大孔树脂吸附技术分离红霉素A及其异构体的基础研究
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摘要
红霉素(Erythromycin,简称EM)属于传统的大环内酯类抗生素品种,具有抗菌作用强、效率高、毒副作用少、衍生物临床应用广等特点。然而,现有的红霉素生产工艺中还存在许多亟待解决的问题,如产品质量差,提取效率低,溶剂消耗量大,环境污染严重等。本文针对这些问题,以绿色、高效、经济为理念,提出了一条创新的膜分离与大孔树脂吸附耦合的分离工艺路线,从而达到精简流程、高效分离、降低污染的目的。
本文的主要内容和结论如下：
(1)通过固定床连续实验,研究了红霉素在SP825树脂上的吸附动力学,考察了进料浓度、温度、床层高度和高径比等因素对红霉素吸附性能的影响,采用同时考虑液膜扩散阻力、孔内扩散阻力和轴向扩散阻力的综合速率模型对吸附过程进行模拟,计算得到相关动力学参数,并对模型进行了误差分析。结果表明：进料浓度的增加对红霉素固定床吸附过程不利,温度和床层高径比的增加可以提高固定床吸附效率,而床层高度的变化对固定床吸附过程影响不大；液膜扩散阻力和孔内扩散阻力均对红霉素固定床吸附过程有重要影响,轴向扩散影响较小；模型的相对误差在10%以内,说明综合速率模型较好的描述了红霉素在SP825树脂上的固定床吸附行为。
(2)通过间歇吸附平衡实验,研究了红霉素A、C组分在SP825树脂上的竞争吸附热力学,测定了不同温度、pH及离子强度下,红霉素A、C组分的竞争吸附相平衡数据。实验范围内,温度、pH及离子强度的增加均对红霉素A、C组分的吸附过程有利。采用扩展Langmuir吸附等温线模型对平衡数据进行拟合,并对该模型进行了误差分析,其相对误差在20%以内,说明该模型能够较好的描述红霉素A、C组分在SP825树脂上的竞争吸附行为。考察了不同温度、pH及离子强度时,SP825树脂对红霉素A、C组分的选择性系数。结果表明,SP825树脂对红霉素A的吸附力略强于红霉素C,KCA随温度及离子强度的增大而增大,随pH的增大先增大后减小,pH为7.0时有最大值1.317。估算了红霉素A、C组分的吸附热力学参数,发现SP825树脂对红霉素A、C组分的吸附均为自发进行的、吸热的以及熵增的物理吸附过程。相同实验条件下,ΔGAAHC,ΔSA>ΔSC。
(3)在前述研究的基础上,采用优选的吸附条件,测定了红霉素碱、红霉素A和红霉素C组分的固定床穿透曲线。结果表明,红霉素A组分在固定床吸附过程中对红霉素C组分具有一定的竞争吸附优势,由此构建了适用于红霉素A、C组分分离的两阶段阶跃洗脱层析工艺过程。筛选了层析过程合适的流动相,考察了第一阶段洗脱条件对红霉素A、C组分分离过程的影响。结果表明,采用3%乙酸乙酯的水溶液以0.5 BV·h-1进行第一阶段洗脱5BV时对红霉素A组分的纯化效果最好。
(4)在固定床阶跃洗脱层析实验的基础上,为了进一步提高层析过程的收率,构建了双柱摆动层析工艺,并对工艺过程进行优化。结果表明,双柱摆动层析工艺在制备出高品质红霉素A产品(红霉素A组分含量为95.2%,红霉素C组分含量为2.3%,红霉素B组分含量为2.5%)的同时,显著提高了固定床阶跃洗脱层析过程的收率(红霉素A组分总收率为93.3%),实现了红霉素A、C组分的有效分离,从而达到了高效分离、有效回收的目的。
(5)为避免发酵液中色素、蛋白等杂质对分离纯化过程的影响,通过膜分离技术对发酵液进行预处理。以色素、蛋白去除率和红霉素收率为指标,考察了50nm无机陶瓷膜对红霉素发酵液的过滤效果。结果表明,所得滤液的平均脱色率为54.2%,平均脱蛋白率为66.6%,红霉素平均收率为95.0%,满足大孔树脂吸附的条件。
(6)提出了以吸附、杂质洗涤、脱附和洗脱液成盐等为步骤组成的大孔树脂吸附技术从发酵液中分离纯化红霉素A的整套工艺流程。研究和优化了各单元操作的工艺条件和实际效果,采用pH为10.0左右的硼砂—NaOH缓冲溶液对吸附完毕的树脂进行杂质洗涤,筛选出50%丙酮和50%0.40mol·L-1 NaOH溶液组成的混合溶液对洗脱完毕的树脂进行再生。结果表明,整个工艺过程的总收率一般在90%以上,且可以使红霉素C组分含量达到高品质红霉素产品的要求,而再生后树脂的饱和吸附量不低于新鲜树脂饱和吸附量的80%。
本文提出了一条可直接应用于工业化规模生产的从发酵液中分离纯化红霉素A的新工艺,研究成果为生产装置的开发和设计提供了理论和实验基础,具有广阔的发展前景。
As a traditional macrolide antibiotic, erythromycin(EM) has become one of the most popular antibiotics due to its features of good curative effect, low side effect and wide clinical use of its derivatives. However, some urgent problems still exist in the present production process of EM, such as the poor quality of products, low extraction efficiency, high consumption of chemicals, and serious pollution of the environment. To solve these problems, an innovative separation process combining the macroporous resin adsorption with the membrane filtration has been proposed in the present paper based on the conception of "green, effective and economic".
