The structure of bismuth subsalicylate, the active ingredient of the stomach relief drug Pepto-Bismol and one of the most commercially important bismuth compounds, has finally been discovered.
Although the substance has been used to treat gastrointestinal disorders for over 120 years, its chemical structure has remained a mystery. “We felt it was important to determine the structure of one of the most iconic bismuth compounds,” says study co-leader Ken Inge of the University of Stockholm in Sweden.
Glen Briand, an inorganic chemist at Mount Allison University in Canada who was not involved in the study, points out that the structures for this type of material are typically determined using X-ray crystallography. “This technique requires the growth of crystals. .. where the molecules in the material group together in an ordered arrangement, “he says. But bismuth subsalicylate forms as very small and disordered crystals that cannot be studied in this way.
Inge and a team of researchers have now used a transmission electron microscope to determine the compound’s structure. They combined 3D electron diffraction (3DED) with scanning transmission electron microscopy (STEM), which allowed them to obtain both a 3D model of the average crystal structure and additional images with atomic resolution. “We could see that the packaging of the molecules was uneven, which is one of the reasons why this structure hasn’t been determined for so long,” explains Inge’s colleague Tom Willhammar.
“For both techniques, it is important to have a sensitive and fast detector, as well as to function quickly, as samples containing organic molecules are typically quickly damaged by the electron beam,” adds Inge. He likens the structure of the compound to an ice cream sandwich. ‘It can be imagined that the bismuth and oxygen ions form the [ice cream] filling and organic salicylate ions into the wafers, ‘he says. «In the crystals, these [sandwiches] stack on top of each other. Some time [they] they are turned upside down when they are messy. ‘
But since the disturbance isn’t everywhere in the crystals, scientists had to zoom in to find it. “In bismuth subsalicylate, the size of the crystals in which the molecules are massed regularly without errors and disorder is limited to a few hundred nanometers”, comments Mauro Gemmi, expert in electronic crystallography at the Italian Institute of Technology. ‘Only a technique capable of capturing information from such small areas as these domains can succeed in determining the structure. This approach does exactly that. ‘
Inge points out that 3DED and STEM have already been used to elucidate other crystal structures and believes the popularity of both techniques will continue to grow. Gemmi agrees. “The possible application of these methods goes far beyond determining the structure of molecules of pharmaceutical interest,” he says. ‘It comes into the picture whenever the crystal size falls below the micron range. I can think of small proteins that are almost impossible to crystallize, or nanocrystals in planetary materials such as meteorites or interplanetary dust. This is the future of crystallography. ‘