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

• Published in: Chinese journal of chemical engineering 2022-01, Vol.41 (1), p.430-440
• Main Authors: Shang, Zeren, Li, Mingchen, Hou, Baohong, Zhang, Junli, Wang, Kuo, Hu, Weiguo, Deng, Tong, Gong, Junbo, Wu, Songgu
• Format: Article
• Language: English
• Subjects: Cephalexin monohydrate; Crystal habit control; Fine-crystal dissolution policy; Nucleation kinetics; Sonocrystallization
• ISSN: 1004-9541; 2210-321X
• DOI: 10.1016/j.cjche.2021.07.034

[Display omitted] •The influence of ultrasound on nucleation of cephalexin monohydrate was studied.•The nucleation mechanism was discussed qualitatively and quantitatively.•Different crystallization conditions were tested to improve the product quality.•The optimal policy could achieve crystal habit control effectively. With the high-quality requirements for cephalexin monohydrate, developing a robust and practical crystallization 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.