The sustainable preparation of hydantoin-based Active Pharmaceutical Ingredients (APIs) using modern non-conventional activation methods, including mechanochemistry is herein described.

The eco-compatible, base- and waste-free, energy-efficient, low-environmental-impact, gram-scale, mechanochemical preparation of marketed drugs such as nitrofurantoin (Furantin^©), dantrolene (Dantrium^©) and their structurally related derivatives is herein reported. Not a drop of organic solvent was used for the entire process and high yields of pure compounds were obtained without post-reaction work-up. Hydrazones were stable in the presence of water and gaseous HCl, formed as by-products during the synthesis. Comparative mechanochemical experiments were performed using diverse milling devices and jar materials, the active pharmaceutical ingredients were analyzed by PXRD and green metrics are calculated.