CN1247580C - Method of ion liqid extraction for separating penicillin - Google Patents
Method of ion liqid extraction for separating penicillin Download PDFInfo
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- CN1247580C CN1247580C CN 200410009007 CN200410009007A CN1247580C CN 1247580 C CN1247580 C CN 1247580C CN 200410009007 CN200410009007 CN 200410009007 CN 200410009007 A CN200410009007 A CN 200410009007A CN 1247580 C CN1247580 C CN 1247580C
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Abstract
The present invention relates to the field of liquid-liquid extraction, particularly to an extracting method for penicillin by using ionic liquid as an extracting agent. The method determines an operating method used during the extracting process and the influence of pH, a phase ratio and penicillin concentration to an extracting rate, and an extracting mode capable of single-stage extraction, cross-current extraction or counter-current extraction is determined; furthermore, the extracting concentration of penicillin in the ionic liquid [BMIM]PF6(1-ethyl-3-methyl imidazole hexafluorophosphate is determined, and an operating method for reversely extracting the penicillin in the ionic liquid [BMIM]PF6 is also determined.
Description
Technical field
The present invention relates to the liquid-liquid extraction field, particularly is the penicillin g extract and the reextraction method of extraction agent with the ionic liquid.
Background technology
Penicillin is a kind of clinical microbiotic that is widely used in.In recent years, along with the development of semi-synthetic pharmaceutical technology, penicillin is used as the raw material of synthetic β-lactam drugs in a large number.Penicillin production generally is made up of processes such as fermentation, solvent extraction, reextraction, crystallization, dryings, and solvent extraction and reextraction are important steps wherein.Constantly the new extraction system of research and development is the problem that the researchist pays close attention to always.
The more extraction system of research comprises N-BUTYL ACETATE extraction system, organic amine extraction system, neutral phosphine extraction system, sulfoxide class extraction system, two phase aqueous extraction system and reverse micelle extraction system at present.N-BUTYL ACETATE extraction system is extensively adopted by industrial production, and its process is under the condition of pH=2, and penicillin solution also separates with 2: 1 the hybrid reaction of comparing with N-BUTYL ACETATE; Adopting salt of wormwood or potassium bicarbonate aqueous solution is strippant, strips under the condition of pH=6.0～7.5; Utilize system material acid-basicity and different solubility to realize the purpose of separation and purification.Although the N-BUTYL ACETATE extracting penicillin is high extensively for industrial production adopts because of its partition ratio, the danger that organic solvents such as N-BUTYL ACETATE exist volatilization to cause environmental pollution and blast easily; Organic amine extraction system can extract under the condition of pH=4.0～5.0, strips under the condition of pH=7.0～9.0, and is better to the penicillin g extract effect, but have the shortcoming of easy emulsification and extracting impurities; Neutral phosphine extraction agent and N-BUTYL ACETATE belong to neutral extraction agent, can under the condition of pH=3.1, extract, strip under the condition of pH=7.0, percentage extraction raises with the increase of tributyl phosphate concentration, its biggest advantage is the pH value that has improved extraction, reduced the destruction of penicillin, but still had emulsion, quality product remains further to be improved; Studies show that sulfoxide extractant is neutral extraction agent, the petrolenum sulfoxide with 40%--kerosene carries out penicillin g extract, and at pH=3.0, under the condition of O/W=1/2, the single-stage extraction rate reaches 93%, but extraction process still has emulsification problem; Two phase aqueous extraction system can be from the direct extracting penicillin of fermented liquid, technology is simple, avoid operations such as fermentation liquor pretreatment, required quantity of solvent significantly reduces, but because the polyoxyethylene glycol price of two phase aqueous extraction system is higher, recycle difficulty, cause production cost too high, temporarily can't be applied to produce; Reverse micelle is applied to penicillin g extract and extracts the result who has obtained satisfaction under the condition of room temperature, pH=5.0～8.0.In the reverse micelle extraction system, increase with ionic strength, the penicillin g extract rate changes little, but the percentage extraction of impurity such as pigment sharply descends, and the penicillin g extract rate changes little with pH.Like this, can under higher pH value, extract on the one hand, reduce penicillin and destroy, can utilize ionic strength to change on the other hand and remove impurity.Reverse micelle extraction is used for the such high throughput of penicillin, low value-added products production is also very difficult.
Up to now, overwhelming majority extraction is all carried out in molecular solvent.In recent years, the ion liquid extensive concern that the various countries scholar occurs causing.Ionic liquid is the liquid of being made up of ion fully, generally is made up of organic cation and inorganic anion, is in a liquid state in room temperature, is (＜100 ℃=salt that is in a liquid state under the low temperature.Studies show that ionic liquid can dissolve multiple organism and mineral compound.Ionic liquid is applied to existing many pieces of report (Huddleston eta1. of extracting and separating of water phase organic matters and metal ion as extraction agent, Room temperature ionic liquids as novel media for " clean " liquid-liquidextraction, Chem.Commun., 1998 (16): 1765-1766; Visser et al, Task-specific ionicliquids for the extraction of metal ions from aqueous solutions.Chem.Commun, 2001,135-136; Dai et a1., Solvent extraction of strontium nitrate by acrown ether using room temperature ionic liquids J.Chem.Soc.Dalton.Trans., 1999 (8), 1201-1202).Ion liquid abstraction and reextraction separating penicillin yet there are no report.
