异戊酰螺旋霉素Ⅱ和异戊酰螺旋霉素Ⅲ的层析分离过程研究
|
摘要
异戊酰螺旋霉素是由将克隆自碳霉素产生菌的4"-O-异戊酰基转移酶基因整合到螺旋霉素产生菌Streptomyces spiramyceticus F-21的染色体上而构建成的一株稳定的生物工程菌WSJ-1-195产生的具有一系列相似结构的混合物,由于其活性高、稳定性好以及相对耐药性好等特点,而成为主要的抗生素产品之一,其中,异戊酰螺旋霉素Ⅲ具有最好的稳定性和最高的活性。但由于异戊酰螺旋霉素发酵液中存在与异戊酰螺旋霉素Ⅲ(主要抗菌活性成分)相似的杂质组分,采用常规的分离技术难以获得高纯度的异戊酰螺旋霉素Ⅲ产品,成为制约异戊酰螺旋霉素Ⅲ工业化生产的瓶颈之一
本文针对异戊酰螺旋霉素Ⅱ和异戊酰螺旋霉素Ⅲ组分的分离难点,以提高异戊酰螺旋霉素Ⅲ组分的纯度和收率为目标,对分离纯化过程进行了系统的研究以及模拟计算,提出了间歇柱层析分离工艺路线,以解决异戊酰螺旋霉素Ⅱ和异戊酰螺旋霉素Ⅲ组分分离的关键技术难题。
本文的主要内容和结论如下：
(1)以吸附剂对异戊酰螺旋霉素Ⅲ组分的选择性系数为主要指标,分别考察了吸附剂、离子强度及pH对异戊酰螺旋霉素Ⅲ选择性吸附效果的影响。比较筛选得出较优吸附剂和吸附条件：以异戊酰螺旋霉素粗品为原料,HZ820树脂为吸附剂,离子强度0.5 mol/L、pH 6.5时,对异戊酰螺旋霉素Ⅲ组分的选择性系数较高(KⅡⅢ为1.67),表现出较好的吸附选择性。根据热力学计算可知,该过程为自发熵增的吸热过程。
(2)测定了不同温度、pH及离子强度下,异戊酰螺旋霉素Ⅱ、Ⅲ组分在HZ820大孔吸附树脂上的竞争吸附平衡数据。实验范围内,温度、pH及离子强度的增加均对异戊酰螺旋霉素Ⅱ、Ⅲ组分的吸附过程有利。分别采用了扩展Langmuir模型、扩展Langmuir-Freundlich模型和扩展Jovanovic-Freundlich模型对平衡数据进行拟合和对比,其中扩展Langmuir-Freundlich模型取得了最好的拟合结果。根据扩展Langmuir-Freundlich吸附等温线模型的拟合结果,对该模型进行了误差分析,其相对误差在15%以内,说明该模型能够较好的描述异戊酰螺旋霉素Ⅱ、Ⅲ组分在HZ820树脂上的竞争吸附行为。
(3)测定了异戊酰螺旋霉素在HZ820树脂上的间歇吸附动力学数据,考察了温度、pH及离子强度等因素对动力学过程的影响,分别采用拟一级、拟二级和颗粒内扩散模型对比拟合异戊酰螺旋霉素在HZ820大孔吸附树脂上的吸附过程,结果表明该过程为一个非均相的优惠吸附过程,吸附速率由液膜扩散和颗粒内扩散综合控制。
(4)研究了进料流速、浓度、床层高径比等因素对固定床内异戊酰螺旋霉素在HZ820大孔吸附树脂上的吸附性能的影响,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：进料流速和浓度的增加对异戊酰螺旋霉素固定床吸附过程不利,床层高径比的增加可以提高固定床吸附效率；液膜扩散阻力和孔内扩散阻力均对异戊酰螺旋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,说明液膜、颗粒内扩散及轴向扩散综合速率模型较好的描述了异戊酰螺旋霉素在HZ820树脂上的固定床吸附行为。
(5)在前述研究的基础上,以异戊酰螺旋霉素粗品为原料,研究了固定床吸附和解吸过程。从采用前述优选的HZ820吸附剂和吸附条件时测得的异戊酰螺旋霉素Ⅱ和异戊酰螺旋霉素Ⅲ组分的穿透曲线,吸附过程中异戊酰螺旋霉素Ⅱ和异戊酰螺旋霉素Ⅲ组分表现出了明显的竞争吸附特性；随后采用石油醚为洗脱剂,以1.20 BV/hr流速洗脱,洗脱剂用量6.00 BV时,对异戊酰螺旋霉素Ⅲ的洗脱选择性(KⅡⅢ为1.60)和收率(94.2%)均较好。
(6)以异戊酰螺旋霉素发酵液为原料,经过膜过滤、树脂吸附、树脂洗涤、树脂洗脱、结晶等步骤制备异戊酰螺旋霉素粗品。研究和优化了各单元操作的工艺条件和实际效果,采用pH 8.0,1=0.2 mol-L-1的磷酸盐缓冲液对吸附完毕的树脂进行杂质洗涤,选用石油醚为洗脱剂,对洗涤完毕的树脂进行洗脱,可使异戊酰螺旋霉素Ⅲ得到富集的同时,对异戊酰螺旋霉素Ⅱ组分有一定的去除作用,从而得到高品质的异戊酰螺旋霉素产品。
本文针对国内菌种的异戊酰螺旋霉素发酵液中存在副产物组分多,浓度高,和主要产物异戊酰螺旋霉素Ⅲ之间分离的难点,提出了一条分离纯化异戊酰螺旋霉素Ⅲ的新工艺,研究成果为异戊酰螺旋霉素Ⅲ生产工艺的开发和设计提供了理论和实验基础。该技术与膜过滤、结晶等技术组合可形成先进的异戊酰螺旋霉素提取分离生产工艺,能够显著提高异戊酰螺旋霉素Ⅲ产品的质量和收率,具有广阔的发展前景。
4"-O-isovalerylspiramycin is a new macrolide antibiotic produced by genetically engineered Streptomyces spiramyceticus transformed with the 4"-O-acyltransferase gene from S. mycarofaciens.4"-O-isovalerylspiramycin is a mixture of 4"-O-isovalerylspiramycin I, II, and III, which all possess similar molecular structures. During fermentation, 4"-O-isovalerylspiramycinⅢis the main and active product. However, separation of 4"-O-isovalerylspiramycinⅡandⅢis very difficult because they have very similar chemical structures and characteristics.
In the present work, the separation process of 4"-O-isovalerylspiramycinⅡand III has been studied systematically. According to the difficulties of separation and purification, an innovative chromatographic technology routine has been presented, which can solve the difficulties in the separation of 4"-O-isovalerylspiramycin II and III.
The main contents and conclusions are listed as follows:
(1)With impure 4"-O-isovalerylspiramycin (4"-O-isovalerylspiramycinⅡ:Ⅲ=2:3, w/w) as raw material, the appropriate selective adsorption conditions for 4"-O-isovalerylspiramycinⅢ, which have been obtained by batch adsorption experiments, are as follows:HZ820 as adsorbent, ionic strength 0.5 mol/L, pH 6.5, KⅡⅢis 1.67, indicating that HZ820 has a good selectivity for 4"-O-isovalerylspiramycin III under these conditions. According to thermodynamics results, this adsorption is a spontaneous, entropy increase and endothermic process.
(2)The competitive adsorption equilibrium data for the binary system of 4"-O-isovalerylspiramycinⅡandⅢonto a macroporous resin HZ820 were tested and modeled using the extended Langmuir, extended Langmuir-Freundlich and extended Jovanovic-Freundlich equation at different pH, ionic strengths and temperatures. For both 4"-O-isovalerylspiramycinⅡandⅢ, the adsorption was enhanced with the increase of pH, ionic strength and temperature. The extended Langmuir-Freundlich adsorption model gave the best competitive isotherm fits for both 4"-O-isovalerylspiramycin II and III. The relative errors of the extended Langmuir-Freundlich model were within 15%.
