Shake it up: A greener method for upset tummy medicine.

André, V, A Hardeman, I Halasz, RS Stein, GJ Jackson, DG Reid, MJ Duer, C Curfs, MT Duarte and T Friščić. 2011. Mechanosynthesis of the metallodrug bismuth subsalicylate from Bi2O3 and structure of bismuth salicylate without auxiliary organic ligands. Angewandte Chemie International Edition http://dx.doi.org/10.1002/anie.201103171.

Synopsis by: Audrey Moores and Wendy Hessler, Dec 15, 2011

This sounds like a kitchen recipe: mix A with B, add a few drops of water, a pinch of salt and then shake. Except, researchers followed these simple directions in a laboratory to make the main ingredient in the popular stomach and intestinal remedy sold under the brand name Pepto-Bismol.

To make the drug this new way, they mixed the two main dry ingredients then added the rest and vigorously shook the paste in a special shaker. The breakthrough – an important step forward in the emerging field of mechanochemistry – uses less energy and solvent than the current way the drug is produced. And it creates no harmful by-products.

This discovery is showing that using simpler chemistry methods can improve processes as complex as drug synthesis and also aids understanding of how drugs work.

 

Context

The image of chemistry is intimately linked with the idea of mixing together liquids. But a new field of chemistry – namely mechanochemistry – proposes to make molecules by mixing solids without adding copious amounts of liquid solvents.

In mechanochemistry, the reagents are loaded into a small cylinder with two metal or ceramic balls. This cylinder is shaken very fast to allow proper mixing. The advantages of this technique are multiple. The products are collected pure, the reactions proceed faster than in solution, and less energy is required to perform the mixing compared to what is needed to heat large amount of solvents.

Variations of this method include addition of a few drops of solvent or a very small amount of salts. This permits the use of slower shaking, thus reducing energy use even more.

Pepto-Bismol is a popular stomach and intestinal relief medication. It is composed of a metal called bismuth and aspirine. To be active, bismuth and aspirine have to form chemical bonds together.

Currently, the drug is made by mixing water solutions of these two ingredients. After reacting, the excess water is removed, which costs energy, time and money. Previous efforts to find simpler, less wasteful, mechanical ways to manufacture the compounds have failed.

This bismuth-aspirin drug has been used for more than a century, yet chemists do not know exactly what its chemical structure looks like when the active ingredients combine. This has limited understanding of how the drug functions in the stomach.

 

What did they do?

A group of researchers from Cambridge, United Kingdom, wanted to improve the existing synthesis of a pharmaceutical group of compounds called bismuth salicylates. The most well-known variety is bismuth subsalicylate, the active ingredient in Pepto-Bismol, an over-the-counter medicine used to treat nausea, heartburn, diarrhea and other stomach and intestinal symptoms.

They were looking for a way to make the desired bismuth subsalicylate using a method that was more energy efficient, faster, yielded fewer harmful byproducts and used less solvent than the current way to make the drug.

Instead of first dissolving the two key ingredients – bismuth oxide and aspirine – in liquid solvents and then mixing the two fluids together, the researchers chose a simpler method. They mixed the dry powders in a mechanochemical mill.

It was not the first attempt to produce this drug in such a simple fashion, but past trials were met with little success. This time, the research group added a few drops of water and a pinch of salt. During ingredient shaking, the presence of the water and the salt enabled the formation of the drug in very high yields.

They tested different ratios of bismuth oxide and aspirine, different volumes of water and a variety of salts. After each attempt, they identified the products produced during the reaction.

 

What did they find?

The researchers first added a few drops of water to the bismuth oxide and aspirine powders. This helped the reaction and products did form, but none were the active ingredient bismuth subsalicylate they were looking for.

They redid the experiment adding a little bit of salt with the water to the powders. A series of different salts were tested. They discovered that potassium nitrate and ammonium nitrate were very efficient in promoting the reaction and afforded the desired drug in high yields.

The reason why the addition of water and salt is required is not completely understood, but the researchers believe that it helps the molecules organize and “find their place” in the final molecular architecture.

 

What does it mean?

By testing a new method of mixing ingredients, this group of chemists was able to produce a commercially important drug using less energy and solvent. They also are the first to identify the chemical structure of a compound similar to bismuth subsalicylate.

The discovery of this new synthetic method is important because it opens the way toward more energy efficient and less polluting drug fabrication. The chemists only had to mix two essential ingredients with tiny amounts of water and nitrate salts – less than 5 percent. Interestingly, these salts do not seem to mix with the final product, which allows for easy separation in the end. Also, this new process generates only water as a by-product. It is thus compatible with drug synthesis.

The secondary discovery of the compound’s chemical structure may seem surprising. Although it has been known for more than a century that the ingredient in Pepto-Bismol is active, the actual way it works is still unclear. In fact, no chemist had isolated and identified the three-dimension chemical structure of any bismuth salicylates. It is a little bit as if engineers were trying to understand the way an engine works without having the knowledge of the shape of its mechanical pieces.

In this study, the researchers were able to decipher the structure of a compound very close to the ingredient bismuth subsalicylate found in over-the-counter medicine. This is a vital step towards understanding the biological activity of this much-used drug. This discovery was possible because the method afforded an unusually pure product, another common advantage of mechanochemistry.

The use of mechanochemistry at a production scale has been demonstrated, for example, on the synthesis of an anti-inflammatory drug/carrier composite. This new discovery may thus lead to a more optimal production of Pepto-Bismol and other medicines. Read more science at Environmental Health News.