The main contents and conclusions are as follows:
(1) The effect of feed concentration, temperature, bed height and aspect ratio on the fixed-bed adsorption characteristics of EM was investigated by using a macroporous resin SP825 as adsorbent. The general rate model taking the film mass transfer, pore diffusion and axial dispersion into account was adopted to describe the breakthrough curves. The mass transfer coefficients and the relative errors of the model were consequently determined. The results showed that the increase of feed concentration was not in favor of the fixed-bed adsorption performance, while the increase of temperature and aspect ratio could improve the mass transfer. In addition, the variation in bed height had little effect on adsorption characteristics. By calculating the mass Biot number and Peclet number, it is clear that both liquid film mass transfer and pore diffusion play important roles in the fixed-bed adsorption of EM onto SP825, whereas the axial dispersion could be negligible in the experimental range. The relative errors of the model were within 10%, indicating a satisfactory simulation.
(2) The competitive adsorption equilibrium data for the binary system of EA and EC onto a macroporous resin SP825 were tested through batch experiments and modeled using the extended Langmuir equation at different pH, ionic strengths and temperatures. For both EA and EC, the adsorption was enhanced with the increase of pH, ionic strength and temperature. The relative errors of the extended Langmuir model were within 20%, showing a good agreement between the experimental and the model-predicted data. Selectivity coefficients for adsorption of EA and EC onto SP825 were determined. The results suggested that the adsorption ability of SP825 for EA was little stronger than EC, and a higher KCA value was observed at pH 7.0 with the increase of ionic strength and temperature. Some thermodynamic parameters of EA and EC were also calculated. It can be seen that the adsorption of both EA and EC onto SP825 was a spontaneous, endothermic and entropy incresing physisorption process. Under the same experimental condition,△GA<△GC,△HA>△HC, ASA>△SC
(3) On the basis of the results above, the breakthrough curves for adsorption of EM, EA and EC in the fixed-bed were measured under the optimum condition. EA was found to breakthrough later than EC, thus a 2-stepwise elution chromatography process was established for the separation of EA and EC. The mobile phase and the first step elution mode of the chromatography was determined. By eluting the column with 3% ethyl acetate solution at the flowrate of 0.5 BV·h-1 for 5BV in the first step,the purity of EA could reach 95.4% in product.
(4) To improve the EA yield of the stepwise elution chromatography process, a double-column swing chromatography process was further proposed and optimized. The results showed that the new process could not only produce high quality EM products(EA: 95.2%, EC:2.3%, EB:2.5%), but also increase the EA yield of the whole process obviously(EA total yield:93.3%). With the new process, the effective seraration of EA and EC components was finally realized.
(5) Since the fermentation broth contains a lot of impurities, such as color, protein, etc, the effect of pretreatment of fermentation broth using membrane filtration technology was investigated. As a result, the 50nm ceramic membrane was selected, for the average decolorization rate, the average deproteinization rate and the average EM yield rate of the filtrate was 54.2%,66.6% and 95.0%, respetively. After the membrane filtration, the fermentation broth was then qualified for the adsorption process by macroporous resins.
(6) A complete set of separation process for recovering EA from fermentation broth was introduced, including adsorption, impurity washing, desorption and salification in the eluate. The technological conditions and its practical effect of each unit operation were studied and optimized. The borax buffer solution with pH 10.0 was chosen to wash impurities and the mixture of 50% acetone and 50% 0.40mol·L-1 NaOH solution was selected to regenerate the resins. Through the whole separation process, the content of EC in product could meet the requirement of high quality EM product with a total yield over 90%. Moreover, the saturated adsorption capacity of the regenerated resin was no less than 80% compared with that of the fresh resin.