(3)The effects of the operation parameters, which is mentioned above, on the adsorption kinetics of 4"-O-isovalerylspiramycin to HZ820 resin have been determined. Pseudo-first-order, Pseudo-second-order and intra-particle diffusion model each have been used to describe 4"-O-isovalerylspiramycin adsorption profile in thermostatic shaker. The results showed that Pseudo-second-order model successfully described the adsorption of 4"-O-isovalerylspiramycin on HZ820. The adsorption was favorable process.
(4)The effect of flow velocity, feed concentration, and aspect ratio on the fixed-bed adsorption characteristics of 4"-O-isovalerylspiramycin was investigated by using a macroporous resin HZ820 as adsorbent. The film, porous and axial diffusion 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 flow velocity and feed concentration was not in favor of the fixed-bed adsorption performance, while the increase of aspect ratio could improve the mass transfer. It is clear that both liquid film mass transfer and pore diffusion play important roles in the fixed-bed adsorption of 4"-O-isovalerylspiramycin onto HZ820, whereas the axial dispersion could be negligible in the experimental range. The relative errors of the model were within 10%, indicating a satisfactory simulation.
(5)On the basis of those above, the adsorption and desorption processes with impure 4"-O-isovalerylspiramycin as raw material have been studied by using the optimal conditions in fixed bed. It shows that a competitive adsorption between 4"-O-isovalerylspiramycin II andⅢoccurred; petroleum ether as eluent, flow velocity 1.20 BV/hr, the elution volume 6.00BV, KⅡⅢis 1.60, and thus 4"-O-isovalerylspiramycin III desorption rate can reach 94.2%.
(6)A complete set of separation process for recovering 4"-O-isovalerylspiramycin III from fermentation broth was introduced, including membrane filtration, adsorption, impurity washing, desorption and crystallization in the eluate. The technological conditions and its practical effect of each unit operation were studied and optimized. The phosphate hydrate buffer solution (pH 8.0,1=0.2 mol·L-1)was chosen to wash impurities. Through the whole separation process, the content of 4"-O-isovalerylspiramycin III in product could meet the requirement.
Aim at the difficulties of separation of 4"-O-isovalerylspiramycin II and III, an innovative technology routine for separation and purification of 4"-O-isovalerylspiramycin III has been presented in this paper. This research provides the experimental foundation for the development and design of large-scale industrial equipment. With the combination of membrane filtration and crystallization, an advanced 4"-O-isovalerylspiramycin production technology can be established, which can improve the purity and yield of 4"-O-isovalerylspiramycin III significantly and be of great prospect in practical application.
本文针对异戊酰螺旋霉素Ⅱ和异戊酰螺旋霉素Ⅲ组分的分离难点,以提高异戊酰螺旋霉素Ⅲ组分的纯度和收率为目标,对分离纯化过程进行了系统的研究以及模拟计算,提出了间歇柱层析分离工艺路线,以解决异戊酰螺旋霉素Ⅱ和异戊酰螺旋霉素Ⅲ组分分离的关键技术难题。
本文的主要内容和结论如下：
(1)以吸附剂对异戊酰螺旋霉素Ⅲ组分的选择性系数为主要指标,分别考察了吸附剂、离子强度及pH对异戊酰螺旋霉素Ⅲ选择性吸附效果的影响。比较筛选得出较优吸附剂和吸附条件：以异戊酰螺旋霉素粗品为原料,HZ820树脂为吸附剂,离子强度0.5 mol/L、pH 6.5时,对异戊酰螺旋霉素Ⅲ组分的选择性系数较高(KⅡⅢ为1.67),表现出较好的吸附选择性。根据热力学计算可知,该过程为自发熵增的吸热过程。
(2)测定了不同温度、pH及离子强度下,异戊酰螺旋霉素Ⅱ、Ⅲ组分在HZ820大孔吸附树脂上的竞争吸附平衡数据。实验范围内,温度、pH及离子强度的增加均对异戊酰螺旋霉素Ⅱ、Ⅲ组分的吸附过程有利。分别采用了扩展Langmuir模型、扩展Langmuir-Freundlich模型和扩展Jovanovic-Freundlich模型对平衡数据进行拟合和对比,其中扩展Langmuir-Freundlich模型取得了最好的拟合结果。根据扩展Langmuir-Freundlich吸附等温线模型的拟合结果,对该模型进行了误差分析,其相对误差在15%以内,说明该模型能够较好的描述异戊酰螺旋霉素Ⅱ、Ⅲ组分在HZ820树脂上的竞争吸附行为。
(3)测定了异戊酰螺旋霉素在HZ820树脂上的间歇吸附动力学数据,考察了温度、pH及离子强度等因素对动力学过程的影响,分别采用拟一级、拟二级和颗粒内扩散模型对比拟合异戊酰螺旋霉素在HZ820大孔吸附树脂上的吸附过程,结果表明该过程为一个非均相的优惠吸附过程,吸附速率由液膜扩散和颗粒内扩散综合控制。
(4)研究了进料流速、浓度、床层高径比等因素对固定床内异戊酰螺旋霉素在HZ820大孔吸附树脂上的吸附性能的影响,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：进料流速和浓度的增加对异戊酰螺旋霉素固定床吸附过程不利,床层高径比的增加可以提高固定床吸附效率；液膜扩散阻力和孔内扩散阻力均对异戊酰螺旋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,说明液膜、颗粒内扩散及轴向扩散综合速率模型较好的描述了异戊酰螺旋霉素在HZ820树脂上的固定床吸附行为。
(5)在前述研究的基础上,以异戊酰螺旋霉素粗品为原料,研究了固定床吸附和解吸过程。从采用前述优选的HZ820吸附剂和吸附条件时测得的异戊酰螺旋霉素Ⅱ和异戊酰螺旋霉素Ⅲ组分的穿透曲线,吸附过程中异戊酰螺旋霉素Ⅱ和异戊酰螺旋霉素Ⅲ组分表现出了明显的竞争吸附特性；随后采用石油醚为洗脱剂,以1.20 BV/hr流速洗脱,洗脱剂用量6.00 BV时,对异戊酰螺旋霉素Ⅲ的洗脱选择性(KⅡⅢ为1.60)和收率(94.2%)均较好。
(6)以异戊酰螺旋霉素发酵液为原料,经过膜过滤、树脂吸附、树脂洗涤、树脂洗脱、结晶等步骤制备异戊酰螺旋霉素粗品。研究和优化了各单元操作的工艺条件和实际效果,采用pH 8.0,1=0.2 mol-L-1的磷酸盐缓冲液对吸附完毕的树脂进行杂质洗涤,选用石油醚为洗脱剂,对洗涤完毕的树脂进行洗脱,可使异戊酰螺旋霉素Ⅲ得到富集的同时,对异戊酰螺旋霉素Ⅱ组分有一定的去除作用,从而得到高品质的异戊酰螺旋霉素产品。
本文针对国内菌种的异戊酰螺旋霉素发酵液中存在副产物组分多,浓度高,和主要产物异戊酰螺旋霉素Ⅲ之间分离的难点,提出了一条分离纯化异戊酰螺旋霉素Ⅲ的新工艺,研究成果为异戊酰螺旋霉素Ⅲ生产工艺的开发和设计提供了理论和实验基础。该技术与膜过滤、结晶等技术组合可形成先进的异戊酰螺旋霉素提取分离生产工艺,能够显著提高异戊酰螺旋霉素Ⅲ产品的质量和收率,具有广阔的发展前景。
4"-O-isovalerylspiramycin is a new macrolide antibiotic produced by genetically engineered Streptomyces spiramyceticus transformed with the 4"-O-acyltransferase gene from S. mycarofaciens.4"-O-isovalerylspiramycin is a mixture of 4"-O-isovalerylspiramycin I, II, and III, which all possess similar molecular structures. During fermentation, 4"-O-isovalerylspiramycinⅢis the main and active product. However, separation of 4"-O-isovalerylspiramycinⅡandⅢis very difficult because they have very similar chemical structures and characteristics.
In the present work, the separation process of 4"-O-isovalerylspiramycinⅡand III has been studied systematically. According to the difficulties of separation and purification, an innovative chromatographic technology routine has been presented, which can solve the difficulties in the separation of 4"-O-isovalerylspiramycin II and III.
