| Azithromycin is a macrolide antibiotic and its pharmaceutical forms aremonohydrate and dihydrate. In the present work, the crystallization process ofazithromycin hydrates was studied systematically.As the basis of thermodynamics data of crystallization, the solubilities ofazithromycin monohydrate and dihydrate were determined by dynamic laser methodin acetone-water solvent mixture. The thermodynamic relative stability of twohydrates was investigated according to experimental data and the influence oftemperature and solvent composition on the solubilities was anaylised. Besides, a3Dsolubility diagram was drawn which can provide some useful information for thecrystallization of azithromycin. The solubility data were correlated using Apelblat, λhand Wilson models, and some thermodynamic properties were calculated.A phase diagram was obtained through slurry experiments, which correlated thewater content to the pseudopolymorphism closely. The water activities werecalculated using UNIFAC model and the influence of water activites was discussed inthis work. The solvent-mediated phase transformation of azithromycin hydrates wasmonitored using in situ Raman and microscope, and the influence of solvent,temperature and agitation on the transformation was observed and the limiting stepwas determined. These can give guidance for the crystallization process.In the process of industrial production, the phenomenon of azithromyindihydrate agglomeration is commonly encountered and it has significant influence onthe products properties such as bulk density, residue of solvent and so on. Themorphologies of azithromycin monohydrate and dihydrate were simulated usingMaterial Studio and isothermal/growth experiment was carried out. According to theresults above, the influence of solvent, supersaturation and agitation on theagglomeration were investigated and the mechanism governing the agglomerationwere determined.Up to date, results in this work were not found in literatures. |
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