Structure determination of pharmaceutical compounds is invaluable for drug development but remains challenging for those that form as small crystals with defects. Bismuth subsalicylate, among the most commercially significant bismuth compounds, is an active ingredient in over-the-counter medications such as Pepto-Bismol, used to treat dyspepsia and H. pylori infections. Despite its century-long history, the structure of bismuth subsalicylate is still under debate. Here we show that advanced electron microscopy techniques, namely three-dimensional electron diffraction and scanning transmission electron microscopy, can give insight into the structure of active pharmaceutical ingredients that are difficult to characterize using conventional methods due to their small size or intricate structural features. Hierarchical clustering analysis of three-dimensional electron diffraction data from ordered crystals of bismuth subsalicylate revealed a layered structure. A detailed investigation using high-resolution scanning transmission electron microscopy showed variations in the stacking of layers, the presence of which has likely hindered structure solution by other means. Together, these modern electron crystallography techniques provide a toolbox for structure determination of active pharmaceutical ingredients and drug discovery, demonstrated by this study of bismuth subsalicylate.

Structure determination of pharmaceutical compounds is invaluable for drug development but is challenging for those that form as small crystals with defects. Bismuth subsalicylate (BSS), among the most commercially significant bismuth compounds, is an active ingredient in over-the-counter medications such as Pepto-Bismol, used to treat dyspepsia and H. pylori infections. Despite its century-long history, the structure has remained unknown. Three-dimensional electron diffraction and hierarchical clustering analysis were applied on select data from ordered crystals, revealing a layered structure. In other less ordered crystals, high-resolution scanning transmission electron microscopy revealed variations in the stacking of layers. Together, these modern electron crystallography techniques provide a new toolbox for structure determination of active pharmaceutical ingredients and drug discovery, demonstrated by this study of BSS.

Structure determination of pharmaceutical compounds is invaluable for drug development but is challenging for materials that form as small crystals with defects. Bismuth subsalicylate (BSS), among the most commercially significant bismuth compounds, is an active ingredient in over-the-counter medications such as Pepto-Bismol (genericized trademark), used to treat dyspepsia and H. pylori infections. Despite its century-long history, the structure has remained unknown. Three-dimensional electron diffraction and hierarchical clustering analysis were applied on select data from ordered crystals, revealing a layered structure. In less ordered crystals high-resolution scanning transmission electron microscopy revealed various disorders, including variations in the stacking of layers. These modern electron crystallography techniques provide insight into differences in BSS crystals and the possibility to develop new analogs or polymorphs.

Structure determination of pharmaceutical compounds is invaluable for drug development but is challenging for materials that form as small crystals with defects. Bismuth subsalicylate (BSS), among the most commercially significant bismuth compounds, is an active ingredient in over-the-counter medications such as Pepto-Bismol (genericized trademark), used to treat dyspepsia and H. pylori infections. Despite its century-long history, the structure has remained unknown. Three-dimensional electron diffraction and hierarchical clustering analysis were applied on select data from ordered crystals, revealing a layered structure. In less ordered crystals high-resolution scanning transmission electron microscopy revealed various disorders, including variations in the stacking of layers. These modern electron crystallography techniques provide insight into differences in BSS crystals and the possibility to develop new analogs or polymorphs.The physical, chemical and therapeutic properties of active pharmaceutical ingredients (APIs) are governed by their molecular structures and intermolecular interactions. Many APIs are crystalline substances, having periodic arrangements of their constituent molecules or ions. The specific arrangement of molecules in an API and their intermolecular interactions affect its stability and solubility, which in turn influences bioavailability, efficacy, and dosage. Therefore, determining the structures of pharmaceutical compounds is an integral part of drug formulation. Traditionally the method of choice for crystal structure determination has been single-crystal X-ray diffraction (SCXRD). However, the technique requires large specimens and is not readily applicable for sub-micrometer crystals. While structure determination of small crystallites can often be performed by powder X-ray diffraction (PXRD), the technique can at times struggle with complicated and disordered structures.

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