You wake up with a burning sensation fluttering in your stomach. Just today, with a full schedule of meetings and activities… so you decide to reach into your first aid kit and take an omeprazole. Quick and easy, isn’t it? But let me tell you something: behind that little capsule there are at least 10 different solvents involved.
Methanol, ethanol, ethyl acetate and acetonitrile are an important part of drug synthesis. Dichloromethane and hexane are often used for purification, while glycerol or polyethylene glycol stabilise the drug inside the capsule. Ethanol or isopropanol ensure that the drug is not degraded prematurely and is administered effectively. And what about the packaging? Of course, to manufacture the plastic pellicles and blisters in which the pills come in, we will need toluene or ethyl acetate.
It may not sound impressive, but we are talking about a single capsule: global consumption of omeprazole in 2023 was estimated in 38,000 tonnes. And that’s from just one active ingredient: think about all the many medicines available today. Moreover, you should bear in mind that the pharmaceutical industry uses solvents in many of its products administered both orally and topically, and especially when they are injectables.
From household to factories
The magnitude of omeprazole use can certainly help us understand the importance of solvents in the medicines we take. But the scope of solvents in our lives is much wider: they are also in the cosmetics and make-up, the paint on our living room wall, our favourite perfume, the clothes we wear and an unimaginable number of other products.
We ourselves make solvents in our daily lives, for instance when we prepare coffee or tea in the morning. To do that, we use water, which is commonly considered the “universal solvent”. Water is in almost every product in our homes and in almost every food we eat. Beyond water, there are many other solvents, some of which are well known, such as acetone and hexane. If they are important in a domestic environment, they become indispensable in industry.
Solvents such as hexane are widely used in cleaning and degreasing processes, while toluene is employed in the manufacture of cleaning products and in the pharmaceutical industry. Oh, and it is one of the components used to make explosives. The best known use of acetone is as a nail polish remover, although it is also very useful in chemical laboratories and is often an ingredient in paints. Chlorinated compounds have a large range of uses, although their use is increasingly restricted because of their toxicity. Alcohols play an important role in the production of cosmetics and perfumes, and then there is benzene, which is better known for its toxicity than for its uses. In a nutshell: solvents are always present in products around us.
Present as pollutants as well
When we say that solvents are everywhere, we are not only referring to their involvement in make-up, clothes or paint: they are also found in nature, and some of them are truly toxic and polluting.
Volatile organic compounds (VOCs) evaporate at room temperature, which means they are present in the air we breathe. And as our atmosphere is in constant motion, VOCs can travel long distances, which means that no one is exempt from breathing these gases. Solvents are found on land, at sea and in the air, as they also have the ability to leach into groundwater.
One aspect that several solvents share is that they can accumulate in living organisms: they have a direct action on flora and fauna, and end up affecting the whole food chain. In this way, they can reach us through our menus: this is the case of certain chlorinated compounds such as dichloromethane, chloroform or trichloroethylene, which, in addition to being persistent, are harmful to our health and the environment.
Another major problem is waste management: in the pharmaceutical industry, solvents are constantly used in all kinds of processes, such as compound purification and organic synthesis. On the way to the final product, a huge amount of waste is generated, and almost all of it (around 80-90% according to a series of studies), consists of solvents.
This high percentage makes us even more aware of our current dependence on these substances for the production of medicines and for the chemical industry in general.
Fortunately, there are currently several techniques that help us to recycle a large proportion of this waste: distillation, filtration and the use of adsorbent materials such as activated carbon are just a few examples. And, to a greater or lesser extent, they allow us to recover some of the original substance.
Another option when recycling is difficult is incineration, commonly referred as controlled burning in the industry, which allows us to eliminate toxic compounds while producing energy in the form of heat. This energy, in turn, can be used to generate electricity. But, as always, there is a downside: the incineration process also releases greenhouse gases, which contribute to global warming and, of course, are toxic when inhaled.
A long journey through regulation
To understand the restricted use of solvents today, we need to think about the history of how their toxicity was discovered. To do this, let us travel back to England in 1825, where a scientist who would go down in history, Michael Faraday, discovered and identified a substance called benzene.
In the 20th century, Kathleen Lonsdale, a true pioneer of chemistry and X-ray crystallography, was able to demonstrate the curious structure of this substance by analysing hexamethylbenzene, one of its derivatives. Lonsdale’s groundbreaking work was crucial to understanding the symmetry and flat nature of benzene’s aromatic rings.
Benzene became an essential substance for industry during the 19th century. It was used for absolutely everything and was applied to all kinds of products, including some intended for human consumption. But the workers who handled or were exposed to this solvent soon began to develop various health problems: all of them suffered from severe headaches and dizziness.
At first, it was not easy to see the connection: after all, you could be exposed to any number of substances in a factory. But the toxicity of benzene became clearer around the turn of the century, when workers began to develop very serious illnesses, including a rare type of anaemia.
After many studies, a direct link between benzene and aplastic anaemia was finally established in the 1970s. Seven years later, the substance was classified as a human carcinogen, and regulations restricting its use followed in the United States and the European Union. It took more than a century to find out what was going on, but the benzene case certainly set a precedent for regulations and legislation on the use of solvents and safe exposure limits for these substances.
Many solvents are currently regulated by the European Chemicals Agency (ECHA) an organisation that focuses on identifying hazardous substances and establishing regulations and restrictions by analysing the risks and use requirements of each individual compound.
Some of these include chlorinated solvents, such as trichloroethylene, perchloroethylene or dichloromethane, which was also recently strongly regulated in the United States in May 2024. These solvents, while very useful, cause serious health problems– all of them are considered possible carcinogens. One of the aims of these regulatory restrictions is to ensure that safe exposure limits are set for workers and that the use of these solvents is not mandated unless it is the only viable option.
Isn’t it paradoxical? In order to develop and produce medicines that heal us, we have to use substances that are harmful.
So, what should we do now?
We still need medicines. Our life expectancy is increasing, and diseases such as diabetes and hypertension affect a large and growing proportion of the world’s population. On the other hand, we cannot continue at the current rate of production in pharmaceutical industry using toxic and polluting substances.
For years now, scientific research into finding green alternatives to solvents has increased significantly, and many resources are being devoted to this. We are undoubtedly at the dawn of a new chemistry, but we have the same old problems: how do we make it economically viable?
At IMPACTIVE, it is clear to us that it is not enough for a technique to be greener: it has to fit the realities of industry. Our goal is to take solvents out of the equation by replacing their use with mechanochemistry, where we employ physical force and mechanical energy to carry out all the steps involved in drug development. And we are getting there!
This year, our researchers achieved the first mechanochemical synthesis of paracetamol, a drug that needs no introduction. To do so, they used a very simple but effective technology: bead milling. Not only did they succeed in synthesising the drug in a more eco-friendly way, but the results were even better than if they had used the more traditional solvent-based technique.
For now, we are taking it one step at a time, and while what we are achieving is certainly important, we still face many challenges, such as scalability: as I said at the beginning, we are not just talking about one omeprazole pill, but hundreds of thousands of drugs and medicines.
We need to be able to transform the industry to respond to a new global landscape, where environmental concerns are urgent, but we also need to be able to meet current health demands.