In continuous flow

The research carried out at CiTOS over the last ten years all has one thing in common: new micro/mesofluidic process technologies. These make it possible to maintain chemical reactions in a continuous flow.

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he CITOS (Center for Integrated Technology and Organic Synthesis) laboratory at ULiège, headed by Professor Jean-Christophe Monbaliu, is first and foremost a synthetic organic chemistry laboratory. By definition, its work focuses on carbon derivatives, like thousands of others worldwide. However, the multidisciplinary and technological approach it uses sets it apart. When we think of chemistry, images of retorts and other balloons, or even big bubbling vats in factory halls come to mind. This chemistry of large reactors has worked perfectly well for decades. But not without its drawbacks. And these drawbacks have become increasingly apparent in recent years.

The first of these," sums up Jean-Christophe Monbaliu, "is the lack of flexibility and adaptability of these global, centralised, mass-production approaches to major variations in demand. This was cruelly demonstrated during the Covid period we have just experienced. The production of medicines in Europe is, for the most part, dependent on primary components and intermediaries from Asia. When factories there began to close, shortages became a reality throughout the manufacturing chain. This is mainly because chemical production for organic compounds, such as pharmaceuticals, is generally a step-by-step process: for example, a component is purified first, then, when there is sufficient stock, the next step is taken, and so on. We work on large volumes, but discontinuously. If a problem arises, it has repercussions for the whole chain. Hence the stock-outs and other supply problems, although this is not the only factor responsible.

Environmental and safety aspects pose another problem. The larger the scale of production, the greater the impact in the event of a disaster. This explains the relocation phenomenon that has taken place in Europe. Legislation there imposes very strict environmental and safety constraints. Europe has therefore positioned itself as the end user of components produced elsewhere, and is often only involved in the final stages of the value chain. The coronavirus has undermined this redistribution," says Professor Monbaliu. The idea of repatriating everything to Europe has resurfaced, but it comes up against European legislative constraints, so it's almost impossible to bring the big reactors back from Asia and start pharmaceutical production here from scratch.

SMALL IS BEAUTIFUL

The difficulties encountered in traditional chemical production have brought another technology to the fore, known as 'micro' or 'mesofluidic'. Briefly, this technology allows chemical reactions to take place not in large macroscopic tanks (reactors) of several hundred or thousands of litres but in a confined volume in the submacroscopic range. Despite the significant size reduction, these fluidic technologies nevertheless enable potentially infinite production because of their continuous nature. The reaction uninterruptedly takes place in a channel that is often submillimetre in size (see photo).

Compared with the traditional macroscopic tank approach, this technique has several advantages, the most obvious of which is size: a conventional fluidic module fits in hand and is transportable, so it is unlikely to cause major damage in the event of an accident. Another advantage of this tiny size is that there is no longer any need to build large factories with an inordinate overall environmental footprint.

But above all, in addition to the fact that production is in continuous flow, there are advantages linked to the specific chemistry features in sub-millimetre channels. The particular fluid dynamics involved mean that mixing is faster and more precise," explains Jean-Christophe Monbaliu. The speed of the reagent mixture and its quality are two essential parameters for guaranteeing the speed of a reaction and helping to ensure high purity by avoiding spurious secondary reactions. This precision and homogeneity can be difficult to achieve in large tanks. We can achieve it with surgical precision. Another advantage is that a chemical reaction must often be heated or maintained at a certain temperature to release excess energy. "These exchanges take place through the reactor wall. In a macroscopic tank reactor, the ratio between the wall's surface area and the volume is not favourable. On the other hand, a fluid reactor has a very large surface area for a very small internal volume. The result is more efficient, faster energy transfer". In short, such reactors enable chemistry to be better controlled and more precise; it can be carried out more quickly and more selectively. This means we can react more quickly to changes in the market and produce more cleanly, with less waste. "An extraordinary tool for synthetic organic chemistry", Jean-Christophe Monbaliu sums up.

