IMPACTIVE, a project on mechanochemistry and sustainable pharmaceutical production

The search for sustainable chemical processes has always been a challenge, especially in the pharmaceutical manufacturing sector. The complexity of therapeutic drugs and the many steps involved in their production present significant barriers to reducing environmental waste. The review of existing pharmaceutical legislation, presented by the European Commission on 26 April, aims to further mitigate the environmental impact of pharmaceutical production, in line with the goals of the European Green Deal. This, as also expressed in the guidelines established by EMA in this regard, may require changes in drug manufacturing. This is where mechanochemistry comes into play.

Mechanical chemistry is a branch of chemistry based on the principle that molecules react when they collide with each other in the absence of a solvent: unlike traditional chemistry which relies on solutions and various stirring techniques, mechanical chemistry crushes molecules together using tools such as ball mills or extruders. These devices, which are commonly used in industries such as plastics manufacturing, are excellent at grinding, crushing and pressing materials together.

The possibilities of mechanochemistry lie at the heart of IMPACTIVE, a European project funded by the European Commission with €7.7 million through the Horizon programme. Evelina Colacino, Professor of Organic Chemistry and Green Chemistry at the University of Montpellier, France, directs the project: “The application of mechanical chemistry in the manufacture of pharmaceuticals has enormous potential. By exploiting the mechanical force generated by impacts, pressure and friction, some chemical reactions can be facilitated without the need for solvents, which reduces waste and toxicity.In addition, chemical-mechanical methods often require shorter reaction times and exhibit higher yields than traditional solvent-based methods, which contributes to more efficient and cost-effective production.”

in one Stady Published in the journal ACS Sustainable Chemistry and Engineering, which represented the starting point for IMPACTIVE, the research group led by Colacino compared the traditional synthesis method for producing the active ingredient nitrofurantoin (an antibacterial), on a solvent basis, with mechanochemistry by reactive extrusion. The method using solvents was found to produce an amount of 603 kg of carbon dioxide₂ per kilogram of active substance produced. Thanks to the application of mechanical chemistry, this emission has been significantly reduced to only 74 kg of carbon dioxide₂ per kilogram of product. Similar results have been observed for terrestrial environmental toxicity, which includes water, soil and air pollution.

These positive changes were mainly attributed to a significant reduction in the amount of reagents used (the process does not require excess reagents) and the complete removal of solvents. To estimate potential annual greenhouse gas emissions from commercial production of nitrofurantoin, the researchers calculated an impressive reduction of 87 percent if mechanochemistry was used. They also found a significant cost reduction, with annual expenses dropping from $162,000 using the solvent-based method to just $19,000 for mechanochemistry. To broaden the perspective to consider the costs of manufacturing and selling different pharmaceutical products, the implications of this study are profound.

The IMPACTIVE project represents a major collaboration between many European countries, including France, Germany, Italy, the Netherlands, Belgium, Ireland, Estonia, Spain, Portugal, Switzerland and Israel. It includes such prestigious research institutes as BAM in Berlin, the Max Planck Institute in Mülheim and the Interuniversity Consortium for the Development of Large Phase Systems (CSGI), with offices in Cagliari, Florence, Parma and Salerno. “We will apply mechanistic chemistry in the synthesis of six drugs that have already been commercialized, including anti-cancer therapies, diabetes drugs, and anti-hypertensive drugs,” Colacino explains. “The ultimate goal is to develop prototypes that big pharma companies can adopt. We have chosen to develop drug active ingredients (also called key intermediates to get to the final molecules) for which there are development issues in solution. These problems can be of different types, for example chemical, regulatory, safety-related, or related to the very nature of the molecule. If we can reduce the environmental impact or increase the safety of the process by changing the way these particles are made, then there are certainly gains in terms of safety, in terms of time, resource optimization, lower energy costs, and disposal costs, because there is less waste.”

If successful, the project would represent an opportunity to keep production of active ingredients in Europe: “The EU is asking for solutions to ensure that what is currently being made abroad due to cost issues is made in Europe instead. Our project can make a contribution in this sense.”

One of the main goals of the project is to deliver results that can be easily implemented by the pharmaceutical industry. To ensure the scalability and feasibility of project results in an industrial context, two leading European companies, Merck and Novartis, are actively participating in the consortium. “Novartis is a partner in a specific work program for IMPACTIVE, which covers life cycle, safety and risk assessment,” explains Wojciech Nowak, Novartis’ senior director of global public affairs. «This group aims to create ecological medicines, analyzing the entire production cycle, closely monitoring all processes, to take into account the environmental, health and social impacts. Our company has pledged to help by providing support for program metrics. The group’s common goal remains the exchange of information, with the aim of understanding whether technology is a viable option in terms of sustainability. There have been strong and growing expectations in recent months, thanks to the good momentum and high level of energy in the group, combined with the urgent need to rapidly reduce the environmental footprint of our operations, but the group’s current and medium-term effort will form a maximum proof of concept, way more realistic. Only in the event of a positive outcome can one assume a quick and decisive breakthrough in technology. Our experts involved in this program consider mechanochemistry to be a very attractive technology, which can lead to significant improvement in sustainability and CO2 savings₂, especially compared to classical chemistry. At the moment we cannot say more, as we are witnessing and trying to facilitate the first attempts to link academic research and the possibility of a more realistic application of this technology in our complexes ».

Although more research is needed and technical challenges are met, the IMPACTIVE project on mechanochemistry seeks to lay the foundations for a new era of sustainable manufacturing of pharmaceuticals, which can have a significant impact on the sector and meet the goals set by the European Union.