液膜法提取青霉素G的实验研究
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摘要
青霉素G是目前生产量最大的β-内酰胺类抗生素,也是半合成青霉素类抗生素的重要原料。传统的提取工艺大多采用溶媒萃取法从发酵液萃取青霉素G,传统工艺在低pH条件下操作,存在着青霉素降解严重、生产能耗大、萃取设备昂贵、溶剂回收困难等缺点。液膜分离技术作为一种新型的分离纯化手段,可实现萃取/反萃取过程耦合,具有传质效率高、选择性好的优点,可以克服传统萃取工艺中的不足,液膜技术已成为青霉素分离领域的一个研究热点。
本文分别采用大块液膜(BLM)和中空纤维更新液膜(HFRLM)技术,对模拟青霉素发酵液进行分离纯化。在最佳条件下,进行了HFRLM提取青霉素的工业应用小试研究。
建立了适用于萃取过程的青霉素G的HPLC分析方法,结果表明在0.02M磷酸二氢钾溶液(pH=3.5):甲醇=38:62的流动相条件下青霉素G保留时间短,色谱峰形尖锐,重复性好,不受缓冲盐和有机溶剂的干扰。
基于青霉素G两种不同的萃取机理—物理萃取和反应萃取,分别考察了载体浓度、稀释剂、温度、pH、料液浓度等不同操作条件对萃取分配系数的影响,并针对不同萃取剂的萃取机理进行了探讨。其中物理萃取在较低的pH下具有较高的分配系数,但青霉素降解严重。反应萃取在较高的pH范围内(5-7)仍具有良好的萃取效果,可以在常温下操作。
通过大块液膜实验验证了液膜过程在青霉素G提取过程中的可行性和优势,进行了中空纤维更新液膜技术在青霉素G提取过程中的实验研究,考察了操作方式、两相流速、两相pH、载体浓度、料液初始浓度、相比等操作条件对传质系数的影响。改变料液侧的流速有利于传质;两相pH差值是青霉素G提取过程的主要传质推动力;HFRLM传质系数随载体浓度的增大而增大;HFRLM的传质通量高于支撑液膜的传质通量,一定程度上可以超过膜萃取的传质通量。
HFRLM对中高浓度50000u青霉素G料液的提取和浓缩效果良好,料液去除率99.2%,反萃收率达到92.2%。处理较高浓度(100000u)料液,浓缩比仍可达到3.5。采用串级操作处理高浓度(100000u)青霉素的模拟工艺小试研究,最终料液相去除率达到88.76%,由于料液中大量晶体析出,反萃侧的收率仅有62.59%。
结果表明,中空纤维更新液膜技术应用于青霉素G的提取,可以克服传统提取工艺的缺陷,大大提高分离效率,在生物制品的分离纯化领域具有广阔的发展前景。
Penicillin G (PG) is a widely used antibiotic and also serves as an important raw material for semisynthetic penicillins. During traditional physical solvent extraction of PG from filtered broth , the lost of PG are considerable at pH values of 1.8-2.2. A low temperature of 0 to 5℃must be applied and expensive centrifugal extractors are necessary for the phase separation in extraction. Liquid membranes (LM) technical is a alternative which can combine extraction and back-extraction processes in one step. With the the advantages of high mass transfer efficiency and good selectivity, liquid membrane has become one of the most advantageous techniques in the purification and separation biochemical products such as penicillin G.
In this work, Bulk liquid membrane (BLM) and a new liquid membrane, named hollow fiber renewal liquid membrane (HFRLM ) were applied to study the separation of penicillin G. The following achivedment were gotten in this work:
A HPLC method for penicillin G determination in its solvent extraction process was established. 0.2 mol·L~(-1) KH_2PO_4 (pH=3.5)—methanol (38:62) was chose as the mobile phase. The method is rapid, accurate and reliable and the influence of buffer and organic solvents can be omitted.
Several kinds of extractants were used to study the extraction behavior with different pH, temperature, carrier content, diluent. The patition coefficients of physical extraction processes was higher but considerable PG were lost. Reactive extraction process can be conducted under mild pH (5-7) and room temperature.
Bulk liquid membrane experiment was performed to testify the feasibility and advantages of liquid membrane in penicillin G separation. The effects of operation mode, flow rate, carrier concentration, pH on the mass transfer performance of HFRLM were determined. The pH difference between the feed and strip is the main driving force during the mass transfer process of penicillin G.
