大孔树脂制备层析分离红霉素A和红梅素C的基础研究
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摘要
由于多种红霉素衍生药物在临床上应用十分广泛,红霉素A硫氰酸盐(硫氰酸红霉素A)作为合成红霉素衍生药物的基础原料,其需求量日益增加。硫氰酸红霉素A的纯度直接影响着后续合成反应的收率及红霉素衍生药物的质量,所以,对硫氰酸红霉素A的纯度要求较高。随着高产基因工程菌的使用,红霉素发酵液的效价得到显著提高,大大提高了硫氰酸红霉素A的生产效率并降低了能耗,但与此同时,抗菌活性低且毒性较大的红霉素C的含量也大大增加。因此,对硫氰酸红霉素A的分离纯化工艺提出的新的要求,即需要有效地分离红霉素C。然而,现有的工业化分离纯化工艺主要采用溶剂萃取法,由于其对红霉素组分的分离无特异性,难以高效地分离红霉素C。
本文围绕红霉素A与红霉素C分离的基础数据研究和分离工艺研究两方面展开工作。本文先使用大孔吸附树脂SP825作为吸附剂,通过调整溶液极性以提高红霉素A的吸附选择性,并系统研究了红霉素A与红霉素C的间歇竞争吸附相平衡行为,以及在固定床上的吸附传质动力学过程。在此研究基础上,以绿色、经济、可规模化生产为理念,提出了一条以迎头色谱法为主,磷酸盐缓冲溶液洗涤洗脱液为辅的适宜于从红霉素C杂质含量较高的红霉素发酵液中分离纯化红霉素A并得到硫氰酸红霉素A的工艺路线。
本文的主要研究内容和结论如下：
(1)以提高红霉素A与红霉素C在大孔吸附树脂上的分离效果为目标,通过调节溶液极性,优选出较佳溶剂为含3%(v/v)乙酸乙酯的磷酸盐缓冲溶液。分别采用洗涤层析法和迎头色谱法研究了分离红霉素A与红霉素C的过程,结果表明迎头色谱法比洗涤层析法更适合应用于工业生产。
(2)通过间歇吸附平衡实验,研究了不同温度和不同溶液极性下,红霉素A与红霉素C在大孔树脂SP825上吸附等温线。采用竞争Langmuir吸附等温线模型拟合平衡数据,结果表明该模型能较好地描述红霉素A与红霉素C在SP825上的竞争吸附相平衡关系。用所得的模型参数计算了红霉素A的吸附选择系数及红霉素A与红霉素C的部分吸附热力学参数。
(3)通过固定床吸附实验,分别考察了进料浓度和流速对红霉素A与红霉素C在SP825固定床内穿透行为的影响,并建立综合考虑了轴向扩散、液膜扩散及孔内扩散影响的通用速率模型。该模型能较好地模拟实验穿透曲线。利用该模型模拟计算了轴向扩散系数及红霉素A与红霉素C各自的液膜扩散系数和孔内扩散系数对红霉素A与红霉素C在SP825固定床内穿透行为的影响,结果表明轴向扩散和孔内扩散对红霉素A与红霉素C在SP825固定床内的吸附影响较大,而液膜扩散影响则较小。
(4)提出了由大孔树脂迎头色谱法分离红霉素A和红霉素C-洗涤杂质-洗脱红霉素A、洗涤洗脱液中的红霉素C、反应结晶成盐等步骤组成的从红霉素发酵液中分离纯化红霉素A并得到硫氰酸红霉素A的新工艺方法。此工艺的特点为：采用迎头色谱法及用磷酸盐缓冲溶液洗涤洗脱液共同强化对红霉素C的分离。将此工艺得到的硫氰酸红霉素A中红霉素A与红霉素C的含量与溶剂萃取结合盐沉淀法对比可知,此工艺更能有效分离红霉素C。
With the continuous development of semi-synthetic erythromycin drugs and a widely uses in clinical medicine, erythromycin thiocyanate A, as an antibiotic API, has been increasingly important. Since the purity of erythromycin thiocyanate A has a great impact on the yield and quality of the semi-synthetic erythromycin drugs, it has a strict requirement. With high-yield genetically engineered bacterium applied extensively, the concentration of erythromycin in fermentation broth had been increased a lot and energy consumption was cut down, but, at the same time, erythromycin C which has low antimicrobial activity and high toxicity were accumulated. So separating erythromycin C effectively is a new challenge. However, solvent extraction as the common way for purification of erythromycin A is ineffective to separate erythromycin A and erythromycin C, and the impurity of erythromycin C can't be removed effectively.
