The European Commission, given these first results, believed in the potential of this methodology and in October 2022 it launched the first funded project ever carried out to evaluate the scalability of mechanochemistry in the large pharmaceutical industry. This is a far from simple challenge: researchers will have to respond to various requests, from studying the way in which mechanochemical reactions take place, to verifying the reproducibility of processes and optimizing them on a small scale and gradually larger. It will be a golden opportunity for the pharmaceutical industry, pressed as it is by the EU which, through the Green Deal, is asking to bring the production of medicines back within European borders and to drastically reduce the environmental impact deriving from its processes .
The evidence of the green method
Why is the study published in 2022 in the journal of the American Chemical Society so important? Colacino explains: «For the first time ever, we are applying the life cycle assessment system of a product to a mechanochemical study to calculate the environmental impact of this technology compared to traditional methods. We have compared the classic solvent-based method with the mechanochemical method – in this case extrusion – for the synthesis of the active ingredient nitrofurantoin. For each of the two methods, we have studied the entire life cycle of the active ingredient, from the entire synthesis chain of each reagent to the chemical reaction itself to obtain the compound, and we have quantitatively measured its impact on global warming, l ‘eco-toxicity and costs’.
Together with another Italian engineer, Giacomo Cerfeda, Sabrina Spatari performed a series of calculations on the basis of all the information and results produced by the team of chemists: «With the method that uses solvents, to produce 1 kg of active produced 603 kg of CO2. With extrusion we only produced 74 kg of CO2».
The same results were obtained for terrestrial ecotoxicity, ie the pollution of water, soil and air. This is mainly due to the reduction in the amount of reagents used and a reduction in the amount of waste produced by the mechanochemical process. The researchers then estimated the potential annual greenhouse gas emissions for the commercial production of nitrofurantoin: using mechanochemistry would result in an 85% reduction. They also calculated the annual cost, which would go from $162,000 with the solvent method to $19,000 with mechanochemistry. «I no longer have costs for the elimination of waste or related to the use of an excess of raw materials», explains Colacino. On a larger scale, considering the costs of manufacturing and selling certain drugs, one can imagine savings of millions of dollars by the pharmaceutical industries.
The Impactive project and the industry response
As mentioned, the Impactive project started from these premises, involving France, Germany (with the BAM of Berlin and the Max Planck Institute of Mülheim), Italy (with the Interuniversity Consortium for the Development of Large Interphase Systems, Csgi, offices in Cagliari, Florence, Parma and Salerno), Holland, Belgium, Ireland, Estonia, Spain, Portugal, Switzerland and Israel. The researchers are focusing on 6 drugs already developed and marketed by big industry: these are anticancer drugs, diabetes drugs and antihypertensives. The six active ingredients will now be synthesized using mechanochemistry. The choice was based on the importance of these drugs in treatment pathways and on discussions with the pharmaceutical industry regarding the need to improve the production processes of those active ingredients. Evelina Colacino will take the reins of the project and will dialogue with the various research centers and pharmaceutical industries involved. Francesco Delogu, coordinating the research unit of the CSGI, will provide a thirty-year knowledge of the mechanisms of mechanochemistry and of the instruments that can be used. The attempt will be to give answers to still open questions. In other words, he will try to understand what happens at the level of the synthesis mechanism, in the perspective of an industrial scale-up: