Innovative Mechanochemical Processes to synthesize green ACTIVE pharmaceutical ingredients.

Project Information

IMPACTIVE

Grant agreement ID: 101057286

DOI

10.3030/101057286

EC signature date 23 May 2022

Start date 1 October 2022

End date 30 September 2026

Funded under

• Health

Total cost

€ 7 665 520,00

EU contribution

€ 7 438 705,00

Coordinated by

UNIVERSITE DE MONTPELLIER
France

Periodic Reporting for period 2 - IMPACTIVE (Innovative Mechanochemical Processes to synthesize green ACTIVE pharmaceutical ingredients.)

Reporting period: 2024-04-01 to 2025-09-30

Summary of the context and overall objectives of the project

The environmental impact of the pharmaceutical industry is a huge problem. The production and use of pharmaceuticals cause high CO2 emissions (52 Mtons in 2015, which is more than the automotive industry), contamination of soils, biota, and water, and even dangers to human health through carcinogenic impurities. Although there have been efforts to reduce the environmental impact of active pharmaceutical ingredient (API) production, the use of organic solvents (responsible for 75% of energy used) is still a critical step in many processes. Clearly, new methods to produce pharmaceuticals in a green, efficient, and economically friendly way are required. The IMPACTIVE project brings together the expertise and knowledge from two COST Actions and develops novel green methods to produce active pharmaceutical ingredients (APIs) using mechanochemistry as a disruptive technology. Mechanochemistry uses mechanical processes, such as ball milling, twin-screw extrusion, resonant acoustic mixing, and spray drying, to induce chemical reactions. Mechanochemistry is a solvent-free, highly efficient, environmentally friendly, and affordable disruptive technology to produce APIs. Mechanochemistry has been successfully adopted in other industries already, including aerospace, cosmetics, biomass transformation and agro-foods. IMPACTIVE is moving mechanochemistry from a promising green chemistry concept towards a credible route for more sustainable pharmaceutical manufacturing. The project has advanced the total synthesis of targeted APIs, explored multiple mechanochemical routes for producing them, and developed several new multicomponent crystal forms designed to improve key pharmaceutical properties such as solubility, stability and bioavailability. In parallel, the project has generated high-quality kinetic datasets, improved modelling tools to compare reactions across different mechanochemical setups, and strengthened the basis for scaling up from laboratory synthesis towards industrially relevant production. Progress has also been made on batch and continuous processing, on defining recovery and recirculation strategies for material and energy streams. To contribute to the green chemistry landscape, IMPACTIVE has also launched an Educational Platform. IMPACTIVE is also focused on protecting key results, and has filed 5 European patent demands, 3 of which are now published, and 2 have reached the PCT status.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During the second reporting period, IMPACTIVE produced 5 additional publications, 2 book chapters and filed 5 european patent demands focusing in the mechanochemical processes and multi-step synthesis of selected active pharmaceutical ingredients (APIs) and their key intermediates, altogether currently marketed as crucial for treating several diseases such as cancer. The traditional solvent-based approaches have been taken as starting points, and alternative mechanochemical processes in the absence of solvents have been investigated, leading to the development of several key transformations with different degrees of advancements, depending on the complexity of the targeted scaffold. For each of these API’s, the potential mechanochemical alternatives have been identified. These have now been partly explored, tested and optimized at different scales, with different technologies. In the reporting period, the IMPACTIVE consortium has made major advancements in replacing at least one solvent-based step in the synthesis of 10 APIs from four different compound families by a mechanochemical alternative at a laboratory scale, both in batch and in continuous. Due to the sensitive information contained in the exploitation strategy, we cannot include the structure of the Active Pharmaceutical Ingredients (APIs) or their key intermediates (KIs) in this summary. For the anticancer drugs APIs, two mechanochemical synthetic strategies are currently ongoing and significative progress has been obtained joining the efforts of the different partners of the Consortium. For some of the compounds within these families, continuous processes are still under investigation. All the syntheses developed by a mechanochemical approach overcome frequent problems encountered in solution-based chemistry such as s high catalyst loading and long reaction times, generation less waste than conventional processes in solution. The mechanochemical preparation of APIs belonging to the fourth family of target compounds is still ongoing. The results will be presented in due course.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

IMPACTIVE has already delivered results beyond several of its original objectives. During the reporting period, the consortium replaced at least one solvent-based step in the synthesis of 11 APIs, achieved the total mechanochemical synthesis of 7 APIs across 3 families, prepared and characterised more than 6 multicomponent systems, and investigated 3 formulation prototypes. The project also advanced its modelling framework for mechanochemical transformations, launched pilot-scale scale-up activities, and started benchmarking the new processes through life-cycle and techno-economic assessment. Overall, the report concludes that the project is on track across its objectives, with results already feeding industrial design, impurity assessment, crystallographic studies and sustainability analysis across multiple work packages.

In parallel, IMPACTIVE has built a strong basis for future uptake and impact. The consortium reports 45 dissemination activities, including 5 peer-reviewed articles, 2 book chapters and 29 conference presentations, alongside the launch of its Educational Platform and use of Zenodo as a long-term open-access hub. On the exploitation side, the project filed 5 European patent demands, of which 3 are now published, and 2 had reached PCT status. Altogether, IMPACTIVE has several publications in the pipeline.

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