The basic data and process of the separation of erythromycin A and erythromycin C were studied in this paper. Solution polarity were adjusted in order to increase the adsorptive selectivity of erythromycin A. Competitive adsorption equilibrium behavior in batch mode and adsorption mass transfer process on fixed-bed of erythromycin A and erythromycin C in the binary system using macro-porous resin SP825were investigated systematically. Then, an innovative process based on frontal chromatography and special eluent washing was proposed to purify and obtain erythromycin thiocyanate A from erythromycin fermentation broth with high content of impurity erythromycin C. This process is environmental friendly, economic and suitable for large-scale production.
The main contents and results of this research are included below:
(1) The influence of the polarity of erythromycin solution on adsorptive selectivity of erythromycin A over erythromycin C was studied in detail. The suitable solvent was phosphate buffer with3%(v/v) ethyl acetate. Washing chromatography and frontal chromatography were investigated comparatively. It showed that frontal chromatography was more suitable for the separation of erythromycin A and erythromycin C than washing chromatography in industrial application.
(2) The effects of the polarity of erythromycin solution on adsorption behavior of erythromycin A and erythromycin C on SP825at different temperatures were discussed by batch adsorption equilibrium experiments. By using competitive Langmuir adsorption isotherms to fit the equilibrium data, it showed that this model could describe the competitive adsorption equilibrium of erythromycin A and erythromycin C on SP825well. Selective coefficient of erythromycin A and some thermodynamic parameters of both erythromycin A and erythromycin C were calculated.
(3) The influences of feed concentration and flow rate on breakthrough behavior of erythromycin A and erythromycin C were studied on SP825in fixed bed. A general rate model was established with the consideration of all the effects including axial dispersion, film diffusion and pore diffusion. The model fitted well with the experimental breakthrough curve. The effects of axial diffusion coefficient, film diffusion and pore diffusion of both erythromycin A and erythromycin C on the penetration behavior of erythromycin A and erythromycin C were also investigated in details. It was found that axial dispersion and pore diffusion affected the adsorption behavior of both erythromycin A and erythromycin C greatly, while film diffusion did slightly.
(4) An innovative purification process was proposed to separate and purify erythromycin thiocyanate A from its fermentation broth based on adsorption chromatography with macro-porous resin. It mainly includes the following steps:separating erythromycin A and erythromycin C by frontal chromatography、washing impurities in the bed、eluting erythromycin A, washing erythromycin C in the eluent and obtaining the product by reactive crystallization. In the process, two original steps could separate erythromycin C effectively, which are adsorbing erythromycin A by frontal chromatography and using phosphate buffer to wash the eluent. Content of erythromycin A and erythromycin C in erythromycin thiocyanate A obtained by this process and solvent extraction accompanied with salt precipitation method were compared, and the former could separate erythromycin C more effectively.
本文围绕红霉素A与红霉素C分离的基础数据研究和分离工艺研究两方面展开工作。本文先使用大孔吸附树脂SP825作为吸附剂,通过调整溶液极性以提高红霉素A的吸附选择性,并系统研究了红霉素A与红霉素C的间歇竞争吸附相平衡行为,以及在固定床上的吸附传质动力学过程。在此研究基础上,以绿色、经济、可规模化生产为理念,提出了一条以迎头色谱法为主,磷酸盐缓冲溶液洗涤洗脱液为辅的适宜于从红霉素C杂质含量较高的红霉素发酵液中分离纯化红霉素A并得到硫氰酸红霉素A的工艺路线。
本文的主要研究内容和结论如下：
(1)以提高红霉素A与红霉素C在大孔吸附树脂上的分离效果为目标,通过调节溶液极性,优选出较佳溶剂为含3%(v/v)乙酸乙酯的磷酸盐缓冲溶液。分别采用洗涤层析法和迎头色谱法研究了分离红霉素A与红霉素C的过程,结果表明迎头色谱法比洗涤层析法更适合应用于工业生产。
(2)通过间歇吸附平衡实验,研究了不同温度和不同溶液极性下,红霉素A与红霉素C在大孔树脂SP825上吸附等温线。采用竞争Langmuir吸附等温线模型拟合平衡数据,结果表明该模型能较好地描述红霉素A与红霉素C在SP825上的竞争吸附相平衡关系。用所得的模型参数计算了红霉素A的吸附选择系数及红霉素A与红霉素C的部分吸附热力学参数。
(3)通过固定床吸附实验,分别考察了进料浓度和流速对红霉素A与红霉素C在SP825固定床内穿透行为的影响,并建立综合考虑了轴向扩散、液膜扩散及孔内扩散影响的通用速率模型。该模型能较好地模拟实验穿透曲线。利用该模型模拟计算了轴向扩散系数及红霉素A与红霉素C各自的液膜扩散系数和孔内扩散系数对红霉素A与红霉素C在SP825固定床内穿透行为的影响,结果表明轴向扩散和孔内扩散对红霉素A与红霉素C在SP825固定床内的吸附影响较大,而液膜扩散影响则较小。
(4)提出了由大孔树脂迎头色谱法分离红霉素A和红霉素C-洗涤杂质-洗脱红霉素A、洗涤洗脱液中的红霉素C、反应结晶成盐等步骤组成的从红霉素发酵液中分离纯化红霉素A并得到硫氰酸红霉素A的新工艺方法。此工艺的特点为：采用迎头色谱法及用磷酸盐缓冲溶液洗涤洗脱液共同强化对红霉素C的分离。将此工艺得到的硫氰酸红霉素A中红霉素A与红霉素C的含量与溶剂萃取结合盐沉淀法对比可知,此工艺更能有效分离红霉素C。
