A Study On Crystal Habit Control Of Cephalexin Monohydrate From Crystallization Process

Crystal habits directly affect the performance of crystal products like bulk density and flowability.Expected crystal habits could be obtained by the design of crystallization process,so that product performance would get promoted.Cephalexin is a widely used antibiotic with a large market demand.However,cephalexin crystal products are needle-like or slender rod-like,leading to low bulk density and poor flowability.Currently,production process of pharmaceutical raw materials are mainly batch or semi-batch crystallization,resulting in batch-to-batch variations and unsteady control.Therefore,aiming at improving crystal habits of cephalexin as well as improving bulk density and flowability,developing new continuous crystallization technology for pharmaceutical products,crystallization process research of cephalexin in aqueous solution was studied in this thesis.Crystallization thermodynamics and kinetics are the basis of process development.The metastable zone and induction time of cephalexin in aqueous solution were measured by the laser dynamic method.And the suitable operation interval for crystallization process was determined.Kinetic parameters such as interfacial surface tension,critical Gibbs free energy and critical nuclear radius were calculated by the induction time data.Continuous crystallization of drugs can stabilize the preparation of qualified products.A continuous crystallization process of cephalexin was exploratorily developed in this thesis.Operation parameters like temperature,p H,residence time and reflux ratio were investigated to find out the effects on crystal habits and product parameters.And the suitable operation interval for continuous crystallization process was determined,under the operation interval,rod-like crystal products were prepared,aspect ratio of which decreased by over 20%.Based on the continuous crystallization process developed,a new crystallizer with multi-partition and reflux was designed,which could reduce fine crystal proportions and increase main crystal sizes.At present,this crystallizer design has been applied for Chinese invention patent.In batch crystallization processes,improving the crystallization habits of cephalexin products is still a realistic challenge.Therefore,a batch crystallization process with ultrasonication was developed.Firstly,the induction time of cephalexin with ultrasonication was determined.It was found that the mass transfer coefficient D_ABwas promoted because of ultrasonication.At the same time,ultrasonic mode,ultrasonic time and ultrasonic power were investigated and optimized.Combined with supersaturation control strategy and fine-crystal resolution strategy,the rod-like crystal products were stably prepared.The aspect ratio of products was increased by more than30%.The bulk density of optimized products was more than 0.3g/m L and increased by60%and the angle of repose was decreased by 30% than the original technology.