Study And Optimization On Reactive Crystallization Process Of Tetracycline Hydrochloride

Tetracycline hydrochloride (TCH) is a broad-spectrum antibiotics which iswidely used. To solve the problems existing in the present process including datedprocess, low purity and non-uniform size distribution, a systematic study of the wholereactive crystallization was completed, which can provide information for furtherindustrial usage.As to crystal morphology, the crystal cell parameters, crystal system and spacegroup were obtained by analyzing the single crystal. Then, based on the results of thesingle crystal, BFDH and AE models were used to predict the crystal habit of TCH,which can provide theoretical information for the selection of crystal habit.As to the thermodynamics, the solubility of TCH in six pure solvents and binarymixing solvents: methanol, ethanol,1-propanol,1-butanol, acetone, acetonitrile and1-butanol-A binary systems were measured by a static method combined with UV-visspectrophotometer. The experimental solubility were then correlated by the modifiedApelblat equation, NRTL model and UNIQUAC model, on the basis of which, weobtained the mixing properties and the heat of dissolution. All these data can providethe basic thermodynamic data for the optimization of the reactive crystallization andreactive crystallization kinetics.As to kinetics, an intermittent dynamic method was used to determine the reactivecrystallization kinetics of TCH in1-butanol-A with the help of ATR-FT-IR andMalvern Mastersizer analysis; a method combing the Runge-Kutta-Jill method and theleast squares method was used to fit the data of reaction kinetics, after which we gotthe reaction kinetics; the calculation of nucleation, growth and aggregation kineticswas obtained by using the discretized method. All these results can be used for theoptimization of the reactive crystallization process.Based on the results above, comprehensive investigation about the influence ofthe operation conditions including the ratio of mixing solvent, dissolution temperature,the ratio of reactant, stirring rate, temperature of dissolution, crystal seed amount andtemperature controlling program on the product quality such as purity, crystalmorphology and the yield of final products were carried out. The optimal operationschedule in1-butanol-A system was obtained. The product crystals obtained under the optimal operating condition had the higher purity (≥98%) and main distribution.Results showed that the quality of final products met the requirements of the factory.No related reports have been reported in literature up to date.