Mechanochemical kilogram-scale synthesis of rac-ibuprofen:nicotinamide co-crystals using a drum mill

Abstract

Within pharmaceutical research and development, co-crystallization has emerged as a common strategy to modify the physicochemical properties of active pharmaceutical ingredients, tackling a wide array of challenges in drug formulation. Contrasting with conventional solution-based methods that typically consume substantial amounts of solvents and energy, we herein present a more eco-friendly and efficient mechanochemical process for producing co-crystals at kilogram scale. Our study pioneers the use of a drum mill for pharmaceutical co-crystal synthesis, using rac-ibuprofen:nicotinamide as a representative example. Our findings demonstrate the viability of repurposing common industrial milling equipment for potential large-scale production of pharmaceutical co-crystals. With the optimized system and utilizing liquid-assisted grinding techniques, the reaction was completed within 90 min and yielded 99% of pure rac-ibuprofen:nicotinamide co-crystals by simply sieving off the grinding media. Examination of the resulting co-crystals showed minimal metal contamination from abrasion, with levels well within acceptable regulatory standards for daily intake. Our findings underscore the promise of drum mill technology in creating greener processes for large-scale pharmaceutical co-crystal synthesis, paving the way for more sustainable industrial drug manufacturing practices.