Jeziorna Agata, Malinska Maura, Sugden Isaac, Paluch Piotr, Dolot Rafał, Dudek Marta K
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, Lodz 90-363, Poland.
Faculty of Chemistry, University of Warsaw, Pasteura 1, Warsaw, Poland.
IUCrJ. 2025 Jan 1;12(Pt 1):109-122. doi: 10.1107/S2052252524011898.
Crystal structure determination is a crucial aspect of almost every branch of the chemical sciences, bringing us closer to understanding crystallization, polymorphism, phase transitions, and the relationship between a structure and its physicochemical and functional properties. Unfortunately, many molecules notoriously crystallize as microcrystalline powders, providing a significant challenge in establishing their structures. In this work, we describe the crystal structure determination of three elusive polymorphs of the anti-inflammatory drug meloxicam (MLX) using three approaches, of which only one was successful for each crystal phase. Single-crystal X-ray diffraction allowed us to solve the structure of MLX-III, MLX-II was solved by a combination of NMR crystallography and crystal structure prediction (CSP) calculations, and MLX-V (Z' = 4 polymorph) was only solvable using electron diffraction. By considering the factors influencing the choice of crystal structure determination method, we showcase their strengths and weaknesses as an indication of their applicability. Additionally, we discuss the issues encountered in the CSP search for MLX-II and MLX-III (both Z' = 2 polymorphs) which turned out to be computationally elusive, in addition to being so in crystallization experiments. This indicates a complex crystal energy landscape for MLX and hints at more general challenges in CSP.
晶体结构测定是化学科学几乎每个分支的关键方面，使我们更接近理解结晶、多晶型性、相变以及结构与其物理化学和功能性质之间的关系。不幸的是，许多分子 notoriously 以微晶粉末形式结晶，这在确定其结构方面带来了重大挑战。在这项工作中，我们描述了使用三种方法对抗炎药物美洛昔康（MLX）的三种难以捉摸的多晶型物进行晶体结构测定，其中每个晶相只有一种方法成功。单晶X射线衍射使我们能够解析MLX-III的结构，MLX-II通过核磁共振晶体学和晶体结构预测（CSP）计算相结合的方法解析，而MLX-V（Z' = 4多晶型物）仅使用电子衍射才可解析。通过考虑影响晶体结构测定方法选择的因素，我们展示了它们的优缺点，以表明其适用性。此外，我们讨论了在CSP搜索MLX-II和MLX-III（两者均为Z' = 2多晶型物）过程中遇到的问题，这些问题在结晶实验中也难以解决，结果证明在计算上也难以捉摸。这表明MLX具有复杂的晶体能量景观，并暗示了CSP中更普遍的挑战。
