Scale-Up of Mechanochemical Amidation in Agitator Bead Mills: From Laboratory to Commercial Scale

Abstract

Bead mills are widely used in industry for particle size reduction across diverse applications; however, their use as reactors for mechanochemical synthesis has largely remained limited to laboratory studies, with no prior demonstration at a manufacturing-relevant scale. Here, we report the direct scale-up of a mechanochemical amidation using agitator bead mills. Starting from a laboratory protocol, the process was translated via a pilot unit to an industrial mill, achieving a 22-fold increase in scale (up to 15 kg per batch) without altering core reaction parameters. Ethyl acetate was used in small quantities as a liquid-assisted grinding additive, while equimolar reagent conditions were maintained throughout, eliminating the need for excess reagents and enabling straightforward product isolation without organic solvents, thereby minimizing waste generation. Both semicontinuous and continuous single-pass operation modes delivered high conversion and selectivity within short residence times. At the largest scale, product formation rates reached 65 kg/h. The close consistency between equipment across scales enabled a straightforward transfer, demonstrating that bead milling under reactive conditions provides a viable and scalable platform for sustainable mechanochemical manufacturing.