Study On The Crystallization Process Of Ceftazidime

Ceftazidme is one of ‘third generation cephalosporin’, which not only has a wideranti-bacterial spectrum just as other cephalosporin, but also efficient anti-bacterialactivity against P. aeruginosa, instead of cephalosporin antibiotic of theaminoglycoside, therefore, referred to as the ‘fourth-generation cephalosporins’. Asceftazidime pentahydrate is the most stable, compared with the other formations, ithas been widely applied to clinical treatment as injection. However, there exist manyproblems in the production of ceftazidime, such as lower product yield, poor atomeconomy, undesired ceftazidime crystal habit, small size and uneven distribution. Inthis paper, the research of ceftazidime crystallization process was carried systematically in order to improve the quality of the product, which can be divided just asfollowing:Ceftazidime crystallization water molecule was analysed by DSC and TG, X-raypowder diffraction and infrared spectroscopy; the crystal cell parameters and spacegroup was conformed through the X-ray powder diffraction data calculated byMaterial Studio3.1; crystal habit of ceftazidme was simulated with the application ofBFDH and AE model, which was concluded that AE model was more suitable thanBFDH model, with more similarity with experiment crystal habit.In this paper, dynaminc and static analysis method were respectively used tomeasure the solubility of ceftazidime with different pH in solution, and differenttemperatures in water, acetone and mixed solvent of water and acetone. Solubilitydata were fitted with three empirical equations by non-linear regression, where ABCequation was proved to be the best. Moreover, ionization balance constants ofceftazidime were determined with potentiometric titration method on the condition ofdifferent temperatures. The viscosities of the suspension solution at differenttemperatures were measured by rotational viscositimeter as well as acquired betterfitted results.The metastable zone and induction time at different temperatures and withdifferent pH was measured with use the online technology of FBRM. The effects oftemperature, pH and crystal seeds on metastable zone were discussed. The inductionperiods of ceftazidime were analysed to study the mechanism of nucleation andgrowth.. Meanwhile, according to the fitting results，corresponding kinetic parameterswere calculated.On the basis of researched results above, the optimization of crystallizationprocess was done with the purpose of the better particle size distribution and ideal crystal habit of ceftazidime. At last, the product of the particle size and ideal crystalhabit was acquired by the optimized process. These research results above can be usedto provide theoretical support in the industrialization of ceftazidime crystallizationprocess, the design of crystallizer and industrial scaling-up.