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Reactive Crystallization Process Of 7-Amino-cephalsporanic Acid

Posted on:2006-10-23Degree:DoctorType:Dissertation
Country:ChinaCandidate:S WangFull Text:PDF
GTID:1101360182476069Subject:Chemical Engineering
Abstract/Summary:PDF Full Text Request
7-amino-cephalsporanic acid (7-ACA) is an important intermediate in themanufacture of semisynthetic cephalosporanic antibiotics. With the increasingdemand for cephalosporins and higher quality 7-ACA in recent years, the requirementof 7-ACA was increased correspondingly. Crystallization process is the critical step ofdeciding the quality of product. In this thesis, the reactive crystallization process of7-ACA was studied systematically both in experiment and theory.By indexing the 7-ACA powder X-ray diffraction data using indexing program namedTREOR90, the crystal Miller indices and crystal system were determined. The crystalspace lattice of 7-ACA was calculated by running Polymorph in commercial softwareCerius2. The theoretical crystal habit of 7-ACA was predicted by BFDH and AEmodel respectively. It has been proved that the products, which were produced fromdifferent reactive crystallization processes, belong to the same crystal system with thesame chemical composition, based on the measured data with IR spectra and powderXRD instruments.Using the SEM and powder XRD instruments, the agglomeration values of twocrystallization processes, with acid or basic crystallization condition were studied.The effects of agitation speed on 7-ACA product agglomerating values were observed.By dealing with SEM photographes of above two processes, it can be seen that thegrayscale distributions for the same sample are extremely similar, which indicates thatthe morphology of 7-ACA crystallization exhibits self-similarity at different scales.The fractal dimensions of 7-ACA crystals from two different crystallization processeswere determined by box-dimension method. According to fractal dimensions of7-ACA crystals, agglomeration mechanism has been presumed. Zeta potentials weremeasured for differential pH value by zeta potential analyzer. In addition, the capillaryrise of liquid in columns packed with 7-ACA powder was measured and thewettabilities of acetone and water to two 7-ACA samples were determined.Combining the test results of IR and powder X-ray diffraction, the functional groupson the surfaces of crystals manufactured from above two processes were presumed.The 7-ACA agglomeration rate model was established.Crystal yield is decided by crystallization thermodynamics. The solubility of 7-ACAunder different temperature, solvent and pH were measured by the light extinctionmeasurement. The solubility data in binary mixture solvent acetone+water were fittedwith both the R-K equation and the λ h-equation, and the correlative parameters wereestimated by linear and nonlinear least square regression methods respectively.Crystallization mtastable zone of 7-ACA in acidic and basic crystallization conditionswere determined. The effect of seeding on 7-ACA metastable zone width weremeasured. The dissociation constants pK1 and pK2 of 7-ACA were determined by therelativation of pH and concentration, and the isoelectric points also were determined.Crystallization kinetics are the basis for crystallization behavior and crystallizer scaleup design. Estimation of kinetic parameters of nucleation, crystal growth andagglomeration are of essential importance in analysis, design and operation ofindustrial crystallization processes. The 7-ACA nucleation and crystal growth kineticparameters were measured by batch dynamic method, and agglomeration rate modelwas established.On the basis of population balance equations and crystallization thermodynamics,kinetics, as well as mass balance equations, the mathematical model of the 7-ACAcrystallization process was established. The model was simulated by numericalmethod. The effects of temperature, rotation rate and crystal seed on product CSD andquality were studied by both experiments and model simulation. The newcrystallization method was discovered and its theoretical optimal operating strategywas established. The high quality product was produced under the optimizedoperation condition. So far as we are aware, no similar research report has beenpublished yet.
Keywords/Search Tags:7-ACA, reactive crystallization, crystallization thermodynamics, crystallization kinetics, agglomerate, light extinction measurement, fractal, wettability
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