Systematic Scale-Up of Mechanochemical Paracetamol–Oxalic Acid Cocrystal Synthesis across Multiple Milling Technologies

Mechanochemical cocrystallization provides an efficient, solvent-minimized route for the production of pharmaceutical cocrystals. Although the small-scale synthesis of cocrystals is well established, strategies for the gradual scale-up to multigram and kilogram quantities remain limited. By systematically analyzing and comparing different scale-up stages, this study investigates the scale-up of paracetamol-oxalic acid (PCA-OXA) cocrystals using a range of milling technologies, including planetary ball mills, attritor mill, and drum mill. We aim to provide practical guidance on the capabilities and limitations of these devices and identify suitable milling parameters and strategies that ensure complete conversion and high product quality as batch sizes increase. In practice, planetary ball mills were used to prepare multigram quantities, while attritor mills generated hundred-gram batches under dry milling conditions. At the kilogram scale, drum milling required liquid-assisted grinding (LAG) with ethyl acetate to prevent caking and achieve full conversion. The results show that the gradual scale-up of PCA-OXA cocrystals is feasible when milling conditions and appropriate milling technologies are carefully selected, maintaining high yields and product quality across different scales. The findings contribute to a better understanding of the opportunities and limitations of mechanochemistry in pharmaceutical cocrystal development and offer guidance for the transition from laboratory-scale discovery to larger-scale production.