Rapid and sustainable production of nano and micro medicine crystals via freeze-dissolving technology

Abstract

Modern pharmaceutical manufacturing emphasizes the need for sustainable technologies. Fine particles, including nano and micro-sized crystals, are increasingly important, particularly in the production of inhalation medicines. A novel application of freeze-dissolving technology has been demonstrated in the production of metronidazole, a model drug. This process involves creating frozen spherical particles by introducing a tert-butanol solution containing dissolved metronidazole into liquid nitrogen. Various antisolvents, such as n-hexane, n-heptane, ethanol, n-propanol, n-butanol, or n-pentanol, were employed to dissolve these frozen templates at temperatures ranging from 248.15 to 278.15 K. During this process, pre-formed metronidazole fine particles within the frozen template were released into the antisolvent solution. An alternative method involved placing these frozen particles into a vacuumed freeze dryer to extract the fine particles. The new freeze-dissolving technology can save 99% both energy and time compared to the traditional freeze-drying method, demonstrating a significantly more efficient and sustainable pharmaceutical manufacturing approach.