Study On The Process Of Dilution Crystallization Of Spectinomycin Dihydrochloride

Spectinomycin dihydrochloride pentahydrate (abbreviated as SDP) is a broad-spectrum antibiotic, which belongs to aminoglycoside. It is mostly used in the treatment of gonorrhea. There are some serious problems in refining process of SDP, such as low yield and poor quality. In this thesis a better refining scheme for SDP is presented based on a systematic study on the dilution crystallization process of SDP.The SDP crystal cultivated by cooling was analyzed by X-ray single crystal diffraction and its structure was determined. X-ray powder diffraction showed that crystals prepared by cooling and dilution crystallization were of the same structure. By the use of Cerius2 software, the crystal morphology in the vacuum was calculated based on BFDH principle. The factors that may affect the crystal habit were discussed. In addition thermal analysis was made.In order to control the crystallization process, it is necessary to determine the physicochemical data of product, such as the thermodynamic and kinetics data. The solubility of SDP at different solvent ratio and temperature was determined by dynamic method. Since the absence of melt point, simultaneous equations of R-K equation and general solubility equation were used for regression the solubility data by linear least square method and the data was also regressed in the form of λh equation by Marquardt nonlinear least square technique. The solubility data of SDP in the multi-solvent at the present of inorganic salt and the dissolution heat of SDP in pure water were measured. The metastable zone for dilution crystallization of SDP was also studied by laser method. The effect of operation temperature and solvent ratio on the metastability was examined. The solid-liquid surface tension was estimated by polynucleation theory.The equation of crystallization growth rate of different growth model was derived by moment method and s domain analysis respectively. Mechanism of crystal growth from different solvent was disclosed and primary nucleation parameters for dilution crystallization of SDP were calculated. The empirical equations for secondary nucleation and crystal growth kinetics were determined by moment method. On the basis of population balance, crystallization kinetics and mass balance equations, the mathematical model for dilution crystallization of SDP was established. Process simulation was developed by Ronge-Kutta-Gill algorithm and FORTRAN language. Four operation modes, crystallization from previously supersaturated solution, constant change of volume rate of diluent, constant change of weight percent of diluent and constant growth rate were investigated. The characteristic of each mode, the effect of addition rate of diluent, temperature, agitation intensity and seed amount on the yield, crystal size and crystal size distribution were analyzed by simulation.According to the crystal growth habit, metastable zone character, crystallization kinetics and simulation analysis, the factors that influence crystallization of SDP such as temperature for remove of pyrogen, crystallization temperature, breeding time, addition mode and addition rate of diluent were explored experimentally in detail. The optimum operation schedule for dilution crystallization of SDP was discovered. The mathematical model of crystallization process has been verified by the consistent results of crystallization from simulation and experiment.The paper supplied basic data and important foundation for scale up and further research on crystallization of SDP. The new process of dilution crystallization has been successfully used for industry manufacture of SDP and the product quality and yield were enhanced. There is no similar report to above study result has been published in literature up to date.