An innovative technology routine which can be applied to industrial production directly for separation and purification of EA from fermentation broth has been presented in this paper. The results of this research provides the experimental foundation for the design and development of large-scale industrial equipments and has an expansively prospect.
本文的主要内容和结论如下：
(1)通过固定床连续实验,研究了红霉素在SP825树脂上的吸附动力学,考察了进料浓度、温度、床层高度和高径比等因素对红霉素吸附性能的影响,采用同时考虑液膜扩散阻力、孔内扩散阻力和轴向扩散阻力的综合速率模型对吸附过程进行模拟,计算得到相关动力学参数,并对模型进行了误差分析。结果表明：进料浓度的增加对红霉素固定床吸附过程不利,温度和床层高径比的增加可以提高固定床吸附效率,而床层高度的变化对固定床吸附过程影响不大；液膜扩散阻力和孔内扩散阻力均对红霉素固定床吸附过程有重要影响,轴向扩散影响较小；模型的相对误差在10%以内,说明综合速率模型较好的描述了红霉素在SP825树脂上的固定床吸附行为。
(2)通过间歇吸附平衡实验,研究了红霉素A、C组分在SP825树脂上的竞争吸附热力学,测定了不同温度、pH及离子强度下,红霉素A、C组分的竞争吸附相平衡数据。实验范围内,温度、pH及离子强度的增加均对红霉素A、C组分的吸附过程有利。采用扩展Langmuir吸附等温线模型对平衡数据进行拟合,并对该模型进行了误差分析,其相对误差在20%以内,说明该模型能够较好的描述红霉素A、C组分在SP825树脂上的竞争吸附行为。考察了不同温度、pH及离子强度时,SP825树脂对红霉素A、C组分的选择性系数。结果表明,SP825树脂对红霉素A的吸附力略强于红霉素C,KCA随温度及离子强度的增大而增大,随pH的增大先增大后减小,pH为7.0时有最大值1.317。估算了红霉素A、C组分的吸附热力学参数,发现SP825树脂对红霉素A、C组分的吸附均为自发进行的、吸热的以及熵增的物理吸附过程。相同实验条件下,ΔGA
(3)在前述研究的基础上,采用优选的吸附条件,测定了红霉素碱、红霉素A和红霉素C组分的固定床穿透曲线。结果表明,红霉素A组分在固定床吸附过程中对红霉素C组分具有一定的竞争吸附优势,由此构建了适用于红霉素A、C组分分离的两阶段阶跃洗脱层析工艺过程。筛选了层析过程合适的流动相,考察了第一阶段洗脱条件对红霉素A、C组分分离过程的影响。结果表明,采用3%乙酸乙酯的水溶液以0.5 BV·h-1进行第一阶段洗脱5BV时对红霉素A组分的纯化效果最好。
(4)在固定床阶跃洗脱层析实验的基础上,为了进一步提高层析过程的收率,构建了双柱摆动层析工艺,并对工艺过程进行优化。结果表明,双柱摆动层析工艺在制备出高品质红霉素A产品(红霉素A组分含量为95.2%,红霉素C组分含量为2.3%,红霉素B组分含量为2.5%)的同时,显著提高了固定床阶跃洗脱层析过程的收率(红霉素A组分总收率为93.3%),实现了红霉素A、C组分的有效分离,从而达到了高效分离、有效回收的目的。
(5)为避免发酵液中色素、蛋白等杂质对分离纯化过程的影响,通过膜分离技术对发酵液进行预处理。以色素、蛋白去除率和红霉素收率为指标,考察了50nm无机陶瓷膜对红霉素发酵液的过滤效果。结果表明,所得滤液的平均脱色率为54.2%,平均脱蛋白率为66.6%,红霉素平均收率为95.0%,满足大孔树脂吸附的条件。
(6)提出了以吸附、杂质洗涤、脱附和洗脱液成盐等为步骤组成的大孔树脂吸附技术从发酵液中分离纯化红霉素A的整套工艺流程。研究和优化了各单元操作的工艺条件和实际效果,采用pH为10.0左右的硼砂—NaOH缓冲溶液对吸附完毕的树脂进行杂质洗涤,筛选出50%丙酮和50%0.40mol·L-1 NaOH溶液组成的混合溶液对洗脱完毕的树脂进行再生。结果表明,整个工艺过程的总收率一般在90%以上,且可以使红霉素C组分含量达到高品质红霉素产品的要求,而再生后树脂的饱和吸附量不低于新鲜树脂饱和吸附量的80%。
本文提出了一条可直接应用于工业化规模生产的从发酵液中分离纯化红霉素A的新工艺,研究成果为生产装置的开发和设计提供了理论和实验基础,具有广阔的发展前景。
As a traditional macrolide antibiotic, erythromycin(EM) has become one of the most popular antibiotics due to its features of good curative effect, low side effect and wide clinical use of its derivatives. However, some urgent problems still exist in the present production process of EM, such as the poor quality of products, low extraction efficiency, high consumption of chemicals, and serious pollution of the environment. To solve these problems, an innovative separation process combining the macroporous resin adsorption with the membrane filtration has been proposed in the present paper based on the conception of "green, effective and economic".
