Utilizing an attritor mill for solvent-free mechanochemical synthesis of rac-ibuprofen:nicotinamide co-crystals

Abstract

The co-crystal formed from the WHO essential drug rac-ibuprofen (IBU) and the food additive nicotinamide (NIC) exhibits enhanced physicochemical and analgesic properties compared to the pure active pharmaceutical ingredient (API), exemplifying how co-crystallization can modify pharmaceutical characteristics. Herein, we present a more sustainable, solvent-free mechanochemical process for synthesizing rac-ibuprofen:nicotinamide (IBU:NIC) co-crystals, moving beyond conventional solution-based methods that typically require substantial amounts of solvents and energy. For the first time, we investigate the application of a horizontal attritor mill for co-crystal synthesis. Our findings demonstrate the effectiveness of this milling technology in facilitating the co-crystallization process, achieving pure co-crystals within 30 min. Additionally, initial experiments were conducted to explore the transition from a batch process to a sequential process. While our approach demonstrate the use of attritor mills for pharmaceutical co-crystal synthesis on a multigram scale, it also indicates opportunities for scaling up this process using industrial attritor mills. This work underscores the adaptation of existing grinding technologies to facilitate mechanochemical reactions, showcasing greener alternatives for pharmaceutical manufacturing.