Research On Purification Process Of Tobramycin Sulfate

Tobramycin sulfate is an aminoglycoside antibiotic. There are some serious problems in the productions processes of tobramycin sulfate, such as low purity of the product, low yield, high residual solvent content of product, forming gel during the process of purification etc.. In this these, a better manufacturing scheme for tobramycin sulfate was presented based on a systematic study of purification process. By means of the new delution technology and vacuum freeze-drying and spray drying in this work, the high quality products were produced under the optimum schedule of purification, and all indexes have surpassed the United States Pharmacopoeia standards.The solid-liquid equilibrium behavior of tobramycin sulfate in 14 solvents was investigated. The solubilities in 4 pure solvents and two binary solvents systems were determined and the dilution solvent system was choosen according to the properties of solutility. The Apelblat empirical equation was used to correlate the data of the solubilities of tobramycin sulfate in pure solvents system and the model equations were estabilished. And the data of solubilities in water + ethanol binary mixtures was corelated by CNIBS/Redlich-Kister equation and the mathematical model was estabilished.The supersolubility and induction time of tobramycin sulfate in water + ethanol binary mixtures were determined by laser monitoring method. The influence of width between the supersolubility curve and solubility curve was investigated by regulating the concentration of tobramycin sulfate in the solution and agitation rate, also with the ultrasonic apparatus. The induction time under different relative supersaturation degree was researched.By means of observartion in microscope,XRPD,SEM and FT-IR technology, the phenomenon of forming gel during the process of delution has been researched. Optimization of operating conditions was determined by means of regulating the addition rate and mode of antisolvent, adjusting the temperature program, etc, and the gelation phenomenon in the purification process has been avoided efficiently.The system of tobramycin salfate in aqueous solution with excipient was researched according to the principle of vacuum freeze drying. The spray drying was applied in the process of drying the product. The influence of residual solvent and purity of product was researched by investigating concentration, the source of feed and pH value. A new rapid, accurate method was developed to measure the water content of tobramycin sulfate product.Through this development of tobramycin sulfate delution and drying craft, the product quality has been improved greatly. The average yield has reached 95%, mean purity reached 698μg/mg, the content of residual solvent was below the 0.17% level.. All the quality index of tobramycin sulfate product reached the requirements of the United States Pharmacopoeia USP24.