The main contents and conclusions are as follows:
(1) The effect of feed concentration, temperature, bed height and aspect ratio on the fixed-bed adsorption characteristics of EM was investigated by using a macroporous resin SP825 as adsorbent. The general rate model taking the film mass transfer, pore diffusion and axial dispersion into account was adopted to describe the breakthrough curves. The mass transfer coefficients and the relative errors of the model were consequently determined. The results showed that the increase of feed concentration was not in favor of the fixed-bed adsorption performance, while the increase of temperature and aspect ratio could improve the mass transfer. In addition, the variation in bed height had little effect on adsorption characteristics. By calculating the mass Biot number and Peclet number, it is clear that both liquid film mass transfer and pore diffusion play important roles in the fixed-bed adsorption of EM onto SP825, whereas the axial dispersion could be negligible in the experimental range. The relative errors of the model were within 10%, indicating a satisfactory simulation.
(2) The competitive adsorption equilibrium data for the binary system of EA and EC onto a macroporous resin SP825 were tested through batch experiments and modeled using the extended Langmuir equation at different pH, ionic strengths and temperatures. For both EA and EC, the adsorption was enhanced with the increase of pH, ionic strength and temperature. The relative errors of the extended Langmuir model were within 20%, showing a good agreement between the experimental and the model-predicted data. Selectivity coefficients for adsorption of EA and EC onto SP825 were determined. The results suggested that the adsorption ability of SP825 for EA was little stronger than EC, and a higher KCA value was observed at pH 7.0 with the increase of ionic strength and temperature. Some thermodynamic parameters of EA and EC were also calculated. It can be seen that the adsorption of both EA and EC onto SP825 was a spontaneous, endothermic and entropy incresing physisorption process. Under the same experimental condition,△GA<△GC,△HA>△HC, ASA>△SC
(3) On the basis of the results above, the breakthrough curves for adsorption of EM, EA and EC in the fixed-bed were measured under the optimum condition. EA was found to breakthrough later than EC, thus a 2-stepwise elution chromatography process was established for the separation of EA and EC. The mobile phase and the first step elution mode of the chromatography was determined. By eluting the column with 3% ethyl acetate solution at the flowrate of 0.5 BV·h-1 for 5BV in the first step,the purity of EA could reach 95.4% in product.
(4) To improve the EA yield of the stepwise elution chromatography process, a double-column swing chromatography process was further proposed and optimized. The results showed that the new process could not only produce high quality EM products(EA: 95.2%, EC:2.3%, EB:2.5%), but also increase the EA yield of the whole process obviously(EA total yield:93.3%). With the new process, the effective seraration of EA and EC components was finally realized.
(5) Since the fermentation broth contains a lot of impurities, such as color, protein, etc, the effect of pretreatment of fermentation broth using membrane filtration technology was investigated. As a result, the 50nm ceramic membrane was selected, for the average decolorization rate, the average deproteinization rate and the average EM yield rate of the filtrate was 54.2%,66.6% and 95.0%, respetively. After the membrane filtration, the fermentation broth was then qualified for the adsorption process by macroporous resins.
(6) A complete set of separation process for recovering EA from fermentation broth was introduced, including adsorption, impurity washing, desorption and salification in the eluate. The technological conditions and its practical effect of each unit operation were studied and optimized. The borax buffer solution with pH 10.0 was chosen to wash impurities and the mixture of 50% acetone and 50% 0.40mol·L-1 NaOH solution was selected to regenerate the resins. Through the whole separation process, the content of EC in product could meet the requirement of high quality EM product with a total yield over 90%. Moreover, the saturated adsorption capacity of the regenerated resin was no less than 80% compared with that of the fresh resin.
An innovative technology routine which can be applied to industrial production directly for separation and purification of EA from fermentation broth has been presented in this paper. The results of this research provides the experimental foundation for the design and development of large-scale industrial equipments and has an expansively prospect.
引文
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