Development of a Circulated Flow Mixing Method with a Tubular Crystallizer for Controlling Indomethacin Polymorphs

作者：Furuta Masashi^*; Katayama Jumpei; Maki Taisuke; Mae Kazuhiro

来源：Journal of Chemical Engineering of Japan, 2017, 50(7): 501-510.

DOI：10.1252/jcej.16we312

• Indomethacin
• Polymorph Control
• Circulated Flow Mixing Crystallization
• Tubular Crystallizer
• Decouple Nucleation and Crystal Growth

A circulated flow mixing method with a tubular crystallizer was designed to separate the nucleation and crystal growth phases of pharmaceutical polymorphs for anti-solvent crystallization. The proposed method provides a fluctuating anti-solvent concentration due to the circulation of the active pharmaceutical ingredient (API) solution, whereas the anti-solvent concentration continually decreases in the simple addition method. The two methods were compared in the anti-solvent crystallization of indomethacin (IMC), a non-steroidal anti-inflammatory drug, in a water-acetone system at 50 degrees C. Furthermore, appropriate operating conditions that control the formation of two IMC polymorphs (i.e., a stable form gamma and an unstable form alpha) were investigated. The water addition rate was a key parameter controlling polymorph formation in both methods. Additionally, the proposed method provided a broader operation window to obtain the stable polymorph form gamma by controlling the water addition rate, which yielded a 20-fold higher productivity than the simple addition method.

• 出版日期2017-7