Reactive Crystallization Of 7-ADCA

7-amino-3-desacetoxycephalosporanic acid (7-ADCA) is one of the mostimportant intermediate in the manufacture of antibiotics. With the increasing demandfor cephalosporins in recent years, the requirement of 7-ADCA was increasedcorrespondingly. In order to improve the quality and increase the yield of 7-ADCAproducts, semi-batch reactive crystallization of 7-ADCA was studied systematicallyboth in experiment and theory.Synthesis processes of 7-ADCA from Cephalosporin G consists of following steps:dissolution of Cephalosporin G, hydrolyzation by enzyme, extraction, decolorationand reactive crystallization. To improve the quality of product and lower the cost, theoptimal operation conditions of above processes were experimental studied in detail.By indexing the 7-ADCA powder X-ray diffraction data, the crystal Miller indices andcrystal system were determined. The crystal space lattice of 7-ADCA was calculatedby running Polymorph in commercial software Cerius2. It has been proved that theproducts, which were produced from different reactive crystallization manners, belongin the same crystal system but different habit, based on the measured data with IRspectra, DSC and powder XRD instruments. The theoretical crystal habit of 7-ADCAwas predicted by BFDH and AE model respectively. The result of AE modelresembles the observed morphology. When crystallizing from the acid manner, certainfaces were stunted by H+, so that those faces can be observed in final crystals.Crystal yield is decided by crystallization thermodynamics. The solubility of 7-ADCAin pure water under different temperature and pH were measured. The solubility of7-ADCA in pure water increases with temperature. The effects of impurity wereobserved. Many salts, such as NH4Cl and PAA, don't have impact on the solubility of7-ADCA with the exception of CefG. As a kind of zwitter, 7-ADCA exists in solutionas three forms: anions, cations and neutral dipolar species. Solution chemistry playsan important role with respect to pH effect on solubility. When pH is lower or higher than isoelectric point, the solubility of 7-ADCA increases dramatically. The effect ofseeding and sulfate acid/ammonia adding rate on 7-ADCA metastable zone widthwere measured. The results show that metastable zone width isn't influenced byseeding when crystallizing by the acid manner. Other basic physicochemical data ofsolution, such as viscosity, density of 7-ADCA solution and dissociation constants,were also measured, which are useful information for design and control ofcrystallization process.Reactive crystallization consists of three steps: mixing, reaction and crystallization.As for 7-ADCA, mixing and reaction is rapid, that is to say, crystallization is thecontrol step of the whole process. In 7-ADCA crystallization process, agglomerationis important for acid manner, while dispersion and aging can be ignored in bothmanner. The effect of operation conditions, for instance temperature, agitation speed,concentration of solution, adding rate of ammonia, on agglomeration were studied.Estimation of kinetic parameters of nucleation, crystal growth and agglomeration areof essential importance in analysis, design and operation of industrial crystallizationprocesses. The primary nucleation and growth rate were determined by laser detectionmethod, which indicated a higher nucleation rate but a lower growth rate in the acidmanner operation compared with the basic manner operation. Nucleation and crystalgrowth kinetic parameters were measured by batch dynamic method, and a sizedependent growth and agglomeration rate model was established. The resultsdemonstrated that primary nucleation is the dominating mechanics in acid manner andcombination of primary and second nucleation occurs in basic side. In bothapproaches, crystal growth is integration control.To obtain high quality (suitable CSD and high purity) product and crystal yield, theeffect of operation conditions on product CSD was experimentally st...