Structure of the active pharmaceutical ingredient bismuth subsalicylate

Abstract

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.

Metals to combat antimicrobial resistance

“…Despite being used for gastrointestinal infections since 1900, the structure of bismuth subsalicylate was only identified in 2022 (ref. 160 ). Colloidal bismuth subcitrate was also found to inhibit metallo-β-lactamase enzymes and restore the in vivo efficacy of meropenem 161 .…”

What’s in That Medicine: An Inquiry-Based Activity to Introduce Medicinally Active Natural Products and Metals

“…subsalicylate, has only recently been fully elucidated. 11 Pepto-Bismol has been the topic of other laboratory activities because of its unique and significant metal content. 12 There are some published traditional laboratory activities that address pharmaceuticals, although many are not suitable for high school students due to their need for specialized equipment, 3,13,14 and few address metals in medicine.…”

“…Pepto-Bismol is the most-sold stomach relief remedy in the USA with over 20 million units sold in 2019. Despite such prevalence, the structure of the active ingredient, bismuth subsalicylate, has only recently been fully elucidated . Pepto-Bismol has been the topic of other laboratory activities because of its unique and significant metal content .…”

Bismuth gallate coordination networks inspired by an active pharmaceutical ingredient

“…This is due their tendency to form as nanocrystalline powders rather than large single crystals, which can prevent structure determination through conventional means such as single-crystal X-ray diffraction (SCXRD). 10,11 Knowledge of a material's structure is fundamental for understanding its physical and chemical properties, which can in turn explain their function and behaviour in biological systems or inspire investigations of previously unexplored properties and applications. For example, the structure of CBS crystallized under acidic conditions was revealed to be a metal-organic framework (MOF), 12 a class of porous materials of interest for applications such as separation and heterogeneous catalysis.…”