The main contents and conclusions are listed as follows:
(1)With impure 4"-O-isovalerylspiramycin (4"-O-isovalerylspiramycinⅡ:Ⅲ=2:3, w/w) as raw material, the appropriate selective adsorption conditions for 4"-O-isovalerylspiramycinⅢ, which have been obtained by batch adsorption experiments, are as follows:HZ820 as adsorbent, ionic strength 0.5 mol/L, pH 6.5, KⅡⅢis 1.67, indicating that HZ820 has a good selectivity for 4"-O-isovalerylspiramycin III under these conditions. According to thermodynamics results, this adsorption is a spontaneous, entropy increase and endothermic process.
(2)The competitive adsorption equilibrium data for the binary system of 4"-O-isovalerylspiramycinⅡandⅢonto a macroporous resin HZ820 were tested and modeled using the extended Langmuir, extended Langmuir-Freundlich and extended Jovanovic-Freundlich equation at different pH, ionic strengths and temperatures. For both 4"-O-isovalerylspiramycinⅡandⅢ, the adsorption was enhanced with the increase of pH, ionic strength and temperature. The extended Langmuir-Freundlich adsorption model gave the best competitive isotherm fits for both 4"-O-isovalerylspiramycin II and III. The relative errors of the extended Langmuir-Freundlich model were within 15%.
(3)The effects of the operation parameters, which is mentioned above, on the adsorption kinetics of 4"-O-isovalerylspiramycin to HZ820 resin have been determined. Pseudo-first-order, Pseudo-second-order and intra-particle diffusion model each have been used to describe 4"-O-isovalerylspiramycin adsorption profile in thermostatic shaker. The results showed that Pseudo-second-order model successfully described the adsorption of 4"-O-isovalerylspiramycin on HZ820. The adsorption was favorable process.
(4)The effect of flow velocity, feed concentration, and aspect ratio on the fixed-bed adsorption characteristics of 4"-O-isovalerylspiramycin was investigated by using a macroporous resin HZ820 as adsorbent. The film, porous and axial diffusion 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 flow velocity and feed concentration was not in favor of the fixed-bed adsorption performance, while the increase of aspect ratio could improve the mass transfer. It is clear that both liquid film mass transfer and pore diffusion play important roles in the fixed-bed adsorption of 4"-O-isovalerylspiramycin onto HZ820, whereas the axial dispersion could be negligible in the experimental range. The relative errors of the model were within 10%, indicating a satisfactory simulation.
(5)On the basis of those above, the adsorption and desorption processes with impure 4"-O-isovalerylspiramycin as raw material have been studied by using the optimal conditions in fixed bed. It shows that a competitive adsorption between 4"-O-isovalerylspiramycin II andⅢoccurred; petroleum ether as eluent, flow velocity 1.20 BV/hr, the elution volume 6.00BV, KⅡⅢis 1.60, and thus 4"-O-isovalerylspiramycin III desorption rate can reach 94.2%.
(6)A complete set of separation process for recovering 4"-O-isovalerylspiramycin III from fermentation broth was introduced, including membrane filtration, adsorption, impurity washing, desorption and crystallization in the eluate. The technological conditions and its practical effect of each unit operation were studied and optimized. The phosphate hydrate buffer solution (pH 8.0,1=0.2 mol·L-1)was chosen to wash impurities. Through the whole separation process, the content of 4"-O-isovalerylspiramycin III in product could meet the requirement.
Aim at the difficulties of separation of 4"-O-isovalerylspiramycin II and III, an innovative technology routine for separation and purification of 4"-O-isovalerylspiramycin III has been presented in this paper. This research provides the experimental foundation for the development and design of large-scale industrial equipment. With the combination of membrane filtration and crystallization, an advanced 4"-O-isovalerylspiramycin production technology can be established, which can improve the purity and yield of 4"-O-isovalerylspiramycin III significantly and be of great prospect in practical application.
引文
[1]Zahner H, MASS W K. Biology of antibiotics[M]. New York, Spinger-Verlag,1972
[2]胡福泉.抗生素研究进展及其应用前景.生物学杂志[J].2003,3(2)：9-60
[3]Kurath P, Jones PH, Egan RS, Perun TJ. Acid degradation of erythromycin A and erythromycin B[J]. Experientia.1971,27:362-365
[4]Periti P, Mazzei T, Mini E, Novelli A. Pharmacokinetic drug interaction of macrolides[J]. Clin. Pharmcokinet.1992.23:106-131
[5]Rubinstein E, Keller N. Spiramycin reaissance[J]. J.Antimicrob.Chemother.1998,42: 572-578
[6]朱峰,王尔健.螺旋霉素的再评价。中国抗生素杂志[J].1991,16：231-236
[7]Chabbert YA. Early studies on in-vitro and experimental activity of spiramycin:a review[J]. J.Antimicrob Chemother.1988,22(Suppl B):1-11
[8]冯闻铮,亓平言,周倜,苗勇,段训宝.螺旋霉素在酸碱溶液中的降解动力学[J].药学学报.1997,32：934-937
[9]Mourier P, Brun A. Study of the metabolism of spiramycin in pig liver[J]. J.Chromatogr. B.1997,704:197-205
[10]Feng W.Z., P.Y. Qi, T. Zhou, Y. Miao, X.B. Duan. Study on the degradation kinetics of spiramycin in acid and alkaline solutions[J]. Acta Pharm. Sin.32 (1997) 934-937
[11]Ramu K., Shringarpure S., Williamson J.S. A solution conformation analysis of forocidins I and isoforocidins I using NMR and molecular modeling[J]. Pharm. Res. 1995,12:621-629.
[12]孙丽文.螺旋霉素类抗生素体内过程探讨[J].国外医药·抗生素分册1990,11：358-365
[13]李显至,王浴生.抗生素抗菌后效作用的研究[J].国外医药·抗生素分册1990,11：439-444
[14]戴自英.实用抗菌药物学[M].上海：上海科技技术出版社,1991,218
[15]Weikel C, Lazenby A, Belitsos P, McDewitt M, Fleming HE Jr, Barbacci M. Intestinal injury associated with spiramycin therapy of cryptoporidium infection in AIDS[J]. J. Protozool.1991,38:147S
[16]Hardy DJ, Hensy DM, Beyer JM, Vojtko C, MoDonald EJ, Fernandes PB. Comparative in vitro activities of new 14-,15-, and 16-membered macrolides. Antimicrob[J]. Agents Chemother.1988,32:1710-1719
[17]Webster C, Ghaznfar K, Slack R. Sub-inhibitory and post-antibiotic effects of spiramycin and erythromycin on Staphylococcus aureus[J]. J. Antimicrob. Chemother. 1988,22 (Suppl B):33-39
[18]Rakhit S, Singh K. Structure activity relationship in sixteen membered macrolide antibiotics[J]. J Antibiotics.1974, ⅩⅩⅦ(3):221-224
[19]王以光.基因工程在大环内酯类抗生素研究中的应用(综述)[J].国外医药抗生素分册.1997,18(2)：92-98
[20]Shi X.G., Zhang S.Q., Paul Fawcett J., Zhong D.F. Acid catalysed degradation of some spiramycin derivatives found in the antibiotic bitespiramycin[J]. Journal of Pharmaceutical and Biomedical Analysis.36 (2004):593-600
[21]游旭.萃取法分离纯化必特螺旋霉素[D]。华东理工大学.2007
[22]元平言,冯闻铮等.螺旋霉素发酵滤液提取过程工艺研究[J].清华大学学报,1997,37(12)：64-67
[23]元平言,冯闻铮.螺旋霉素发酵液凡萃取过程工艺研究[J].中国抗生素杂志,1997,22(3)：178-181
[24]王跃生,王洋.大孔吸附树脂研究进展[J].中国中药杂志.2006,31(12)：961-965.
[25]Vertesy L, Ehlers H, Kogler H, et al. Friulimicins:novel lipopeptide antibiotics with peptidoglycan synthesis inhibiting activity from Actinoplanes friuliensis sp. nov. Ⅱ. Isolation and structural characterization[J]. J Antibiot.2000,53(8):816-827.
[26]Nakai R, Kakita S, Asai A, et al. Chrolactomycin, a novel antitumor antibiotic produced by Streptomyces sp.[J]. J Antibiot.2001,54(10):836-839.
