Weatherston Jake, Probert Michael R, Hall Michael J
Chemistry, School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, U.K.
J Am Chem Soc. 2025 Apr 9;147(14):11949-11954. doi: 10.1021/jacs.4c17826. Epub 2025 Mar 25.
Polymorphism, when a substance can exist in more than one crystalline form yet return to the same liquid or solution phase, is characterized by differences in packing or molecular conformation. Polymorphs often exhibit differing physical properties, and are therefore particularly important in the development of materials and pharmaceuticals. However, gaining a thorough understanding of the solid-state landscape of a molecule requires exhaustive experimental screening of crystallization conditions, a particular challenge when using classical crystallization methods. We show that high-throughput Encapsulated Nanodroplet Crystallization (ENaCt) can enable the rapid and efficient exploration of the solid-state landscape of highly polymorphic molecules, through an in-depth study of 5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile (ROY), the most polymorphic small molecule known. An ENaCt screen encompassing 1536 individual crystallization experiments, spanning 320 unique conditions, resulted in direct access to single crystals, suitable for X-ray diffraction analysis, for all six of the known polymorphs accessible from solution (Y, R, YN, ON, ORP and R18). In addition, two polymorphs (Y04 and Y19) previously accessed only via melt and heteroseeded melt experiments, and a new polymorph of ROY (O22) were obtained. Furthermore, ENaCt screening resulted in the identification of the first ROY solvate (ROY· methyl anthranilate) and the first example of a ROY dimer, formed via in situ oxidation. ENaCt is thus shown to be an impactful tool for the experimental mapping of the solid-state landscape of highly polymorphic molecules and, through the discovery of a new polymorph O22, has ensured that tetradecamorphic ROY retains the record for the most polymorphic small molecule.
多晶型现象是指一种物质能够以不止一种晶体形式存在，但又能回到相同的液相或溶液相，其特征在于堆积方式或分子构象的差异。多晶型物通常表现出不同的物理性质，因此在材料和药物开发中尤为重要。然而，要全面了解分子的固态情况，需要对结晶条件进行详尽的实验筛选，这在使用经典结晶方法时是一个特殊的挑战。我们表明，高通量封装纳米滴结晶法（ENaCt）能够通过对5-甲基-2-((2-硝基苯基)氨基)噻吩-3-腈（ROY，已知多晶型最多的小分子）的深入研究，快速有效地探索高度多晶型分子的固态情况。一个涵盖1536个独立结晶实验、跨越320种独特条件的ENaCt筛选，使得能够直接获得适合X射线衍射分析的单晶，这些单晶对应于从溶液中可获得的所有六种已知多晶型物（Y、R、YN、ON、ORP和R18）。此外，还获得了之前仅通过熔体和异质籽熔体实验得到的两种多晶型物（Y04和Y19），以及ROY的一种新多晶型物（O22）。此外，ENaCt筛选还鉴定出了第一个ROY溶剂化物（ROY·邻氨基苯甲酸甲酯）以及通过原位氧化形成的ROY二聚体的首个实例。因此，ENaCt被证明是用于高度多晶型分子固态情况实验测绘的一个有影响力的工具，并且通过发现新的多晶型物O22，确保了具有十四种多晶型的ROY保持着多晶型最多的小分子的记录。
