Ultrasound-assisted solution crystallization of fotagliptin benzoate: Process intensification and crystal product optimization

Lan Fang; Zhenguo Gao; Songgu Wu; Shengzhe Jia; Jingkang Wang; Sohrab Rohani; Junbo Gong

doi:10.1016/j.ultsonch.2021.105634

Ultrasound-assisted solution crystallization of fotagliptin benzoate: Process intensification and crystal product optimization

Ultrason Sonochem. 2021 Aug:76:105634. doi: 10.1016/j.ultsonch.2021.105634. Epub 2021 Jun 29.

Authors

Lan Fang¹, Zhenguo Gao², Songgu Wu¹, Shengzhe Jia¹, Jingkang Wang¹, Sohrab Rohani³, Junbo Gong¹

Affiliations

¹ School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin 300072, PR China.
² School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin 300072, PR China. Electronic address: zhenguogao@tju.edu.cn.
³ Department of Chemical and Biochemical Engineering, The University of Western Ontario, London, Ontario N6A 5B9, Canada.

Abstract

The ultrasound-assisted crystallization process has promising potentials for improving process efficiency and modifying crystalline product properties. In this work, the crystallization process of fotagliptin benzoate methanol solvate (FBMS) was investigated to improve powder properties and downstream desolvation/drying performance. The direct cooling/antisolvent crystallization process was conducted and then optimized with the assistance of ultrasonic irradiation and seeding strategy. Direct cooling/antisolvent crystallization and seeding crystallization processes resulted in needle-like crystals which are undesirable for downstream processing. In contrast, the ultrasound-assisted crystallization process produced rod-like crystals and reduced the crystal size to facilitate the desolvation of FBMS. The metastable zone width (MSZW), induction time, crystal size, morphology, and process yield were studied comprehensively. The results showed that both the seeding and ultrasound-assisted crystallization process (without seeds) can improve the process yield and the ultrasound could effectively reduce the crystal size, narrow the MSZW, and shorten the induction time. Through comparing the drying dynamics of the FBMS, the small rod-shaped crystals with a mean size of 9.6 μm produced by ultrasonic irradiation can be completely desolvated within 20 h, while the desolvation time of long needle crystals with an average size of about 157 μm obtained by direct cooling/antisolvent crystallization and seeding crystallization processes is more than 80 h. Thus the crystal size and morphology were found to be the key factors affecting the desolvation kinetics and the smaller size produced by using ultrasound can benefit the intensification of the drying process. Overall, the ultrasound-assisted crystallization showed a full improvement including crystal properties and process efficiency during the preparation of fotagliptin benzoate desolvated crystals.

Keywords: Drying efficiency; Fotagliptin benzoate; Process intensification; Solution crystallization; Ultrasonic irradiation.