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Study On The Synthesis And Crystallization Process Of Ciprofloxacin Hydrochloride Monohydrate

Posted on:2004-01-26Degree:DoctorType:Dissertation
Country:ChinaCandidate:Y LiuFull Text:PDF
GTID:1101360092480628Subject:Chemical Engineering
Abstract/Summary:PDF Full Text Request
Ciprofloxacin hydrochloride monohydrate (CPFX), which has the advantage of broad spectrum, is the third generation member of quinolone antibiotics. It has been widely used in the treatment of urinary tract infections since the 1980s. Because of the high operating costs and the poor crystal quality such as poor crystal habit of CPFX, domestic products are incapable of competing with overseas products in CPFX's market. Therefore, it is necessary to solve that problem. A systematic research on the synthesis and crystallization process of CPFX has been done in detail in this thesis. The yield of the synthesis of ciprofloxacin directly affects the costs and the purity of CPFX crystal products. At first, the effects of medium, temperature and time for the condensation reaction of piperazine, and also the downstream processes on synthesis process have been studied systematically based on the properties of SN2 reaction and the molecule structure of reactant. An optimum process of the synthesis of ciprofloxacin has been developed. The crystallization thermodynamics of CPFX was studied in detail. The relationships between the solubility of CPFX and the temperature of solution, the content of ethanol, pH and the concentration of inorganic salt have been determined by laser method. The dissociation constant and the activity product for CPFX in water solution and the metastable zone for cooling or dilution crystallization were given. The interfacial tension has been estimated by induction period data with polynucleation approach under the classical nucleation theory. Based on the values of interfacial tension, the entropy factor f was calculated. The values of f show that the growth mechanism on the CPFX crystal surface is influenced by temperature and content of ethanol. The dehydrate temperature and melt/decomposition temperature of CPFX were measured by the instrument named DSC204. The solubility and the metastable zone of impurity have also been studied.The SEM photos showed that agglomeration phenomena happened in the crystallization process of CPFX. The model for the growth and the agglomeration of CPFX was derived from the population balance equation (PBE) and simulated by numerical method. According to the new concept of effective nucleation and effective growth, and along with mass balance equation (MBE) and PBE, the crystallization kinetics equation of CPFX has been determined by non-linear regression analysis. The crystallization process model for CPFX has been established. The effects of the operation parameters such as the operating mode, the stirring rate, the amount of crystal seed and the primary nucleation on the crystal size distribution(CSD) and the yield of crystallization process have been explored. The empirical optimum operation schedule was obtained.The diffraction data and chart for CPFX crystal were collected by X-ray diffraction technique. The indexed results have been given using the indexing program named TREOR90 included in the software of Cerius2. The unit cell parameters were obtained and the space group for CPFX was determined based upon the extinction theory. The optimum 3D-molecule structure of CPFX was obtained by AM1 method. The effects of temperature, solvent, pH and supersaturation on the crystal habit and the particle morphology have been investigated by SEM, DSC and XRD techniques. The crystal habit and morphology under vacuum condition have been analyzed by the BFDH principle.This thesis supplies a systematic research about CPFX with many thermodynamics data, crystallization kinetics and physicochemical data. In addition it offers a new method for determination of crystallization kinetics and a new approach of modeling the dilution or cooling crystallization process. Upon to now, there is little information and few reports on the above studies in the open literature.
Keywords/Search Tags:Ciprofloxacin hydrochloride monohydrate, Condensation reaction of piperazine, Crystallization thermodynamics, Crystallization kinetics, Crystallization process model, Unit cell parameter, Space group, Crystal habit
PDF Full Text Request
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