With the continuous development of semi-synthetic erythromycin drugs and a widely uses in clinical medicine, erythromycin thiocyanate A, as an antibiotic API, has been increasingly important. Since the purity of erythromycin thiocyanate A has a great impact on the yield and quality of the semi-synthetic erythromycin drugs, it has a strict requirement. With high-yield genetically engineered bacterium applied extensively, the concentration of erythromycin in fermentation broth had been increased a lot and energy consumption was cut down, but, at the same time, erythromycin C which has low antimicrobial activity and high toxicity were accumulated. So separating erythromycin C effectively is a new challenge. However, solvent extraction as the common way for purification of erythromycin A is ineffective to separate erythromycin A and erythromycin C, and the impurity of erythromycin C can't be removed effectively.
The basic data and process of the separation of erythromycin A and erythromycin C were studied in this paper. Solution polarity were adjusted in order to increase the adsorptive selectivity of erythromycin A. Competitive adsorption equilibrium behavior in batch mode and adsorption mass transfer process on fixed-bed of erythromycin A and erythromycin C in the binary system using macro-porous resin SP825were investigated systematically. Then, an innovative process based on frontal chromatography and special eluent washing was proposed to purify and obtain erythromycin thiocyanate A from erythromycin fermentation broth with high content of impurity erythromycin C. This process is environmental friendly, economic and suitable for large-scale production.
The main contents and results of this research are included below:
(1) The influence of the polarity of erythromycin solution on adsorptive selectivity of erythromycin A over erythromycin C was studied in detail. The suitable solvent was phosphate buffer with3%(v/v) ethyl acetate. Washing chromatography and frontal chromatography were investigated comparatively. It showed that frontal chromatography was more suitable for the separation of erythromycin A and erythromycin C than washing chromatography in industrial application.
(2) The effects of the polarity of erythromycin solution on adsorption behavior of erythromycin A and erythromycin C on SP825at different temperatures were discussed by batch adsorption equilibrium experiments. By using competitive Langmuir adsorption isotherms to fit the equilibrium data, it showed that this model could describe the competitive adsorption equilibrium of erythromycin A and erythromycin C on SP825well. Selective coefficient of erythromycin A and some thermodynamic parameters of both erythromycin A and erythromycin C were calculated.
(3) The influences of feed concentration and flow rate on breakthrough behavior of erythromycin A and erythromycin C were studied on SP825in fixed bed. A general rate model was established with the consideration of all the effects including axial dispersion, film diffusion and pore diffusion. The model fitted well with the experimental breakthrough curve. The effects of axial diffusion coefficient, film diffusion and pore diffusion of both erythromycin A and erythromycin C on the penetration behavior of erythromycin A and erythromycin C were also investigated in details. It was found that axial dispersion and pore diffusion affected the adsorption behavior of both erythromycin A and erythromycin C greatly, while film diffusion did slightly.
(4) An innovative purification process was proposed to separate and purify erythromycin thiocyanate A from its fermentation broth based on adsorption chromatography with macro-porous resin. It mainly includes the following steps:separating erythromycin A and erythromycin C by frontal chromatography、washing impurities in the bed、eluting erythromycin A, washing erythromycin C in the eluent and obtaining the product by reactive crystallization. In the process, two original steps could separate erythromycin C effectively, which are adsorbing erythromycin A by frontal chromatography and using phosphate buffer to wash the eluent. Content of erythromycin A and erythromycin C in erythromycin thiocyanate A obtained by this process and solvent extraction accompanied with salt precipitation method were compared, and the former could separate erythromycin C more effectively.
引文
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