[27]Sasaki T, Igarashi Y, Saito N, et al. Cedarmycins A and B, new antimicrobial antibiotics from Streptomyces sp.TP-A0456[J]. J Antibiot.2001,54(7):567-572.
[28]Cang S, Ohta S, Chiba H, et al. New naphthyridinomycin-type antibiotics, aclidinomycins A and B, from Streptomyces halstedi[J]. J Antibiot.2001,54(3): 304-307.
[29]Sasaki O, Igarashi Y, Saito N, et al. Watasemycins A and B, new antibiotics produced by Streptomyces sp.TP-A0597[J]. J Antibiot.2002,55(3):249-255.
[30]Yun BS, Cho Y, Lee IK, et al. Sterins A and B, new antioxidative compounds from Stereum hirsutum[J]. J Antibiot.2002,55(2):208-210.
[31]Carney JR, Ashley GW, Arslanian RL, et al. Structure elucidation of new ascomycins produced by genetic engineering [J]. J Antibiot.2005,58(11):715-721.
[32]Vertesy L, Kurz M, Paulus EF, et al. The chemical structure of mumbaistatin, a novel glucose-6-phsphate translocase inhibitor produced by Streptomyces sp.DSM 11641[J]. J Antibiot.2001,54(4):354-363.
[33]Woo EJ, Starks CM, Carney JR, et al. Migrastatin and a new compound, isomigrastatin, from Streptomyces platenis[J]. J Antibiot.2002,55(2):141-146.
[34]He Z., Kisla D., Zhang L.W., et al. Isolation and identification of a Paenibacillus polymyxa strain that coproduces a novel lantibiotic and polymyxin[J]. Applied and Environmental Microbiology.2007,73(1):168-178.
[35]Baur S., Niehaus J., Karagouni A.D., et al. Fluostatins C-E, novel members of the fluostatin family produced by Streptomyces strain Acta 1383[J]. J Antibiot.2006,59(5): 293-297.
[36]Riedlinger J., Schrey S.D., Tarkka M.T., et al. Auxofuran, a novel metabolite that stimulates the growth of fly agaric, is produced by the mycorrhiza helper bacterium Streptomyces strain AcH 505[J]. Applied and Environmental Microbiology.2006, 72(5):3550-3557.
[37]Wu S.J., Fotso S., Li F.C., et al. N-carboxamido-staurosporine and selina-4(14), 7(11)-diene-8,9-diol, new metabolites from a marine Streptomyces sp.[J]. J Antibiot. 2006,59(6):331-337.
[38]Choudhuri S.D., Ayers S., Soine W.H., et al. A pH-stability study of phoslactomycin B and analysis of the acid and base degradation products[J]. J Antibiot.2005,58(9): 573-582.
[39]Wang K, Guo LH, Zhou YS, et al. A new metabolite produced by the Streptomyces sp. 4849 as an inhibitor of IL-4 receptor[J]. J Antibiot.2007,60(5):325-327.
[40]严希康,庄英萍,杨雅琴等.用大网格吸附剂提取麦迪霉素[J].中国抗生素杂志.1990,1 5(5)：353-356.
[41]顾觉奋,任爱华.H-103大孔吸附剂提取螺旋霉素的研究[J].中国抗生素杂志.1991,16(2)：98-102.
[42]刘叶青,邬行彦.用絮凝和大网格吸附法提取螺旋霉素[J].中国抗生素杂志.1993,1 8(6)：447-450.
[43]汤志刚,周荣琪.国产大孔吸附树脂浓集分离赤霉素[J].离子交换与吸附.1999,15(5)：440-446.
[44]阎国华,甘立军,周燮.大孔吸附树脂提取赤霉素A3的初步研究[J].南京农业大学学报.1999,22(1)：22-25.
[45]顾觉奋,李睿岩.大孔网状树脂吸附法分离纯化柱晶白霉素的研究[J].中国抗生素杂志.2002,27(10)：587-589.
[46]张咏梅,张恺瑞,陈贵斌等.大孔吸附树脂提取泰乐星的研究[J].中国抗生素杂志.2000,25(2)：100-102.
[47]刘叶青,张秀萍,曹学君等.泰乐星提取方法的研究[J].中国抗生素杂志,2000,25(6)：412-446.
[48]倪雍富.大网格吸附剂提取3,2’,6’-三-N-乙酰西索米星[J].中国抗生素杂志.2001,26(1)：39-40。
[49]王耀伟,王鲁燕,路兵.大网格吸附剂提取头孢氨苄[J].离子交换与吸附.1998,14(1)：18-22。
[50]白硕可,王南金,郑焕荣等.康乐霉素C的稳定性及其提炼工艺改进[J].中国抗生素杂志.2001,26(4)：30-308.
[51]陈骏,宁方红,张志丕等.一种大孔吸附树脂的合成及在红霉素提取中的应用[J].中国抗生素杂志.2002,27(5)：270-272.
[52]宋应华,朱家文,陈葵等.大孔树脂提纯红霉素的研究[J].中国抗生素杂志.2007,32(5)：284-286.
[53]石磊,史丽娟,蒋沁等.达托霉素发酵液大孔树脂吸附分离的研究[J].中国抗生素杂志.2008,33(2)：84-86.
[54]王海燕,李晓露,王健等.大孔树脂法分离纯化那他霉素的工艺研究[J].中国抗生素杂志.2010,35(3)：194-196.
[55]张虹,柳正良,王洪泉.大孔吸附树脂在药学领域的应用[J].中国医药工业杂志,2001,32(1)：41-44.
[56]顾觉奋.大孔网状吸附剂在抗生素分离纯化中的应用[J].中国抗生素杂志.1991,16(3)：220-230.
[57]McKay G., Bino M.J., Altamemi A.R., The adsorption of various polluants from aqueous solutions onto activated carbon[J]. Water Res.,1985,19:491-495.
[58]Weber T.W., Chakkravorti R.K., Pore and solid diffusion models for fixed bed adsorbers[J]. Amer. Inst. Chem. Eng. J.,1974,20:228-238.
[59]Weber J WJ, Critendent J C. A numeric method for design of adsorption systems[J]. J. Water Poll.Control Fed,1975,47(5):924-940.
[60]刘家棋.分离过程与技术[M].天津：天津大学出版社,2001
[61]傅献彩,沈文霞,姚天扬.物理化学[M].北京：高等教育出版社,1990.
[62]梁锐杰,陈炳稔.流动注射分光光度法研究离子强度与温度对活性炭吸附阴离子燃料的影响[J].化学通报.2004,67：64-71.
[63]Anirudhan T.S., Senan P. Adsorption characteristics of cytochrome C onto cationic Langmuir monolayers of sulfonated poly (glycidylmethacrylate) grafted cellulose: Mass transfer analysis, isotherm modeling and thermodynamics [J]. Chemical Engineering Journal.2011,168(2):678-690
[64]Yousef R. I., El-Eswed B., Al-Muhtaseb A. H. Adsorption characteristics of natural zeolites as solid adsorbents for phenol removal from aqueous solutions:Kinetics, mechanism, and thermodynamics studies[J]. Chemical Engineering Journal. 2011,171(3):1143-1149
[65]Anirudhan T. S., Senan P. Adsorptive potential of sulfonated poly(glycidylmethacrylate)-grafted cellulose for separation of lysozyme from aqueous phase:Mass transfer analysis, kinetic and equilibrium profiles[J]. Colloids and Surfaces A:Physicochemical and Engineering Aspects.2011,377(1-3):156-166
[66]Liu Y. New insights into pseudo-second-order kinetic equation for adsorption [J]. Colloids and Surfaces A:Physicochemical and Engineering Aspects.200,320(1-3): 275-278
[67]Azizian S. Kinetic models of sorption:a theoretical analysis[J]. Journal of Colloid and Interface Science,2004,276:47-52.
[68]Yoshihiko M., Naoya A., Hiroshi S., et al. Branched pore kinetic model analysis of geosmin adsorption on super-powdered activated carbon[J]. Water Research.2009, 43(12):3095-3103
[69]Dominique R., Maria de Lourdes Delgado Nunez, Daniel S. Adsorption of complex phenolic compounds on active charcoal:Breakthrough curves[J]. Chemical Engineering Journal.2010,158(2):213-219
[70]黄子卿.电解质溶液理论导论(修订本)[M].北京：科学出版社,1987.
