Bismuth gallate coordination networks inspired by an active pharmaceutical ingredient.

The effect of solvent has been investigated for the synthesis of bismuth gallate compounds, of which the water-based bismuth subgallate has been used as an active pharmaceutical ingredient (API) for over a century. Using methanol as a solvent, two new bismuth gallates were acquired: first a flexible 3-periodic metal-organic framework (MOF) forms, which transforms upon extended synthesis times into a layered 2-periodic coordination polymer of the same bismuth-to-gallate ratio. The structures were determined by three-dimensional electron diffraction. Synthesis in ethanol resulted in the formation of the MOF phase, but not the layered phase. The layered material of the methanol-based synthesis was used as a Lewis acid catalyst due to its higher stability, showing a comparatively quick and regiospecific conversion of styrene oxide to 2-methoxy-2-phenylethanol, indicating the presence of open metal sites in the material. The acquisition of bismuth gallate structures of varying periodicity highlights the prospect of acquiring novel MOFs and coordination polymers from the same components of APIs.

Structure of the active pharmaceutical ingredient bismuth subsalicylate.

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.