HFRLM has both good extraction and concentration efficiencies for penicillin G. The extraction in the feed reached 99.2% and the recovery in the strip was 92.2% in the circulated experiments with a initial concentration of 50000 u. During the simulated process with HFRLM to separate high concentration (100000 u) feed, the recovery of penicillin G can reach above 88% after 8 stages HFRLM operation.
本文分别采用大块液膜(BLM)和中空纤维更新液膜(HFRLM)技术,对模拟青霉素发酵液进行分离纯化。在最佳条件下,进行了HFRLM提取青霉素的工业应用小试研究。
建立了适用于萃取过程的青霉素G的HPLC分析方法,结果表明在0.02M磷酸二氢钾溶液(pH=3.5):甲醇=38:62的流动相条件下青霉素G保留时间短,色谱峰形尖锐,重复性好,不受缓冲盐和有机溶剂的干扰。
基于青霉素G两种不同的萃取机理—物理萃取和反应萃取,分别考察了载体浓度、稀释剂、温度、pH、料液浓度等不同操作条件对萃取分配系数的影响,并针对不同萃取剂的萃取机理进行了探讨。其中物理萃取在较低的pH下具有较高的分配系数,但青霉素降解严重。反应萃取在较高的pH范围内(5-7)仍具有良好的萃取效果,可以在常温下操作。
通过大块液膜实验验证了液膜过程在青霉素G提取过程中的可行性和优势,进行了中空纤维更新液膜技术在青霉素G提取过程中的实验研究,考察了操作方式、两相流速、两相pH、载体浓度、料液初始浓度、相比等操作条件对传质系数的影响。改变料液侧的流速有利于传质;两相pH差值是青霉素G提取过程的主要传质推动力;HFRLM传质系数随载体浓度的增大而增大;HFRLM的传质通量高于支撑液膜的传质通量,一定程度上可以超过膜萃取的传质通量。
HFRLM对中高浓度50000u青霉素G料液的提取和浓缩效果良好,料液去除率99.2%,反萃收率达到92.2%。处理较高浓度(100000u)料液,浓缩比仍可达到3.5。采用串级操作处理高浓度(100000u)青霉素的模拟工艺小试研究,最终料液相去除率达到88.76%,由于料液中大量晶体析出,反萃侧的收率仅有62.59%。
结果表明,中空纤维更新液膜技术应用于青霉素G的提取,可以克服传统提取工艺的缺陷,大大提高分离效率,在生物制品的分离纯化领域具有广阔的发展前景。
Penicillin G (PG) is a widely used antibiotic and also serves as an important raw material for semisynthetic penicillins. During traditional physical solvent extraction of PG from filtered broth , the lost of PG are considerable at pH values of 1.8-2.2. A low temperature of 0 to 5℃must be applied and expensive centrifugal extractors are necessary for the phase separation in extraction. Liquid membranes (LM) technical is a alternative which can combine extraction and back-extraction processes in one step. With the the advantages of high mass transfer efficiency and good selectivity, liquid membrane has become one of the most advantageous techniques in the purification and separation biochemical products such as penicillin G.
In this work, Bulk liquid membrane (BLM) and a new liquid membrane, named hollow fiber renewal liquid membrane (HFRLM ) were applied to study the separation of penicillin G. The following achivedment were gotten in this work:
A HPLC method for penicillin G determination in its solvent extraction process was established. 0.2 mol·L~(-1) KH_2PO_4 (pH=3.5)—methanol (38:62) was chose as the mobile phase. The method is rapid, accurate and reliable and the influence of buffer and organic solvents can be omitted.
Several kinds of extractants were used to study the extraction behavior with different pH, temperature, carrier content, diluent. The patition coefficients of physical extraction processes was higher but considerable PG were lost. Reactive extraction process can be conducted under mild pH (5-7) and room temperature.
Bulk liquid membrane experiment was performed to testify the feasibility and advantages of liquid membrane in penicillin G separation. The effects of operation mode, flow rate, carrier concentration, pH on the mass transfer performance of HFRLM were determined. The pH difference between the feed and strip is the main driving force during the mass transfer process of penicillin G.
HFRLM has both good extraction and concentration efficiencies for penicillin G. The extraction in the feed reached 99.2% and the recovery in the strip was 92.2% in the circulated experiments with a initial concentration of 50000 u. During the simulated process with HFRLM to separate high concentration (100000 u) feed, the recovery of penicillin G can reach above 88% after 8 stages HFRLM operation.
引文
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