Structure of the active pharmaceutical ingredient bismuth subsalicylate

Abstract

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.

Ψ-Polyhedral symbols for bismuth(III) with an active electron lone pair

“…As bismuth(III) compounds in the solid state take on different shapes, the coordination number of the metal atom is one parameter for cataloguing their crystal structures. A number of bismuth(III) compounds have been used as medicines (Keogan & Griffith, 2014;Kowalik et al, 2019;Wang et al, 2020;Yang et al, 2015;Sadler et al, 1999) and the crystal structures of Bi III derivatives of familiar drugs have been reported, for example, bismuth subsalicylate (Grape et al, 2021;Thurston et al, 2002), bismuth subgallate (Wang et al, 2017b) and bismuth subcitrate (Li et al, 2003;Yang et al, 2010). The reports generally do not provide more complete details on coordination geometry as studies on bismuth compounds largely focus on medical applications (Bond & Rogers, 2021;Lambert & Midolo, 1997;Li et al, 2019;Salvador et al, 2012;Zhang et al, 2006) and pharmacokinetic mechanisms (Li & Sun, 2012;Sandha et al, 1998).…”