Study On Coupling Crystallization Processes Of Dexamethasone Sodium Phosphate

As one kind of important drugs of ardrenal cortex hormone, dexamethasone sodium phosphate(DSP) is widely used in clinical application. Up to now, home-made DSP is not as good as those overseas products in terms of its purity and size distribution etc. In industrial manufacture of DSP, crystallization is one of the most important processes that decide the product quality. Therefore, in order to improve the quality of DSP, a systematic research on the crystallization process of it was done in details.The effects of crystallization method and other factors such as temperature and solvent on crystal habit of DSP were investigated by SEM analysis. It was found that the crystal habit gotten by the new coupling crystallization method is better than others. The diffraction data for DSP crystal was collected by X-ray diffraction technique. Using the indexing program named TREOR90, the unit cell parameters and space group for DSP were obtained by the indexing of its diffraction data. Using the software Cerius2, the ideal crystal habit of DSP under vacuum condition was determined by the BFDH principle. The crystallization thermodynamics of DSP were studied. The solubilities of DSP were determined by laser method and the effects of temperature,solvent,pH on it were discussed. Crystallization metastable zone and induction period of DSP in different solvent systems were determined. The interfacial tension was estimated by induction period data under the classical nucleation theory and the crystal growth mechanism was discussed using the interfacial tension data. The dissociation constants of dexamethasone phosphate were determined by the method of pH and the effects of temperature and solvent on it were discussed. Using the ionization constants of dexamethasone phosphate, the ion balance of DSP in solution was also studied.Crystallization kinetics are the basis for crystallization behavior and crystallizer scale-up design. The reactive and dilution crystallization kinetics of DSP were studied in MSMPR crystallizer and batch-operated crystallizer respectively. The nucleation and growth rate equations of DSP were determined by non-linear regression analysis. Using the crystallization thermodynamics and kinetics data, the mathematical models of coupling crystallization were established based on the population balance equations and mass balance equations. The model was simulated by numerical method. The effects of crystallization method,temperature,rotation rate and crystal seed on the crystal size distribution and product quality were studied by both experiments and model simulation. The new coupling crystallization method was discovered and its empirical optimum operation schedule was defined.Based on above study, the new coupling crystallization method was successfully utilized in industrial manufacture of DSP. The quality of the crystal product is as good as overseas product or better.There is no similar report to above study results have been published in literature up to date.