Abstract：
3D electron diffraction (3D ED) has shown great potential in crystal structure determination in materials, small organic molecules, and macromolecules. In this work, an automated, low-dose and low-bias 3D ED protocol has been implemented to identify six phases from a multiple-phase melt-crystallisation product of an active pharmaceutical ingredient, griseofulvin (GSF). Batch data collection under low-dose conditions using a widely available commercial software was combined with automated data analysis to collect and process over 230 datasets in three days. Accurate unit cell parameters obtained from 3D ED data allowed direct phase identification of GSF Forms III, I and the known GSF inclusion complex (IC) with polyethylene glycol (PEG) (GSF-PEG IC-I), as well as three minor phases, namely GSF Forms II, V and an elusive new phase, GSF-PEG IC-II. Their structures were then directly determined by 3D ED. Furthermore, we reveal how the stabilities of the two GSF-PEG IC polymorphs are closely related to their crystal structures. These results demonstrate the power of automated 3D ED for accurate phase identification and direct structure determination of complex, beam-sensitive crystallisation products, which is significant for drug development where solid form screening is crucial for the overall efficacy of the drug product.
摘要：
3D电子衍射(3DED)在材料的晶体结构测定中显示出巨大的潜力,有机小分子,和大分子。在这项工作中,一个自动化的，已实施低剂量和低偏置3DED协议，以从活性药物成分的多相熔融结晶产品中识别六个阶段，灰黄霉素（GSF）。使用广泛可用的商业软件在低剂量条件下进行批量数据收集与自动数据分析相结合，以在三天内收集和处理230多个数据集。从3DED数据获得的精确晶胞参数允许GSFFormsIII的直接相位识别，I和已知的GSF包合物（IC）与聚乙二醇（PEG）（GSF-PEGIC-I），以及三个次要阶段，即GSF表格II，V和一个难以捉摸的新阶段，GSF-PEGIC-II。然后通过3DED直接确定它们的结构。此外，我们揭示了两种GSF-PEGIC多晶型物的稳定性与其晶体结构密切相关。这些结果证明了自动3DED的功能，用于精确的相位识别和直接结构确定复杂的，光束敏感结晶产品，这对于药物开发具有重要意义，其中固体形式筛选对于药物产品的整体功效至关重要。
