SCI和EI收录∣中国化工学会会刊

中国化学工程学报 ›› 2022, Vol. 41 ›› Issue (1): 430-440.DOI: 10.1016/j.cjche.2021.07.034

• Chemical Engineering Thermodynamics • 上一篇    下一篇

Ultrasound assisted crystallization of cephalexin monohydrate: Nucleation mechanism and crystal habit control

Zeren Shang1, Mingchen Li1, Baohong Hou1, Junli Zhang1,2, Kuo Wang1, Weiguo Hu1,2, Tong Deng1, Junbo Gong1, Songgu Wu1   

  1. 1 School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300072, China;
    2 North China Pharmaceutical Co., Ltd., Shijiazhuang 050015, China
  • 收稿日期:2021-05-07 修回日期:2021-07-21 出版日期:2022-01-28 发布日期:2022-02-25
  • 通讯作者: Baohong Hou,E-mail address:houbaohong@tju.edu.cn;Songgu Wu,E-mail address:wusonggu@tju.edu.cn
  • 基金资助:
    The authors are grateful to the financial support of National Natural Science Foundation of China (22078238) and Special Project for the Transformation of Major Scientific and Technology Achievements of Hebei Province (19042822Z).

Ultrasound assisted crystallization of cephalexin monohydrate: Nucleation mechanism and crystal habit control

Zeren Shang1, Mingchen Li1, Baohong Hou1, Junli Zhang1,2, Kuo Wang1, Weiguo Hu1,2, Tong Deng1, Junbo Gong1, Songgu Wu1   

  1. 1 School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300072, China;
    2 North China Pharmaceutical Co., Ltd., Shijiazhuang 050015, China
  • Received:2021-05-07 Revised:2021-07-21 Online:2022-01-28 Published:2022-02-25
  • Contact: Baohong Hou,E-mail address:houbaohong@tju.edu.cn;Songgu Wu,E-mail address:wusonggu@tju.edu.cn
  • Supported by:
    The authors are grateful to the financial support of National Natural Science Foundation of China (22078238) and Special Project for the Transformation of Major Scientific and Technology Achievements of Hebei Province (19042822Z).

摘要: With the high-quality requirements for cephalexin monohydrate, developing a robust and practical crys-tallization process to produce cephalexin monohydrate with good crystal habit, appropriate aspect ratio and high bulk density as well as suitable flowability is urgently needed. This research has explored the influence of ultrasound on crystallization of cephalexin monohydrate in terms of nucleation mechanism and crystal habit control. The results of metastable zone width and induction time measurement showed the presence of ultrasound irradiation can narrow the metastable zone and shorten induction time. Cavitation phenomena generated by ultrasound were used to qualitatively explain the mechanism of ultrasound promoting nucleation of cephalexin monohydrate. Furthermore, on the basis of classical nucleation theory and induction time data, a series of nucleation-related parameters (such as crystal-liquid interfacial tension, radius of the critical nucleus and etc.) were calculated and showed a decreasing trend under ultrasound irradiation. The diffusion coefficient of the studied system was also determined to increase by 72.73% under ultrasound. The changes in these parameters have quantitatively confirmed the mechanism of ultrasound influence on the nucleation process. In further, the calculated surface entropy factor has confirmed that the growth of cephalexin monohydrate follows continuous growth mechanism under the research conditions of this work. Through the exploration of crystallization conditions, it is found that suitable ultrasonic treatment, seeding, supersaturation control and removal of fine crystals are conducive to improving the quality of cephalexin monohydrate product. Optimizing the crystallization process coupled continuous ultrasound irradiation with fine-crystal dissolution policy has achieved the controllable production of monodisperse cephalexin monohydrate crystal with good performance.

关键词: Cephalexin monohydrate, Sonocrystallization, Nucleation kinetics, Fine-crystal dissolution policy, Crystal habit control

Abstract: With the high-quality requirements for cephalexin monohydrate, developing a robust and practical crys-tallization process to produce cephalexin monohydrate with good crystal habit, appropriate aspect ratio and high bulk density as well as suitable flowability is urgently needed. This research has explored the influence of ultrasound on crystallization of cephalexin monohydrate in terms of nucleation mechanism and crystal habit control. The results of metastable zone width and induction time measurement showed the presence of ultrasound irradiation can narrow the metastable zone and shorten induction time. Cavitation phenomena generated by ultrasound were used to qualitatively explain the mechanism of ultrasound promoting nucleation of cephalexin monohydrate. Furthermore, on the basis of classical nucleation theory and induction time data, a series of nucleation-related parameters (such as crystal-liquid interfacial tension, radius of the critical nucleus and etc.) were calculated and showed a decreasing trend under ultrasound irradiation. The diffusion coefficient of the studied system was also determined to increase by 72.73% under ultrasound. The changes in these parameters have quantitatively confirmed the mechanism of ultrasound influence on the nucleation process. In further, the calculated surface entropy factor has confirmed that the growth of cephalexin monohydrate follows continuous growth mechanism under the research conditions of this work. Through the exploration of crystallization conditions, it is found that suitable ultrasonic treatment, seeding, supersaturation control and removal of fine crystals are conducive to improving the quality of cephalexin monohydrate product. Optimizing the crystallization process coupled continuous ultrasound irradiation with fine-crystal dissolution policy has achieved the controllable production of monodisperse cephalexin monohydrate crystal with good performance.

Key words: Cephalexin monohydrate, Sonocrystallization, Nucleation kinetics, Fine-crystal dissolution policy, Crystal habit control