Structure of Pepto-Bismol active ingredient solved

People have taken bismuth subsalicylate to treat upset stomachs and nausea for more than a century. The compound is the active ingredient in the bright pink concoction sold as Pepto-Bismol. Despite that long history of use, bismuth subsalicylate’s structure has remained a mystery—one that researchers have now solved.

A. Ken Inge, Tom Willhammar, and coworkers at Stockholm University used a combination of electron diffraction and electron microscopy to solve the structure (Nat. Commun. 2022, DOI: 10.1038/s41467-022-29566-0). They found that the compound has a layered structure with variations in the stacking. The heterogeneity caused by the variations helps explain why the structure has been so hard to pin down.

The degree of disorder in the structures differed depending on the source of the bismuth subsalicylate. Compounds filtered out of Pepto-Bismol were too disordered to get a clear structure. But the researchers could obtain a structure by electron diffraction using material purchased from Sigma-Aldrich.

When the chemists analyzed the material with scanning transmission electron microscopy, they could finally see the packing of the subunits in the layers. “Although we found pretty large ordered domains, we also saw domains of the crystal where we had imperfections in the ordering,” Willhammar says. “We could see that this was the source of why it was so challenging to determine the structure originally.”

The new structure shows that O²⁻ anions bridge Bi³⁺ cations in a rodlike structure. Along the structure, the O²⁻ anions alternatingly connect three and four Bi³⁺ cations. Some of the salicylate anions coordinate to Bi³⁺ through only their carboxylate group; others coordinate to Bi³⁺ through both the carboxylate and phenolic groups.

“The results can potentially shed some new light on the mechanism of action of [bismuth subsalicylate],” says Andrea M. Goforth, who studies bismuth nanoparticles at Portland State University. “Since the structure is now known, we can see how the hydrophilic and hydrophobic parts spatially distribute and have a better picture of the intermolecular forces and structural disorder.” The intermolecular forces can affect properties such as solubility and bioavailability, she says.

The Stockholm team plans to dig deeper into the structure of bismuth subsalicylate. “I’m curious, if you have more disorder, how that affects the physical properties of the material,” Inge says. In addition, the researchers plan to use their methods to determine the structures of other bismuth-based drugs whose structures aren’t yet known.