化如何决定多组分共晶中的对映体选择性。通过在乙腈中的悬浮共结晶法合成了一系列手性 DMY 与 CAF 和 THE 的多组分共晶溶剂化物。尽管大多数外消旋混合物结晶为外消旋化合物或外消旋聚集体，但 DMY-CAF 和 DMY-THE 均结晶为手性固溶体，这通过假二元熔融相图和假三元溶液相图得以揭示。首次通过单晶 X 射线衍射报道了 Rac-DMY-CAF、R,R-DMY-CAF、Rac-DMY-THE 和 R,R-DMY-THE 的晶体结构，显示了两种不同类型的固溶体，其对映体混合尺度跨越几个数量级。令人惊讶的是，这种对映体选择性的显著影响仅通过将 CAF 的一个甲基还原为 THE 共晶形成剂来实现，这从它们的晶体结构和分子间相互作用中得到了进一步的解释。总之，这项工作表明，共晶形成剂分子结构的细微变化可以调节晶体材料的对映体选择性，通过共结晶法指导手性外消旋化合物的纯化和固溶体晶体材料的设计。