[71]Crini G. Kinetic and equilibrium studies on the removal of cationic dyes from aqueous solution by adsorption onto a cyclodextrin polymer[J]. Dyes and Pigments.2008,77: 415-426.
[72]肖谷清,龙立平,王姣亮,等.大孔PNaA树脂对黄连素的吸附性能研究[J].化学研究与应用.2010,22(8)：1082-1087.
[73]秦丽红,张凤宝,张国亮,等.NTS在大孔吸附树脂上的吸附动力学及机理[JJ.化学工业与工程.2007,24(3)：245-248.
[74]Felinger A., Cavazzini A., Guiochon G. Numerical determination of the competitive isotherm of enantiomers[J]. Journal of Chromatography A.2003,986:207-225.
[75]Zhou D., Cherrak D. E., Kaczmarski K., et al. Prediction of the band profiles of the mixtures of the 1-indanol enantiomers from data acquired with the single racemic mixture[J]. Chemical Engineering Science.2003,58:3257-3272.
[76]Cavazzini A., Felinger A., Kaczmarski K., et al. Study of the adsorption equilibria of the enantiomers of 1-phenyl-l-propanol on cellulose tribenzoate using a microbore column[J]. Journal of Chromatography A.2002,953:55-66.
[77]Seidel-Morgenstern A. Experimental determination of single solute and competitive adsorption isotherms[J]. J. Chromatogr. A.2004,1037(1-2):255-272.
[78]Srivastava V.C., Mall I.D., Mishra I.M. Removal of cadmium (Ⅱ) and zinc (Ⅱ) metal ions from binary aqueous solution by rice husk ash[J]. Colloids and Surfaces A.2008, 312:172-184.
[79]Li L.J., Liu F.Q., Jing X.S. et al. Displacement mechanism of binary competitiveadsorption for aqueous divalent metal ions onto a novel IDA-chelating resin: Isotherm and kinetic modeling[J]. water research.2011,45(3):1177-1188
[80]Labanda J., Sabate J., Llorens J. Experimental and modeling study of the adsorption of single and binary dye solutions with an ion-exchange membrane adsorber[J]. Chemical Engineering Journal.2011,166(2):536-543
[81]Dickinson E. Mixed biopolymers at interfaces:Competitive adsorption and multilayer structures[J]. Food Hydrocolloids.2011,25(8):1966-1983
[82]Su T.Z., Guan X.H., Tang Y.L. et al. Predicting competitive adsorption behavior of major toxic anionic elements onto activated alumina:A speciation-based approach[J]. Journal of Hazardous Materials.2010,176(1-3):466-472
[83]Xue W.B., Yi A.H., Zhang Z.Q., et al. A New Competitive Adsorption Isothermal Model of Heavy Metals in Soils[J]. Pedosphere.2009,19(2):251-257
[84]Vargas A. M.M., Cazetta A. L., Kunita M. H., et al. Adsorption of methylene blue on activated carbon produced from flamboyant pods (Delonix regia):Study of adsorption isotherms and kinetic models[J]. Chemical Engineering Journal.2011,168(2):722-730
[85]Zhang P.K., Wang L. Extended Langmuir equation for correlating multilayer adsorption equilibrium data[J]. Separation and Purification Technolog.2010,70(3):367-371
[86]Azizian S., Moghadam T.F. Derivation of a new equation for prediction of the thin layer depth of the extended-Langmuir model for dilute binary mixtures[J]. Colloids and Surfaces A:Physicochemical and Engineering Aspects.011,378(1-2):67-71
[87]Jeppu G.P, lement T. P. A modified Langmuir-Freundlich isotherm model for simulating pH-dependent adsorption effects[J]. Journal of Contaminant Hydrology.2012, Available online
[88]Zizian S., Haerifar M., Jalal B.P. Extended geometric method:A simple approach to derive adsorption rate constants of Langmuir-Freundlich kinetics[J]. Chemosphere. 2007,68(11):2040-2046
[89]Yang Y.H., Wu T.T., Suen S.Y, Lin S.C. Equilibrium adsorption of poly(His)-tagged proteins on immobilized metal affinity chromatographic adsorbents[J]. Biochemical Engineering Journal.2011,54(1):1-9
[90]Sips, R. On the structure of a catalyst surface[J], J. Chem. Phys.1948,16(5),490-495
[91]Quinones I., Guiochon G. Derivation and Application of a Jovanovic-Freundlich Isotherm Model for Single-Component Adsorption on Heterogeneous Surfaces[J]. J. Colloid Interface Sci 1996,183,57-67
[92]Jaroniec M., Madey R., Physical Adsorption on Heterogeneous Solids[M], Elsevier, Amsterdam,1998
[93]宋应华,朱家文,陈葵.大孔吸附树脂HZ816对红霉素的固定床吸附过程研究[J].化学工程。2007,35(11)：9-12.
[94]Johnston A., Hearn M.T.W. High-performance liquid chromatography of amino acides, peptides and proteins CⅢa. Mass transfer resistance in ion-exchange and dye affinity chromatography of proteins[J]. Chromatography.1990,512:101-114.
[95]Skidmore G.L., Horstmann B.J., Chase H.A. Modelling single-component protein adsorption to the cation exchanger S Sepharose FF[J]. Chromatography.1990,498: 113-128.
[96]Horstmann B.J., Chase H.A. Modelling the affinity adsorption of immunoglobulin G to protein a immobilized to agarose matrices[J]. Chem Eng Res Des.1989,67(3): 242-254
[97]Gu T.Y., Liu M.G., Cheng K.S., et al. A general rate model approach for the optimization of the core radius fraction for multicomponent isocratic elution in preparative nonlinear liquid chromatography using cored beads[J]. Chemical Engineering Science,2011,66(15):3531-3539
[98]Gao H., Lin B.C. A simplified numerical method for the General Rate model [J]. Computers & Chemical Engineering.2010,34(3):277-285
[99]Dai X.P., Sudipto M., Robert G.L., Kamalesh K.S. Portein loading, elution, and resolution behavior in a novel device that integrates ultrafiltration and chromatographic separation[J]. Biotechnol Bioeng.2003,83(2):125-139.
[100]Pamela R.W., Benjamin J.G. Modeling mass transfer and hydrodynamics in fluidized-bed adsorption of proteins [J]. AIChE.2001,47(2):474-488.
[101]Zhao Q.Y., Zhang T.A., Cao X.C., Jiang X.L. Experimental and model study on flow characteristics in a tubular reactor with stirrer[J]. Chinese Journal of Chemical Engineering.2007,35(9):25-28.
[102]Lanfrey P.Y., Kuzeljevic Z.V., Dudukovic M.P. Tortuosity model for fixed beds randomly packed with identical particles[J]. Chemical Engineering Science.2010,65: 1891-1896.
[103]袁黎明.制备色谱技术及应用[M].北京：化学工业出版社,2004.
[104]王龙耀,杨刚,邢卫红等.头孢菌素C发酵液陶瓷膜过滤过程中的影响因素研究[J].高效化学工程学报.2007,21(4)：604-607.
[105]黄金,陈宁,温廷益.L-苏氨酸发酵液有机膜过滤工艺研究[J].食品与发酵工业.2009,35(2)：87-90.
[106]曾坚贤,邢卫红,徐南平.肌苷发酵液的陶瓷膜过滤研究[J].湖南科技大学学报(自然科学版).2004,19(2)：91-94.
[107]毕生雷,杜平,王垌.对1,3-丙二醇发酵液用金属纳滤膜过滤的研究[J].河南化工2010,27(7)：39-41。
[108]刘杰,秦苏东,于广瑛等.利用陶瓷膜过滤古龙酸发酵液的研究[J].苏州科技学院学报(自然科学版).2008,25(1)：30-34.
[109]徐俭.陶瓷膜过滤在耐热级L-乳酸提取工艺中的应用[D].江南大学,2008.
[11 0]王焕章,许赵辉,邢卫红等.陶瓷膜在谷氨酸发酵液除菌过程中的应用[J].食品与发酵工业.2001,27(5)：42-46.