MEDICINES FOR MARS

The intrinsic qualities of microfluidic technology open up a wide range of prospects in certain fields, not least the pharmaceutical sector. "Pharmaceuticals... on Earth or elsewhere, in other words in space," says Jean-Christophe Monbaliu, who and his team have just published several papers on the subject. A research project funded by NASA has enabled him to develop a system capable of producing a drug that is on the list of those used for future long-duration space travel. Wouldn't carrying a stock of medicines in the shuttles be simpler? On the face of it, yes, except that modern medicines have a very short shelf life in space, where the intensity of the radiation accelerates their deterioration. But to manufacture them in flight, or on Mars for example, you need to carry reagents (of which there are many if you want a large-scale pharmacy!) and solvents, which also run the risk of degradation and, above all, take up a certain amount of space, a critical shortcoming in space.

It's obvious that on board a shuttle there will never be all the chemicals needed as here on Earth," admits Jean-Christophe Monbaliu. What we have done for NASA is a demonstration of capability: can we produce a drug in a reactor that is small enough and safe enough to be taken on board a shuttle? The answer is yes.

The Citos researchers then embarked on a second part of their work, this time funded by the Food and Drug Administration (FDA), which should provide a partial response to the objections raised earlier. "We are now trying to demonstrate whether it is possible to manufacture medicines solely from biomass sources in the broad sense, not necessarily from land. It could be human waste or plants grown in a Mars station or base, etc.". This research is not only of interest to the space sector, as it is also part of the - very terrestrial! - of the transition from petro-based to bio-based materials. The laboratory's work shows that it is possible to do away with basic components derived from petroleum and replace them with others derived from biomass, including organic waste, to manufacture medicines. 

NEUTRALISING CHEMICAL WEAPONS

Another application, perhaps perceived as more marginal, has been the subject of several publications by the team: the neutralisation of chemical weapons. Unfortunately, this is a very topical subject, given the remnants of past and current conflicts. Because of its history, Belgium is very concerned by one of these weapons, mustard gas. Jean-Christophe Monbaliu explains: "A few hundred metres off the Belgian coast, there is a marine cemetery of munitions dating from the two world wars, lying on a sandbank. Over time, the corrosion of these munitions, many of which still contain mustard, represents a significant risk for the population and the environment. The CiTOS scientists aimed to show that it was possible to destroy this type of chemical threat, even during attempted attacks, for example, simply, economically and safely. Today, when munitions of this type are discovered, once the explosive charge has been defused, they are simply transported to special incinerators for destruction. Microfluidic technology, on the other hand, is mobile and compact, so it can be moved without constraint, simply and efficiently. "We have succeeded in neutralising a mustard model, i.e. chemically destroying its toxicity and transforming it into a non-toxic compound that can then be incinerated in complete safety," says Jean-Christophe Monbaliu with satisfaction.

And this result was achieved thanks to affordable and simple chemistry based on compounds that are abundant on a large scale or even available in supermarkets, without using catalysts that are expensive or complicated to produce as other teams have done! Initial research focused on the use of air and light to neutralise toxicity. "As explained above, energy transfer phenomena passing through the wall of fluidic reactors are much more efficient than in macroscopic reactors. From this point of view, light can also be used very effectively," explains Jean-Christophe Monbaliu. This visible light enables us to transform the oxygen in the ambient air into a highly reactive species, singlet oxygen, which enables very rapid chemical neutralisation of the mustard. What's more, the superior mixing capabilities of these fluidic reactors enable us to mix the air with the liquid medium containing the mustard extremely quickly and efficiently. The result? It only took about four minutes to neutralise the asphyxiating gas completely.

Other research has produced even more spectacular results. This time, a mixture of bleach, ethanol and acetic acid killed the mustard almost instantly. The method was even validated using commercial bleach, vodka and 10% wine vinegar - compounds that can be bought in any local supermarket! This method is currently being validated on other more sinister compounds, particularly organophosphate chemical warfare weapons. The simplicity of this 'new' chemistry, as it might be called, poses a problem: it is highly accessible to people with very bad intentions. We are well aware that we are entering a grey area here," insists Jean-Christophe Monbaliu. If we can make medicines, we can also make drugs; if we can neutralise chemical weapons, we can also produce them. Part of my job is to make the federal authorities aware of the fabulous advantages, but also of the risks of abuse associated with these new technologies.

FLOW4ALL

The CiTOS laboratory is also behind the creation of a fluid technology resources platform (FloW4all). It offers a range of technologies and know-how to a large panel of industrial partners, as well as to top-flight academic research. "Our ambition is to position ULiège as a major player on the international scene in the field of applied organic chemistry and fluid processes," adds Jean-Christophe Monbaliu.