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Study On Crystallization Process Of ATMAA

Posted on:2012-05-02Degree:DoctorType:Dissertation
Country:ChinaCandidate:Z M ZhouFull Text:PDF
GTID:1111330368458943Subject:Chemical Engineering and Technology
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With the production of pharmaceutical intermediates promoted by the huge market of cephalosporin rapidly development, China has become the world's leading producer of pharmaceutical intermediates. (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (ATMAA), Thiotriazinone (TTZ) and D(-)-p-Hydroxyphenylglycine Dane Salt (D-HPG) etc are among the largest domestic production of the antibiotic side-chain intermediates. ATMAA, is a side-chain intermediate of the third and fourth generation of cephalosporin. ATMAA is generally synthesized from ethyl acetoacetate via a process which includes the following steps:oximation, methylation, bromination, distillation, cyclization, filtration, hydrolysis and reactive crystallization. Finally, anhydrous ATMAA used for the synthesis the AE-active ester or cephalosporin is re-crystallized from the aqueous methanol or ethanol mixtures through dehydration, filtration and drying.In GMP criterion, the awareness of the effect of the quality of intermediates on the quality of the final products in drug synthesis imposes higher requirements on the quality of intermediates. In recent years, although the production capacity of ATMAA rapidly increasing, there are still some technological and quality problems in its production processes. Therefore, optimzation of the key steps involved in the ATMAA production process based on experimental and theoretical study is necessary and importance for improving the quality of ATMAA and reducing the production cost.Although there are a number of research reports about the synthesis of ATMAA, the data concerning the reactive crystallization and re-crystallization of ATMAA are scare in the open literature. In fact, the crystallization process is very important in the production of ATMAA since it directly accociated with the quality and yield of ATMAA. Therefore, in this paper experimental and theoretical investigations about the reaction crystallization and dehydration re-crystallization process of ATMAA have been systematically carried out.The optimal conditions for the hydrolysis reactive crystallization of ATMAA was firstly determined based on experimental studies. Starting from the analysis of the process of the dehydration re-crystallization of ATMAA, a new technology was proposed and was experimentally investigated. The ATMAA crystals obtained using the new technology of dehydration re-crystallization are in the form of cubic, which diameters are larger than that of the ATMAA crystals obtaioned via the original process and. narrowly distributed. Thus obtained dehydrated ATMAA can be directly used for the next step of synthesis, eliminating the filtration and drying steps that are required in the original process. Therefore, the loss of ATMAA in the filtration equipment can be saved, the production process is significantly simplified. As a whole, the production efficiency can be markedly improved.The crystals of ATMAA can be water-containing (PM-Ⅰ) or water-free polymorph. It has been found that the water-free polymorph obtained with the new dehydration re-crystallization technique (PM-Ⅲ) was totally defferent fron that obtained using the original technique (PM-Ⅱ). It is a new water-free polymorph of ATMAA. The crystalline structure of the three polymorphs of ATMAA has been characterized in terms of SEM, TG, DSC, IR, Raman and XRD techniques. For each polymorph, a crystal system has been assigned and its cell parameters have been determined. PM-Ⅰis monoclinic, with a space group of C2. Its cell parameters are as following:a=11.14, b=15.63, c= 11.80,α=γ=90.00°,β=96.59°. PM-Ⅱis orthorhombic, with a space group of Pbcn. Its cell parameters are as following:a=10.86, b=22.29, c=6.54,α=γ=β= 90.00°. PM-Ⅲis orthorhombic, with a space group of Pbcn, Its cell parameters are as following:a=6.65, b=9.89, c=19.03,α=γ=β= 90.00°.The solvent system used for crystallization singnificantly influences the form and yield of the product crystals. The data of solid-liquid equilibrium of crystallization systems are the foundamentals for the design and optimaization of crystallization process. In order to probe the possibility of improving the solvent systems of ATMAA crystallization, in this paper, the solid-liquid phase equilibrium data of ATMAA in various solvents and solvent mixture systems (H2O with methanol, ethanol and glycol) have been measured in terms of a laser monitoring observation technique. To regress the solubility data with a medel that involing temperature and initio composition of the solvent mixture, a hybrid model was propose based on Apelblat equation and Jouyban-Acree model. In the hybrid model, the solubility of a solute was represented as a function of the system temperature and the initial composition of a binary solvent mixture. Unlike the Jouyban-Acree model, the hybrid model does not invole the the solubility data of the solute in the corresponding pure solvents. The validity of this model has been verified with the experimental data of ATMAA, and excellent agreement between the experimental and simulated results has been observed. At the same time, this model has been verified with the other drug intermediates like (TTZ) and (D-HPG), excellent agreement between the experimental and simulated results was also obtained.The reactive crystallization kinetics of ATMAA has been experimentally investigated in a batch dynamic crystallizer. The particle population conservation equation of crystallization process was simplified based on the assumption of particle size independent growth and was solved using moment transformation method. Equations of nucleation rate and crystal growth rate were obtained via regression of the experimental data of ATMAA dynamic crystallization using least square method. The results indicate that with increase of degree of the supersaturation, the rate of crystal growth will exceed the rate of nucleation. As a consequence, higher degree of the supersaturation and higher stirring strength will facilitate the crystal growth of ATMAA. Based on the analysis of the crystallization process and the thermodynamic as well as the kinetic experimental results, a model that describes the reactive crystallization process of ATMAA in aqueous solution was established. With this model, the reactive crystallization process of ATMAA in aqueous solution has been successfully simulated. The results showed, in the initio period the yield of ATMAA will rapidly increase with increasing time, after a while, it gradually reaches a constant value; further increase of time will not have significant influence on the yield. Increasing temperature will result in an increase of the particle size, but a decrease of the ATMAA yield. The rate of adding HCl solution has basically no effect on the particle size and its distribution. It is expected that the model can be used to optimize the operation parameters of the crystallization process of ATMAA, which provides a guideline for the production of ATMAA.
Keywords/Search Tags:(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid, reactive crystallization, re-crystallization, polymorph, hybrid model, solid-liquid phase equilibrium, crystallization kinetics
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