Université Catholique de Louvain, using crystals to get the right (or left) compound

Our Belgian partners are experts in creating highly interesting enantiopure compounds through a chemical process known as deracemisation. If you want to know more details, keep reading.

Some chemical compounds are like the hands in our body: they have the same form and structure, but you can’t overlap them. In chemistry, we call this chirality. Obtaining only one of these ‘chemical hands’ through synthesis, can be achieved in a chemical process known as deracemisation. And as you will discover below, it’s key to ensure the safety of some pharmaceuticals. The Université Catholique de Louvain (UCLouvain), in Belgium, helps with this task as they focus on chirality control. Our partner’s field of work is chiral systems, especially at the solid state. So, one of their duties focus on the formation of enantiopure compounds — just left or right hands. Let’s discover more about them!

UCLouvain primarily focuses on studying the solid state of compounds, specifically how it can be modified to improve properties such as solubility or stability. In the context of that work, they do chiral control, which involves the selective preparation of left-handed and right-handed enantiomers.

But why is this important? Typically, a chemical compound contains both hands, forming a racemic mixture. However, because they are mirror images of each other, they can behave quite differently. A well-known (and tragic) example of this is the thalidomide case. This drug was marketed in the late 1950s for various uses, including the management of nausea, something highly sought after by pregnant women. The problem was that the two enantiomers of this drug mixture had drastically different effects: one was safe for them, while the other caused severe foetal malformations.

Pack of thalidomide tablets
Thalidomide use by pregnant women has been linked to severe foetal malformations. (Credit: Stephencdickson)

Other examples here are the anti-inflammatory and painkillers naproxen and ibuprofen. In the case of naproxen, one hand produces the desired effects, while the other is toxic to the liver, so it must be removed from the final formulation to avoid poisoning the consumers. The case of ibuprofen is a little bit more harmless: one enantiomer acts as a painkiller, while the other does absolutely nothing. Therefore, the ibuprofen pills we buy actually contain both enantiomers as separating them involves an additional chemical step, which, of course, costs money.

Our researchers from UCLouvain are part of work package 2 (WP2) as they apply their expertise to contribute to the development of our various active pharmaceutical ingredients and key intermediates. Their WP colleagues often synthesise racemic mixtures of compounds because it is, in some ways, easier. The UCLouvain team’s is taking this mixture and getting a single enantiomer compound. They do that through deracemisation, which means converting one enantiomer into the other, so we don’t waste any.

To deracemize using mechanochemistry, you need the two enantiomers to form separate crystals. But this case —the two enantiomers forming separate crystals— is the exception rather than the rule. It only happens in about 10% of compounds. Luckily there’s a way to work around it.

The trick to achieve enantiopure compounds lies in finding another substance that would associate with each hand and force them into separate crystals. The joint association of two compounds is called a co-crystal. The other molecule can often be something as simple as caffeine or sugar, although calling it ‘simple’ should be taken with caution. It is important to highlight that, in IMPACTIVE, we are working on medicines, so the molecules we choose to achieve enantiopure compounds must be safe for us. This, somewhat, limits our partner’s search. Even so, our researchers must carry out a tedious screening process from a list of about 100 molecules known to work for this purpose. Science is sometimes about trial and error.

We could also say that UCLouvain acts as a bridge between WP2 and WP3, the latter focusing on the development of multicomponent systems such as co-crystals and salts. The two fields of chemical synthesis and solid-state research, particularly regarding the crystalline structure of the final compounds, may sometimes diverge in their objectives. UCLouvain facilitates the workflow between these two WPs, as they are, in a way, positioned between both worlds.

So now you know a bit more about who we are! If you want to know more details about our work (or get in touch with any of our partners!), send us an e-mail! We’ll be delighted to talk with you.