Study On The Crystal Morphology Control Of Azithromycin

Azithromycin,a macrolide antibiotic,is widely used to treat respiratory and urinary infections.However,some problems occur in the production process of azithromycin,such as propensity of agglomeration,poor flowability,small particle size and uneven particle size distribution.Taking these problems into account,the crystallization process of azithromycin was investigated systematically in this work.Firstly,three different crystal structures and habits of azithromycin were prepared and characterized by single crystal diffraction,XRD and TG.The effect of solvents on the crystal morphology of azithromycin was studied by molecular simulation from molecular level,which provided a crucial theoretical fundament for the further control of azithromycin crystal.The metastable zone of azithromycin in anti-solvent crystallization process was measured by laser method,and the effects of crystallization conditions on the width of metastable zone were studied.Additionally,the induction period was tested,and the critical nucleation size,solid-liquid surface tension,nucleation and growth mechanism of azithromycin were determined.Based on the above research,the crystal morphology of azithromycin was controlled through the optimization of crystallization process.The effects of concentration,temperature and adding rate of anti-solvent on the particle size and agglomeration degree of product were investigated systematically to determine the optimized crystallization process.The resultant product exhibited better flowability,dispersibility and particle size than those of the commercial products.To further improve the flowability of azithromycin,two spherical crystallization technologies were developed,and the formation mechanism of spherical particles were determined by process analytical technology.Meanwhile,the influences of operation parameters on the spherical crystallization process were detailly studied.These spherical particles exhibit excellent flowability and compressibility.Furthermore,the tablet properties were evaluated to verify that the spherical particles can be directly used for tableting,thus avoiding granulation process and reducing cost.In a word,the crystal morphology of azithromycin was successfully controlled by optimizing crystallization process and developing spherical crystallization technologies.It is significant for solving the problems of azithromycin and its industrial production.