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Study On Phase Equilibrium And Dilution Crystallization Process Of Camptothecin

Posted on:2018-09-07Degree:DoctorType:Dissertation
Country:ChinaCandidate:J J ZhiFull Text:PDF
GTID:1311330512479522Subject:Chemical Engineering
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Camptothecin(CPT)is a natural indole alkaloid that can be used not only for the treatment of cancer,but also for the preparation of camptothecin anticancer drugs intermediates.In the process of camptothecin production and application,there is not enough the necessary basic physical data and controlling the product quality of the theoretical research and methods.Based on this,the camptothecin phase equilibrium and the crystallization process were studied.The solid-liquid equilibrium data of camptothecin in pure solvents and mixed solvents were measured.Based on the solution equilibrium data and thermodynamic parameters,the crystallization process was optimized and the crystallization kinetics of the solution was studied.The crystal structure and the thermodynamics of the solution were also analyzed.The solid-liquid phase balance of camptothecin in different solvents was studied.The solubility data of camptothecin in eight kinds of pure solvents and five kinds of mixed solvents were determined by gravimetric method.The modified Apelblat model,the ?h model and the ideal model were used to correlate the solubility data.The model parameters were determined.The thermodynamic parameters of the camptothecin,the dissolved enthalpy solHo(35),the dissolved entropy solSo(35)and dissolved Gibbs free energy solGo(35),were calculated from the solubility data.solHo(35)?0,indicating that the association of solvent molecules was stronger than that of camptothecin and solvent intermolecular interactions,the breakage of the associative bond dominates,and the camptothecin dissolving process is an endothermic process.Based on the solid-liquid phase equilibrium data and dissolution thermodynamic properties of camptothecin,the camptothecin in N-methylpyrrolidone + water-soluble crystallization process was determined.The effects of the technological conditions on the crystallization of camptothecin were investigated.The optimum conditions were as follows: The dosage of the solution was 5.38 m L / m L.The dropping speed was 1.98 m L / min.The temperature was 308.15 K.The stirring speed was 400 r / min.The initial solution concentration was 10.5 g / L.The seed addition II amount was 0.50%.The aging time was 4 h.Under this condition camptothecin yield,average particle size Dav and coefficient of variation CV respectively were: 81%,14.28 mm and 0.941.The mesophase equilibrium of camptothecin was studied.The temperature and the induction period of camptothecin in N-methylpyrrolidone + water mixed solvent system were determined by laser dynamic method.The solid surface tension and surface entropy factor of camptothecin in the system were calculated.The result indicated that camptothecin crystals growth was an continuous growth process.The crystallization kinetics of camptothecin was studied by intermittent dynamic method.It was confirmed that the crystal growth of camptothecin was the crystal growth process related to the number of grains.After calculation,the nucleation kinetics and crystal growth kinetics equation of camptothecin in dilution crystallization were :The structure of camptothecin was characterized by the circular dichroism(CD),scanning electron microscopy(SEM),thermogravimetric analysis(TG),differential scanning calorimetry(DSC)and X-ray diffraction(XRD).The crystal structure and chiral center of camptothecin remaineded unchanged by analysising of XRD spectrum data using Materials studio software.The cell structure and crystal habit of camptothecin was simulated by using Materials studio software.The cell structure of camptothecin was monoclinic system,and space groups was CC.The crystal cell parameters were as follows: a=9.5483×10-10 m,b=29.4213×10-10 m,c=7.4325×10-10 m,?=?=90°,?=96.3256°.There were four camptothecin molecules in a cell.The crystal habit of camptothecin was simulated by BFDH model in Morphology module,and the results were similar as actual tabular crystal acquisition.The crystal structure was unchang during the crystallization process.The viscosity and density of camptothecin in N-methyl pyrrolidone solution at different quality of molar concentration were measured at 278.15 K ~ 318.15 K temperature range.The viscosity and density date was well correlated by Vogel Tamman-Fulcher equation using the least square method,and the fitting result is well.The viscosity and density of fitting equation were revealed respectively,The correlation coefficients and total standard deviations were 0.999,3.59 × 10-3 and 0.993,1.16 × 10-4,respectively.The results provide theoretical guidance for the large-scale production of camptothecin and have good practical significance.
Keywords/Search Tags:Camptothecin, Solid-liquid phase equilibrium, Thermodynamics, Crystallization kinetics, Solvent-out crystallization
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