Sustainable pharmaceutical manufacturing based on mechanochemistry: A life cycle assessment of rac-Ibuprofen-Nicotinamide cocrystallization routes

Mechanochemistry is emerging as a sustainable alternative to solvent-based synthesis, yet its environmental and process-scale performance for pharmaceutical applications remains underexplored. This work assesses the environmental sustainability and process efficiency of mechanochemical versus conventional solution-based routes for producing rac-ibuprofen– nicotinamide (rac-IBU:NIC) co-crystals, a model pharmaceutical solid form. Experimental data from kilogram-scale eccentric vibrating milling (EVM), attritor mill (AM) and hammer mill (HM) were integrated with process modeling, green chemistry metrics, and cradle-to-gate life cycle assessment (LCA). Mechanochemical performance in batch (EVM, AM and HM) and continuous configurations (hot melt extrusion, HME) was benchmarked against an ethanol-based crystallization process representative of current industrial practice. Green metrics results confirmed that all mechanochemical routes achieved lowest aggregate scores, outperforming the solvent-batch process, demonstrating superior greenness due to solvent elimination, high atom economy, and ambient operation. LCA results, however, indicated higher global warming and fossil resource impacts for some mechanochemical systems compared to the solvent-batch process under fossil-based electricity, reflecting their reliance on electrical power. Scenario analyses revealed that renewable electricity dramatically lowers these impacts, reducing the global warming potential of EVM by more than 90 % and rendering both EVM and HME environmentally competitive with the solvent-batch process, even when considering a green solvent such as bio-ethanol. Mechanochemistry not only eliminates solvent use but also aligns with the global transition to renewable energy, since its impacts scale directly with the cleanliness of the electricity supply, positioning it as a viable pathway toward greener pharmaceutical manufacturing.