Abstract：
Single-crystal X-ray diffraction analysis of small molecule active pharmaceutical ingredients is a key technique in the confirmation of molecular connectivity, including absolute stereochemistry, as well as the solid-state form. However, accessing single crystals suitable for X-ray diffraction analysis of an active pharmaceutical ingredient can be experimentally laborious, especially considering the potential for multiple solid-state forms (solvates, hydrates and polymorphs). In recent years, methods for the exploration of experimental crystallization space of small molecules have undergone a `step-change\', resulting in new high-throughput techniques becoming available. Here, the application of high-throughput encapsulated nanodroplet crystallization to a series of six dihydropyridines, calcium channel blockers used in the treatment of hypertension related diseases, is described. This approach allowed 288 individual crystallization experiments to be performed in parallel on each molecule, resulting in rapid access to crystals and subsequent crystal structures for all six dihydropyridines, as well as revealing a new solvate polymorph of nifedipine (1,4-dioxane solvate) and the first known solvate of nimodipine (DMSO solvate). This work further demonstrates the power of modern high-throughput crystallization methods in the exploration of the solid-state landscape of active pharmaceutical ingredients to facilitate crystal form discovery and structural analysis by single-crystal X-ray diffraction.
摘要：
小分子活性药物成分的单晶X射线衍射分析是确认分子连通性的关键技术,包括绝对立体化学，以及固态形式。然而,获得适用于活性药物成分的X射线衍射分析的单晶可能是实验上费力的，特别是考虑到多种固态形式(溶剂化物，水合物和多晶型物）。近年来,探索小分子实验结晶空间的方法经历了“阶跃变化”，导致新的高通量技术变得可用。这里,高通量包封纳米液滴结晶在一系列六种二氢吡啶中的应用，钙通道阻滞剂用于治疗高血压相关疾病，被描述。这种方法允许对每个分子平行进行288个单独的结晶实验，导致快速获得所有六种二氢吡啶的晶体和随后的晶体结构，以及揭示了硝苯地平的新溶剂化物多晶型物（1,4-二恶烷溶剂化物）和第一个已知的尼莫地平溶剂化物（DMSO溶剂化物）。这项工作进一步证明了现代高通量结晶方法在探索活性药物成分的固态景观中的力量，以促进通过单晶X射线衍射进行晶型发现和结构分析。
