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

• Published in: Powder technology 2024-07, Vol.443, p.119913, Article 119913
• Main Authors: Luo, Jiaqi, Wang, Yingchen, Su, Qifan, Yu, Qiushuo, Zhai, Xinyue, Zou, Yuan, Zhang, Qiutong, Yan, Wenhao, Yang, Huaiyu
• Format: Article
• Language: English
• Subjects: Fine particle; Freeze-dissolving; Freeze-drying; Metronidazole; Nano and micro crystal; Sustainable
• ISSN: 0032-5910
• DOI: 10.1016/j.powtec.2024.119913

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. The freeze-dissolving method is to dissolve the frozen solvent molecules in an antisolvent of the target medicine molecules, and, therefore, the solvent molecules is fast dissolved, but the fine particles will remain. The new technology has potential for large-scale manufacturing in pharmaceutical manufacturing, with low cost and high efficiency and suitability. [Display omitted] •A novel green and efficient method in production of nano and micro medicine crystals•Freeze-dissolving method: 99% less time and energy required as freeze-drying method•Metronidazole crystals were produced and separated by freeze-dissolving method•Metronidazole crystals were similar or smaller than those by freeze drying method