[111]史荣梅,徐亲民.抗生素发酵液的超滤与溶剂萃取[J].国外医药抗生素杂志分册.1997,18(1)：33-39.
[112]李十中,王淀佐,胡永平.抗生素提取过程中溶剂萃取技术新方法—超滤／萃取法[J].中国抗生素杂志.2000,25(1)：12-15.
[113]冯建立,许振良,王学军等.超滤去除红霉素发酵液乳化现象的研究[J].中国抗生素杂志.2007,32(3)：150-153.
[114]柳小强.红霉素发酵液过滤工艺的研究与改进[D].西北大学,2008.
[115]He Y.S., Chen G, Ji Z.J., et al. Combined UF-NF membrane system for filtering erythromycin fermentation broth and concentrating the filtrate to improve the downstream efficiency[J]. Separation and Purification Technology.2009,66:390-396.
[116]余作龙,姜岷,吴昊等.陶瓷膜超滤在丁二酸发酵液纯化中的应用[J].膜科学与技术.201 0,30(2)：93-96.
[117]刘彬彬,沈飞,苏仪等.利用旋转膜组件超滤澄清乳酸发酵液的初步研究[R].第五届全国化工年会.2008：1-4.
[118]徐庆阳,陈宁,方正星.金属膜对L-缬氨酸发酵液过滤的研究[J].天津科技大学学报.2006,21(1)：4-6.
[119]王琴,宋如,任卓等.膜技术在万古霉素生产工艺中的应用[J].河北化工.2007,30(11)：50-51.
[120]凌雪萍,冯杰.膜过滤技术在维生素B12生产中的应用[J].膜科学与技术.2008,28(2)：92-94.
[121]王永斌,王允祥.翘鳞伞胞外多糖无机陶瓷膜分离工艺研究[J].中国酿造.2009,(2)：103-105.
[122]赵南,刘义雄,阙好新等.发酵法生产丙酮酸钠提取工艺的研究[J].江西农业学报.2010,22(3)：161-162.
[2]胡福泉.抗生素研究进展及其应用前景.生物学杂志[J].2003,3(2)：9-60
[3]Kurath P, Jones PH, Egan RS, Perun TJ. Acid degradation of erythromycin A and erythromycin B[J]. Experientia.1971,27:362-365
[4]Periti P, Mazzei T, Mini E, Novelli A. Pharmacokinetic drug interaction of macrolides[J]. Clin. Pharmcokinet.1992.23:106-131
[5]Rubinstein E, Keller N. Spiramycin reaissance[J]. J.Antimicrob.Chemother.1998,42: 572-578
[6]朱峰,王尔健.螺旋霉素的再评价。中国抗生素杂志[J].1991,16：231-236
[7]Chabbert YA. Early studies on in-vitro and experimental activity of spiramycin:a review[J]. J.Antimicrob Chemother.1988,22(Suppl B):1-11
[8]冯闻铮,亓平言,周倜,苗勇,段训宝.螺旋霉素在酸碱溶液中的降解动力学[J].药学学报.1997,32：934-937
[9]Mourier P, Brun A. Study of the metabolism of spiramycin in pig liver[J]. J.Chromatogr. B.1997,704:197-205
[10]Feng W.Z., P.Y. Qi, T. Zhou, Y. Miao, X.B. Duan. Study on the degradation kinetics of spiramycin in acid and alkaline solutions[J]. Acta Pharm. Sin.32 (1997) 934-937
[11]Ramu K., Shringarpure S., Williamson J.S. A solution conformation analysis of forocidins I and isoforocidins I using NMR and molecular modeling[J]. Pharm. Res. 1995,12:621-629.
[12]孙丽文.螺旋霉素类抗生素体内过程探讨[J].国外医药·抗生素分册1990,11：358-365
[13]李显至,王浴生.抗生素抗菌后效作用的研究[J].国外医药·抗生素分册1990,11：439-444
[14]戴自英.实用抗菌药物学[M].上海：上海科技技术出版社,1991,218
[15]Weikel C, Lazenby A, Belitsos P, McDewitt M, Fleming HE Jr, Barbacci M. Intestinal injury associated with spiramycin therapy of cryptoporidium infection in AIDS[J]. J. Protozool.1991,38:147S
[16]Hardy DJ, Hensy DM, Beyer JM, Vojtko C, MoDonald EJ, Fernandes PB. Comparative in vitro activities of new 14-,15-, and 16-membered macrolides. Antimicrob[J]. Agents Chemother.1988,32:1710-1719
[17]Webster C, Ghaznfar K, Slack R. Sub-inhibitory and post-antibiotic effects of spiramycin and erythromycin on Staphylococcus aureus[J]. J. Antimicrob. Chemother. 1988,22 (Suppl B):33-39
[18]Rakhit S, Singh K. Structure activity relationship in sixteen membered macrolide antibiotics[J]. J Antibiotics.1974, ⅩⅩⅦ(3):221-224
[19]王以光.基因工程在大环内酯类抗生素研究中的应用(综述)[J].国外医药抗生素分册.1997,18(2)：92-98
[20]Shi X.G., Zhang S.Q., Paul Fawcett J., Zhong D.F. Acid catalysed degradation of some spiramycin derivatives found in the antibiotic bitespiramycin[J]. Journal of Pharmaceutical and Biomedical Analysis.36 (2004):593-600
[21]游旭.萃取法分离纯化必特螺旋霉素[D]。华东理工大学.2007
[22]元平言,冯闻铮等.螺旋霉素发酵滤液提取过程工艺研究[J].清华大学学报,1997,37(12)：64-67
[23]元平言,冯闻铮.螺旋霉素发酵液凡萃取过程工艺研究[J].中国抗生素杂志,1997,22(3)：178-181
[24]王跃生,王洋.大孔吸附树脂研究进展[J].中国中药杂志.2006,31(12)：961-965.
[25]Vertesy L, Ehlers H, Kogler H, et al. Friulimicins:novel lipopeptide antibiotics with peptidoglycan synthesis inhibiting activity from Actinoplanes friuliensis sp. nov. Ⅱ. Isolation and structural characterization[J]. J Antibiot.2000,53(8):816-827.
[26]Nakai R, Kakita S, Asai A, et al. Chrolactomycin, a novel antitumor antibiotic produced by Streptomyces sp.[J]. J Antibiot.2001,54(10):836-839.
[27]Sasaki T, Igarashi Y, Saito N, et al. Cedarmycins A and B, new antimicrobial antibiotics from Streptomyces sp.TP-A0456[J]. J Antibiot.2001,54(7):567-572.
[28]Cang S, Ohta S, Chiba H, et al. New naphthyridinomycin-type antibiotics, aclidinomycins A and B, from Streptomyces halstedi[J]. J Antibiot.2001,54(3): 304-307.
[29]Sasaki O, Igarashi Y, Saito N, et al. Watasemycins A and B, new antibiotics produced by Streptomyces sp.TP-A0597[J]. J Antibiot.2002,55(3):249-255.
[30]Yun BS, Cho Y, Lee IK, et al. Sterins A and B, new antioxidative compounds from Stereum hirsutum[J]. J Antibiot.2002,55(2):208-210.
[31]Carney JR, Ashley GW, Arslanian RL, et al. Structure elucidation of new ascomycins produced by genetic engineering [J]. J Antibiot.2005,58(11):715-721.
[32]Vertesy L, Kurz M, Paulus EF, et al. The chemical structure of mumbaistatin, a novel glucose-6-phsphate translocase inhibitor produced by Streptomyces sp.DSM 11641[J]. J Antibiot.2001,54(4):354-363.
[33]Woo EJ, Starks CM, Carney JR, et al. Migrastatin and a new compound, isomigrastatin, from Streptomyces platenis[J]. J Antibiot.2002,55(2):141-146.
[34]He Z., Kisla D., Zhang L.W., et al. Isolation and identification of a Paenibacillus polymyxa strain that coproduces a novel lantibiotic and polymyxin[J]. Applied and Environmental Microbiology.2007,73(1):168-178.
[35]Baur S., Niehaus J., Karagouni A.D., et al. Fluostatins C-E, novel members of the fluostatin family produced by Streptomyces strain Acta 1383[J]. J Antibiot.2006,59(5): 293-297.
