2017 Volume 50 Issue 7 Pages 501-510
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°C. Furthermore, appropriate operating conditions that control the formation of two IMC polymorphs (i.e., a stable form γ and an unstable form α) 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 γ by controlling the water addition rate, which yielded a 20-fold higher productivity than the simple addition method.
