Process Optimization Of Oxytetracycline Hydrochloride With A Low Specific Volume

Oxytetracycline,a broad-spectrum antibiotics,can be used to treat a variety of infections.Because of its solubility constraints,oxytetracycline is seldom employed.Instead,oxytetracycline hydrochloride is widely used.The current manufacture techinique for oxytetracycline hydrochloride shows many shortcomings such as the small crystals,the large specific volume,the less fluidity,non-uniform CSD,and coresponding product couldn’t meet the requirements of advanced customers.In order to improve the techonology,the fundmental and the conclusions are as follows.Firstly oxytetracycline hydrochloride crystallization thermodynamics has been studied.The solubility of the oxytetracycline hydrochloride in methanol,ethanol,n-propanol,isopropanol,n-butanol,acetone solvent and methanol and acetone mixed solvent in different proportions including metastable zone and induction period was studied respectively by dynamic laser method.The results showed that the solubility data of oxytetracycline hydrochloride in an organic solvent changed with the temperature was fit well in line with Apelblat model equations.The solid-liquid interfacial tension was deduced by induction period,as:σ=2.7134×10-3 J/m2.Then cooling crystallization kinetics of oxytetracycline hydrochloride in methanol and different ratios of methanol and acetone solvent system were measured respectively by intermittent dynamic method.The effect of over-saturation,the impact of the suspension density,stirring speed and other operating parameters on the crystal nucleation rate and crystal growth rate was studied.Choosed the size-independent growth model,the crystallization process of nucleation kinetics and growth kinetics model equations of oxytetracycline hydrochloride crystals was obtained by the transformation process of moment for Population Balance equations.G=5.36×107 exp(-72670/RT)△C1.94Finally,the combination of the cooling and dilution crystallization of oxytetracycline hydrochloride has been developed.The effects of various operating parameters of the particle size distribution of the product,hematocrit,crystallization yield and so on were systematically investigated.The optimal conditions of oxytetracycline hydrochloride were determined,as follows:the solvent was methanol,the melting temperature was 35℃,the amount of calcium chloride was added and seed crystals were added in an amount of oxytetracycline 0.115 and 0.005,the cooling rate and stirring rate were separately 3℃/20min and 80 r/min,acid alcohol and eluent were separately added in three portions,as follows:the added amount of methanol was 0.3 and 0.1,The quality of the final product was significantly improved.