[36]Riedlinger J., Schrey S.D., Tarkka M.T., et al. Auxofuran, a novel metabolite that stimulates the growth of fly agaric, is produced by the mycorrhiza helper bacterium Streptomyces strain AcH 505[J]. Applied and Environmental Microbiology.2006, 72(5):3550-3557.
[37]Wu S.J., Fotso S., Li F.C., et al. N-carboxamido-staurosporine and selina-4(14), 7(11)-diene-8,9-diol, new metabolites from a marine Streptomyces sp.[J]. J Antibiot. 2006,59(6):331-337.
[38]Choudhuri S.D., Ayers S., Soine W.H., et al. A pH-stability study of phoslactomycin B and analysis of the acid and base degradation products[J]. J Antibiot.2005,58(9): 573-582.
[39]Wang K, Guo LH, Zhou YS, et al. A new metabolite produced by the Streptomyces sp. 4849 as an inhibitor of IL-4 receptor[J]. J Antibiot.2007,60(5):325-327.
[40]严希康,庄英萍,杨雅琴等.用大网格吸附剂提取麦迪霉素[J].中国抗生素杂志.1990,1 5(5)：353-356.
[41]顾觉奋,任爱华.H-103大孔吸附剂提取螺旋霉素的研究[J].中国抗生素杂志.1991,16(2)：98-102.
[42]刘叶青,邬行彦.用絮凝和大网格吸附法提取螺旋霉素[J].中国抗生素杂志.1993,1 8(6)：447-450.
[43]汤志刚,周荣琪.国产大孔吸附树脂浓集分离赤霉素[J].离子交换与吸附.1999,15(5)：440-446.
[44]阎国华,甘立军,周燮.大孔吸附树脂提取赤霉素A3的初步研究[J].南京农业大学学报.1999,22(1)：22-25.
[45]顾觉奋,李睿岩.大孔网状树脂吸附法分离纯化柱晶白霉素的研究[J].中国抗生素杂志.2002,27(10)：587-589.
[46]张咏梅,张恺瑞,陈贵斌等.大孔吸附树脂提取泰乐星的研究[J].中国抗生素杂志.2000,25(2)：100-102.
[47]刘叶青,张秀萍,曹学君等.泰乐星提取方法的研究[J].中国抗生素杂志,2000,25(6)：412-446.
[48]倪雍富.大网格吸附剂提取3,2’,6’-三-N-乙酰西索米星[J].中国抗生素杂志.2001,26(1)：39-40。
[49]王耀伟,王鲁燕,路兵.大网格吸附剂提取头孢氨苄[J].离子交换与吸附.1998,14(1)：18-22。
[50]白硕可,王南金,郑焕荣等.康乐霉素C的稳定性及其提炼工艺改进[J].中国抗生素杂志.2001,26(4)：30-308.
[51]陈骏,宁方红,张志丕等.一种大孔吸附树脂的合成及在红霉素提取中的应用[J].中国抗生素杂志.2002,27(5)：270-272.
[52]宋应华,朱家文,陈葵等.大孔树脂提纯红霉素的研究[J].中国抗生素杂志.2007,32(5)：284-286.
[53]石磊,史丽娟,蒋沁等.达托霉素发酵液大孔树脂吸附分离的研究[J].中国抗生素杂志.2008,33(2)：84-86.
[54]王海燕,李晓露,王健等.大孔树脂法分离纯化那他霉素的工艺研究[J].中国抗生素杂志.2010,35(3)：194-196.
[55]张虹,柳正良,王洪泉.大孔吸附树脂在药学领域的应用[J].中国医药工业杂志,2001,32(1)：41-44.
[56]顾觉奋.大孔网状吸附剂在抗生素分离纯化中的应用[J].中国抗生素杂志.1991,16(3)：220-230.
[57]McKay G., Bino M.J., Altamemi A.R., The adsorption of various polluants from aqueous solutions onto activated carbon[J]. Water Res.,1985,19:491-495.
[58]Weber T.W., Chakkravorti R.K., Pore and solid diffusion models for fixed bed adsorbers[J]. Amer. Inst. Chem. Eng. J.,1974,20:228-238.
[59]Weber J WJ, Critendent J C. A numeric method for design of adsorption systems[J]. J. Water Poll.Control Fed,1975,47(5):924-940.
[60]刘家棋.分离过程与技术[M].天津：天津大学出版社,2001
[61]傅献彩,沈文霞,姚天扬.物理化学[M].北京：高等教育出版社,1990.
[62]梁锐杰,陈炳稔.流动注射分光光度法研究离子强度与温度对活性炭吸附阴离子燃料的影响[J].化学通报.2004,67：64-71.
[63]Anirudhan T.S., Senan P. Adsorption characteristics of cytochrome C onto cationic Langmuir monolayers of sulfonated poly (glycidylmethacrylate) grafted cellulose: Mass transfer analysis, isotherm modeling and thermodynamics [J]. Chemical Engineering Journal.2011,168(2):678-690
[64]Yousef R. I., El-Eswed B., Al-Muhtaseb A. H. Adsorption characteristics of natural zeolites as solid adsorbents for phenol removal from aqueous solutions:Kinetics, mechanism, and thermodynamics studies[J]. Chemical Engineering Journal. 2011,171(3):1143-1149
[65]Anirudhan T. S., Senan P. Adsorptive potential of sulfonated poly(glycidylmethacrylate)-grafted cellulose for separation of lysozyme from aqueous phase:Mass transfer analysis, kinetic and equilibrium profiles[J]. Colloids and Surfaces A:Physicochemical and Engineering Aspects.2011,377(1-3):156-166
[66]Liu Y. New insights into pseudo-second-order kinetic equation for adsorption [J]. Colloids and Surfaces A:Physicochemical and Engineering Aspects.200,320(1-3): 275-278
[67]Azizian S. Kinetic models of sorption:a theoretical analysis[J]. Journal of Colloid and Interface Science,2004,276:47-52.
[68]Yoshihiko M., Naoya A., Hiroshi S., et al. Branched pore kinetic model analysis of geosmin adsorption on super-powdered activated carbon[J]. Water Research.2009, 43(12):3095-3103
[69]Dominique R., Maria de Lourdes Delgado Nunez, Daniel S. Adsorption of complex phenolic compounds on active charcoal:Breakthrough curves[J]. Chemical Engineering Journal.2010,158(2):213-219
[70]黄子卿.电解质溶液理论导论(修订本)[M].北京：科学出版社,1987.
[71]Crini G. Kinetic and equilibrium studies on the removal of cationic dyes from aqueous solution by adsorption onto a cyclodextrin polymer[J]. Dyes and Pigments.2008,77: 415-426.
[72]肖谷清,龙立平,王姣亮,等.大孔PNaA树脂对黄连素的吸附性能研究[J].化学研究与应用.2010,22(8)：1082-1087.
[73]秦丽红,张凤宝,张国亮,等.NTS在大孔吸附树脂上的吸附动力学及机理[JJ.化学工业与工程.2007,24(3)：245-248.
[74]Felinger A., Cavazzini A., Guiochon G. Numerical determination of the competitive isotherm of enantiomers[J]. Journal of Chromatography A.2003,986:207-225.
[75]Zhou D., Cherrak D. E., Kaczmarski K., et al. Prediction of the band profiles of the mixtures of the 1-indanol enantiomers from data acquired with the single racemic mixture[J]. Chemical Engineering Science.2003,58:3257-3272.
[76]Cavazzini A., Felinger A., Kaczmarski K., et al. Study of the adsorption equilibria of the enantiomers of 1-phenyl-l-propanol on cellulose tribenzoate using a microbore column[J]. Journal of Chromatography A.2002,953:55-66.
[77]Seidel-Morgenstern A. Experimental determination of single solute and competitive adsorption isotherms[J]. J. Chromatogr. A.2004,1037(1-2):255-272.
[78]Srivastava V.C., Mall I.D., Mishra I.M. Removal of cadmium (Ⅱ) and zinc (Ⅱ) metal ions from binary aqueous solution by rice husk ash[J]. Colloids and Surfaces A.2008, 312:172-184.