Summary of the invention
The objective of the invention is to overcome and in molecular solvent, carry out the problems such as emulsification that exist in the extracting penicillin process, the method of the simple ion liquid abstraction separating penicillin of a kind of technology is provided, not only make extraction system cheap, reduce production costs, improve the quality of product simultaneously.
The present invention has determined penicillin G/V at ionic liquid, as hydrophobic ionic liquid [Bmim] PF
6In (1-butyl-3-Methylimidazole phosphofluoric acid) working method of extraction with pH, compare, penicillin concn is to the influence of percentage extraction.It is single-stage extraction, cross current solvent extraction or counter-current extraction that the present invention adopts the extraction mode.
The method of ion liquid abstraction separating penicillin of the present invention may further comprise the steps:
(1). get the certain volume benzylpenicillin sodium solution, the water penicillin concn is controlled in 5000u/ml～80000u/ml scope, ionic liquid is with in the tempering tank that stirs by necessarily comparing to add with benzylpenicillin sodium solution, comparing and being controlled at O/W is 1: 1～1: 4 scope, open and stir, make the two-phase thorough mixing, temperature is controlled at 5 ℃～30 ℃ scope;
(2). slowly add souring agent in the solution of step (1), control pH is in 1.5～4.0 scope, and stirring reacted fully in about 15 minutes carries out, and stops stirring, static phase-splitting.
Or
(1). get the ionic liquid solution of certain volume penicillin, penicillin concn is controlled in 5000u/ml～150000u/ml scope, and the ionic liquid solution adding of penicillin is with in the tempering tank that stirs, and temperature is controlled at 5 ℃～30 ℃ scope, opens and stirs;
(2). slowly add the aqueous solution of basifier in the solution of step (1), control pH is in 6.0～9.0 scope, stirs the reextraction sufficient reacting to be carried out in about 15 minutes, stops stirring, and the reextraction process is finished in static phase-splitting.
Described souring agent is mineral acid or their any mixed solutions such as sulfuric acid, hydrochloric acid, phosphoric acid;
Described ionic liquid is a hydrophobic type imidazoles phosphofluoric acid, as 1-butyl-3-Methylimidazole phosphofluoric acid.
The aqueous solution of described basifier is the aqueous solution of carbonate, and the aqueous solution of carbonate is the aqueous solution of salt of wormwood, yellow soda ash, volatile salt, saleratus, sodium bicarbonate or bicarbonate of ammonia or their any mixed solution.
The present invention is after using souring agent, after treating that two-phase interface is clear, available transfer pipet is got the heavy phase ionic liquid and is measured its optical value, the dissolving standard optically-active curve of reference penicillin in ionic liquid draws the concentration of penicillin in the ionic liquid, penicillin concn is no more than 150000u/ml in the ionic liquid, accurately measure the ionic liquid phase volume, calculate percentage extraction.The result shows: in the scope of pH=1.5～2.5, the penicillin g extract rate is the highest, and percentage extraction changes little with pH, be best extraction pH scope, the scope in pH=2.5～4.0, penicillin g extract rate raise with the pH value and reduce, under the situation of pH 〉=4, the single-stage extraction rate is lower than 50%; Comparing O/W=1: 1.5～1: 2.5 scope, the penicillin g extract rate reduces with comparing to increase, comparing 〉=2.5 situation under, the penicillin g extract rate with compare change little; Penicillin concn is the scope of 20000u/ml～30000u/ml, percentage extraction raises with the increase of water penicillin concn, penicillin concn is the scope of 30000u/ml～50000u/ml, percentage extraction increases with the water penicillin concn and changes not quite, be steady state value, penicillin concn is the scope of 50000u/ml～60000u/ml, and percentage extraction increases with the water penicillin concn and reduces.
The present invention is after using basifier, after treating that two-phase interface is clear, available transfer pipet is got the heavy phase ionic liquid and is measured its optical value, and the dissolving standard optically-active curve of reference penicillin in ionic liquid draws the concentration of penicillin in the ionic liquid, accurately measure the ionic liquid phase volume, calculate stripping rate.The result shows, the scope in pH=6.0～9.0, and the penicillin stripping rate raises with the pH value and increases.
The present invention has determined the extraction mode of penicillin G/V in ionic liquid, and percentage extraction is 40%～95%, and concentration is no more than 150000u/ml.
Description of drawings
Fig. 1 embodiment of the invention 1 extracts the synoptic diagram that concerns of pH value and percentage extraction;
Fig. 2 the invention process profit 2 is compared the synoptic diagram that concerns with percentage extraction;
Fig. 3 embodiment of the invention 3 penicillin concns and percentage extraction concern synoptic diagram.
