Low-Temperature Continuous Mechanochemical Synthesis of Hydantoin-Based Active Pharmaceutical Ingredients by Spiral Gas–Solid Two-Phase Flow

Although the mechanochemical synthesis of many active pharmaceutical ingredients (APIs) has been demonstrated, a technology that enables the large-scale continuous synthesis of thermosensitive APIs is lacking. In this work, we investigated the low-temperature continuous mechanochemical synthesis of a series of hydantoin-based derivatives, including the APIs nitrofurantoin and dantrolene, by using the previously proposed spiral gas–solid two-phase flow (S-GSF) technique. The structures of the prepared products were determined by using Fourier transform infrared spectroscopy, nuclear magnetic resonance, and powder X-ray diffractometry. Results showed that not a drop of organic solvent was used for the entire process, and high yields (not less than 94%) of E-isomer pure compounds were obtained without a complex purification step. Even with the low melting point of the raw material 5-nitrofurfural, nitrofurantoin could be synthesized continuously without remarkable amorphization. This situation distinguishes S-GSF from the existing mechanochemical methods. In addition, by improving system reactivity through cocrystallization and the highly efficient S-GSF technology, a continuous mechanochemical complete conversion of dantrolene was achieved for the first time, with a corresponding space-time yield up to 7.5 × 104 kg m–3 day–1. In particular, the crystalline form of dantrolene prepared in this way is a substable form dantr-V.