[79]Li L.J., Liu F.Q., Jing X.S. et al. Displacement mechanism of binary competitiveadsorption for aqueous divalent metal ions onto a novel IDA-chelating resin: Isotherm and kinetic modeling[J]. water research.2011,45(3):1177-1188
[80]Labanda J., Sabate J., Llorens J. Experimental and modeling study of the adsorption of single and binary dye solutions with an ion-exchange membrane adsorber[J]. Chemical Engineering Journal.2011,166(2):536-543
[81]Dickinson E. Mixed biopolymers at interfaces:Competitive adsorption and multilayer structures[J]. Food Hydrocolloids.2011,25(8):1966-1983
[82]Su T.Z., Guan X.H., Tang Y.L. et al. Predicting competitive adsorption behavior of major toxic anionic elements onto activated alumina:A speciation-based approach[J]. Journal of Hazardous Materials.2010,176(1-3):466-472
[83]Xue W.B., Yi A.H., Zhang Z.Q., et al. A New Competitive Adsorption Isothermal Model of Heavy Metals in Soils[J]. Pedosphere.2009,19(2):251-257
[84]Vargas A. M.M., Cazetta A. L., Kunita M. H., et al. Adsorption of methylene blue on activated carbon produced from flamboyant pods (Delonix regia):Study of adsorption isotherms and kinetic models[J]. Chemical Engineering Journal.2011,168(2):722-730
[85]Zhang P.K., Wang L. Extended Langmuir equation for correlating multilayer adsorption equilibrium data[J]. Separation and Purification Technolog.2010,70(3):367-371
[86]Azizian S., Moghadam T.F. Derivation of a new equation for prediction of the thin layer depth of the extended-Langmuir model for dilute binary mixtures[J]. Colloids and Surfaces A:Physicochemical and Engineering Aspects.011,378(1-2):67-71
[87]Jeppu G.P, lement T. P. A modified Langmuir-Freundlich isotherm model for simulating pH-dependent adsorption effects[J]. Journal of Contaminant Hydrology.2012, Available online
[88]Zizian S., Haerifar M., Jalal B.P. Extended geometric method:A simple approach to derive adsorption rate constants of Langmuir-Freundlich kinetics[J]. Chemosphere. 2007,68(11):2040-2046
[89]Yang Y.H., Wu T.T., Suen S.Y, Lin S.C. Equilibrium adsorption of poly(His)-tagged proteins on immobilized metal affinity chromatographic adsorbents[J]. Biochemical Engineering Journal.2011,54(1):1-9
[90]Sips, R. On the structure of a catalyst surface[J], J. Chem. Phys.1948,16(5),490-495
[91]Quinones I., Guiochon G. Derivation and Application of a Jovanovic-Freundlich Isotherm Model for Single-Component Adsorption on Heterogeneous Surfaces[J]. J. Colloid Interface Sci 1996,183,57-67
[92]Jaroniec M., Madey R., Physical Adsorption on Heterogeneous Solids[M], Elsevier, Amsterdam,1998
[93]宋应华,朱家文,陈葵.大孔吸附树脂HZ816对红霉素的固定床吸附过程研究[J].化学工程。2007,35(11)：9-12.
[94]Johnston A., Hearn M.T.W. High-performance liquid chromatography of amino acides, peptides and proteins CⅢa. Mass transfer resistance in ion-exchange and dye affinity chromatography of proteins[J]. Chromatography.1990,512:101-114.
[95]Skidmore G.L., Horstmann B.J., Chase H.A. Modelling single-component protein adsorption to the cation exchanger S Sepharose FF[J]. Chromatography.1990,498: 113-128.
[96]Horstmann B.J., Chase H.A. Modelling the affinity adsorption of immunoglobulin G to protein a immobilized to agarose matrices[J]. Chem Eng Res Des.1989,67(3): 242-254
[97]Gu T.Y., Liu M.G., Cheng K.S., et al. A general rate model approach for the optimization of the core radius fraction for multicomponent isocratic elution in preparative nonlinear liquid chromatography using cored beads[J]. Chemical Engineering Science,2011,66(15):3531-3539
[98]Gao H., Lin B.C. A simplified numerical method for the General Rate model [J]. Computers & Chemical Engineering.2010,34(3):277-285
[99]Dai X.P., Sudipto M., Robert G.L., Kamalesh K.S. Portein loading, elution, and resolution behavior in a novel device that integrates ultrafiltration and chromatographic separation[J]. Biotechnol Bioeng.2003,83(2):125-139.
[100]Pamela R.W., Benjamin J.G. Modeling mass transfer and hydrodynamics in fluidized-bed adsorption of proteins [J]. AIChE.2001,47(2):474-488.
[101]Zhao Q.Y., Zhang T.A., Cao X.C., Jiang X.L. Experimental and model study on flow characteristics in a tubular reactor with stirrer[J]. Chinese Journal of Chemical Engineering.2007,35(9):25-28.
[102]Lanfrey P.Y., Kuzeljevic Z.V., Dudukovic M.P. Tortuosity model for fixed beds randomly packed with identical particles[J]. Chemical Engineering Science.2010,65: 1891-1896.
[103]袁黎明.制备色谱技术及应用[M].北京：化学工业出版社,2004.
[104]王龙耀,杨刚,邢卫红等.头孢菌素C发酵液陶瓷膜过滤过程中的影响因素研究[J].高效化学工程学报.2007,21(4)：604-607.
[105]黄金,陈宁,温廷益.L-苏氨酸发酵液有机膜过滤工艺研究[J].食品与发酵工业.2009,35(2)：87-90.
[106]曾坚贤,邢卫红,徐南平.肌苷发酵液的陶瓷膜过滤研究[J].湖南科技大学学报(自然科学版).2004,19(2)：91-94.
[107]毕生雷,杜平,王垌.对1,3-丙二醇发酵液用金属纳滤膜过滤的研究[J].河南化工2010,27(7)：39-41。
[108]刘杰,秦苏东,于广瑛等.利用陶瓷膜过滤古龙酸发酵液的研究[J].苏州科技学院学报(自然科学版).2008,25(1)：30-34.
[109]徐俭.陶瓷膜过滤在耐热级L-乳酸提取工艺中的应用[D].江南大学,2008.
[11 0]王焕章,许赵辉,邢卫红等.陶瓷膜在谷氨酸发酵液除菌过程中的应用[J].食品与发酵工业.2001,27(5)：42-46.
[111]史荣梅,徐亲民.抗生素发酵液的超滤与溶剂萃取[J].国外医药抗生素杂志分册.1997,18(1)：33-39.
[112]李十中,王淀佐,胡永平.抗生素提取过程中溶剂萃取技术新方法—超滤／萃取法[J].中国抗生素杂志.2000,25(1)：12-15.
[113]冯建立,许振良,王学军等.超滤去除红霉素发酵液乳化现象的研究[J].中国抗生素杂志.2007,32(3)：150-153.
[114]柳小强.红霉素发酵液过滤工艺的研究与改进[D].西北大学,2008.
[115]He Y.S., Chen G, Ji Z.J., et al. Combined UF-NF membrane system for filtering erythromycin fermentation broth and concentrating the filtrate to improve the downstream efficiency[J]. Separation and Purification Technology.2009,66:390-396.
[116]余作龙,姜岷,吴昊等.陶瓷膜超滤在丁二酸发酵液纯化中的应用[J].膜科学与技术.201 0,30(2)：93-96.
[117]刘彬彬,沈飞,苏仪等.利用旋转膜组件超滤澄清乳酸发酵液的初步研究[R].第五届全国化工年会.2008：1-4.
[118]徐庆阳,陈宁,方正星.金属膜对L-缬氨酸发酵液过滤的研究[J].天津科技大学学报.2006,21(1)：4-6.
[119]王琴,宋如,任卓等.膜技术在万古霉素生产工艺中的应用[J].河北化工.2007,30(11)：50-51.
[120]凌雪萍,冯杰.膜过滤技术在维生素B12生产中的应用[J].膜科学与技术.2008,28(2)：92-94.
[121]王永斌,王允祥.翘鳞伞胞外多糖无机陶瓷膜分离工艺研究[J].中国酿造.2009,(2)：103-105.
[122]赵南,刘义雄,阙好新等.发酵法生产丙酮酸钠提取工艺的研究[J].江西农业学报.2010,22(3)：161-162.