Our team at Radboud University, Nijmegen (the Netherlands), co-leads the batch and continuous processing alongside the University of Montpellier, in France. Together, they play a pivotal role in IMPACTIVE’s production line, focusing their efforts on finding new ways to synthesise compounds without using solvents.
This team excels in organic synthesis, crafting small and complex molecules. On the one hand, they focus on creating biologically active molecules and exploring ways to enhance their biological activity. On the other hand, they are deeply committed to advancing sustainable chemical methodologies. A major area of their research was in continuous-flow chemistry, regarded as more sustainable than traditional batch processes. Currently, their focus is more on pioneering efforts to eliminate solvents from reactions—that’s mechanochemistry! —, further aligning with the goal of promoting greener, more sustainable chemical processes.
At IMPACTIVE, we have a diverse array of target compounds. This means exploring various types of reactions required to synthesise them. To streamline our efforts, we have divided responsibilities, with Radboud University focusing on certain reactions and Montpellier handling others. This is not just about task allocation; it’s more of a complementary approach. We ensure that we are not duplicating efforts and that everyone focuses on the reactions in which they have the most expertise. This also accounts for the differences in equipment available at each laboratory. However, that doesn’t mean both teams work independently—quite the opposite! In fact, two weeks ago, a member of the Radboud team visited Montpellier to observe how certain reactions perform on different mechanochemical equipment.
From the classical solution-based process for making a compound, our partners consider how to adapt this into a method that no longer relies on solvents. ‘Can we achieve this transformation with the same reagents?’ or ‘Do we perhaps need a different reaction?’ are among the questions they ask themselves.
But if a reaction is already tricky in solution, removing solvents makes it even more challenging. Experimental conditions often need fine-tuning, sometimes requiring a different reagent or even a small amount of solvent to help the reaction along, a method known as liquid-assisted grinding. There are also some restrictions: one of the Active Pharmaceutical Ingredients (APIs) we’re targeting requires a reagent in its classical synthesis that is potentially explosive—in fact, it’s used in airbags. Using a substance that can explode in ball mills is a recipe for disaster!
The synthesis of the API of medications often involves three, four, five, or even six synthetic steps. The original idea behind IMPACTIVE was to replace at least one of those steps with a mechanochemical method. However, we all set ourselves a more challenging goal: to synthesise these APIs without using solvents at any stage. So far, Radboud’s greatest contribution has been successfully achieving this, developing APIs from start to finish only through mechanochemical synthesis.
By conducting numerous new reactions and optimising the process, our team at Radboud University typically achieves the same level of efficiency as traditional methods, if not better, and in a much greener way! However, since this is lab-scale synthesis, our colleagues at Radboud University typically work on a scale of grams. The goal is to eventually produce these compounds in kilograms, or even hundreds of kilograms.
In IMPACTIVE, we have an entire work package dedicated to exploring how to scale up our compounds. Even at these early stages, while working at such a small scale, we contribute to this scaling-up effort. This includes considerations like the cost of reagents and the overall feasibility of the processes. For instance, if a reaction is very clean, it becomes significantly more attractive for scaling up compared to one that generates side products requiring purification.
Radboud’s work extends beyond compound synthesis. This partner has another task within the IMPACTIVE project. Some compounds are like the two hands of the body: similar yet slightly different, and you can’t overlap them. In chemistry, we call this property chirality. Transforming a mixture of these ‘chemical hands’ into a sample that contains just one of them is a chemical process known as deracemization. This duty falls to Radboud University, along with our partner at the UCLouvain in Belgium. You can read our previous blogpost about this technique here.
In a nutshell, Radboud University plays a key role in avoiding the use of solvents in the synthesis of our compounds by adapting traditional processes to mechanochemical methods.
