Optimizing the Aspect Ratio of Cephalexin in Reactive Crystallization by Controlling Supersaturation and Seeding Policy

Batch crystallization in acidic aqueous solution of cephalexin was conducted by reactive crystallization with or without seeding. Supersaturation was generated by mixing ammonia and acidic aqueous solution of cephalexin and controlled by solution feeding rate and seeding conditions. UV and Morphologi G3 were used to measure supersaturation and aspect ratio. Experimental results demonstrated that burst nucleation occurred and the products were needle-like at high supersaturation;meanwhile, the products were plate-like and had high aspect ratio at low supersaturation. Analysis of the measured supersaturation profi les and corresponding aspect ratio explained the mechanisms governing the aspect ratio. The optimized operating parameters were also proposed (seeding supersaturation is equal to 1.3, seed mass ratio 8% and feeding rate 368 μL/min).

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

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 crystalliquid 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.