Embodiment
Accurately measuring concentration is the penicillin G aqueous solution 350ml of 31276u/ml, with ionic liquid [Bmim] PF
6Once add in the tempering tank of being with whipping appts (single-stage extraction) by comparing 1: 1.5 with benzylpenicillin sodium solution, open and stir, make the two-phase thorough mixing, temperature is controlled at 5 ℃～10 ℃, slowly adds 10wt%H
2SO
4Control pH value is respectively 1.5,2.0,2.5,3.0,3.8, stirred 15 minutes, static phase-splitting, after two-phase interface is clear, gets the heavy phase ionic liquid with transfer pipet and measure its optical value, the dissolving standard optically-active curve of reference penicillin in ionic liquid draws the concentration of penicillin in the ionic liquid, accurately measure the ionic liquid phase volume, calculate percentage extraction and be respectively 83.46%, 84.59%, 83.44%, 73.06%, 43.82%.The relation that shows pH value and percentage extraction.
Accurately measuring concentration is the penicillin G aqueous solution 350ml of 31566u/ml, ionic liquid [Bmim] PF
6Once add in the tempering tank of being with whipping appts (single-stage extraction) by being in a ratio of 1: 1.5,1: 2.0,1: 2.5,1: 3.0 with benzylpenicillin sodium solution, open and stir, make the two-phase thorough mixing, temperature is controlled at 5 ℃～10 ℃, slowly adds 10wt%H
2SO
4Control pH is 2.0, stir and stop after 15 minutes to stir, static phase-splitting, after two-phase interface is clear, gets the heavy phase ionic liquid with transfer pipet and measure its optical value, the dissolving standard optically-active curve of reference penicillin in ionic liquid draws the concentration of penicillin in the ionic liquid, accurately measure the ionic liquid phase volume, calculate percentage extraction and be respectively 91.62%, 86.07%, 85.93%, 86.21%.Show extraction phase than with the relation of percentage extraction.
The penicillin G aqueous solution 350ml of accurately measuring concentration and be 19700u/ml, 31384u/ml, 42409u/ml, 52757u/ml, 60725u/ml adds in the tempering tank of band whipping appts ionic liquid [Bmim] PF
6Once add by being in a ratio of 1: 1.5 with benzylpenicillin sodium solution, open and stir, make the two-phase thorough mixing, temperature is controlled at 5 ℃～10 ℃, slowly adds 10wt%H
2SO
4Control pH value is 2.0, stirred 15 minutes, static phase-splitting, after two-phase interface is clear, gets the heavy phase ionic liquid with transfer pipet and measure its optical value, the dissolving standard optically-active curve of reference penicillin in ionic liquid draws the concentration of penicillin in the ionic liquid, accurately measure the ionic liquid phase volume, calculate percentage extraction and be respectively 89.23%, 91.62%, 91.83%, 91.57%, 90.02%.The relation that shows penicillin concn and percentage extraction.
Measure the ionic liquid that concentration is 57000u/ml [Bmim] PF
6Penicillin solution 40ml place the beaker that installs stirring, system is cooled to below 10 ℃, open to stir, slowly add 1.9%KHCO
3Control pH is 6.5,7.0,7.5, stirred 15 minutes, static phase-splitting in separating funnel then, after two-phase interface is clear, collect the heavy phase ionic liquid and the light aqueous solution mutually respectively, measure its volume, its optical value is measured in water intaking mutually, draws the concentration of aqueous phase penicillin by the standard optically-active curve of penicillin in water.Calculate stripping rate and be respectively 93%, 94.24%, 94.23%.The relation that shows the stripping rate and the pH of penicillin in the ionic liquid.
Embodiment 5
Accurately measuring concentration is the penicillin G aqueous solution 350ml of 31566u/ml, ionic liquid [Bmim] PF
6Add in the tempering tank of being with whipping appts (cross current solvent extraction) with benzylpenicillin sodium solution at twice by being in a ratio of 1: 1.5,1: 2.0,1: 2.5,1: 3.0, add for the first time 60% of ionic liquid cumulative volume, open and stir, make the two-phase thorough mixing, temperature is controlled at 5 ℃～10 ℃, slowly adds 10wt%H
2SO
4Control pH is 2.0, stir and stop after 15 minutes to stir, static phase-splitting, after two-phase interface is clear, get the heavy phase ionic liquid with transfer pipet and measure its optical value, the dissolving standard optically-active curve of reference penicillin in ionic liquid draws the concentration of penicillin in the ionic liquid, accurately measures the ionic liquid phase volume.Add for the second time 40% of ionic liquid cumulative volume in aqueous phase extracted, open and stir, make the two-phase thorough mixing, temperature is controlled at 5 ℃～10 ℃, slowly adds 10wt%H
2SO
4Control pH is 2.0, stir and stop after 15 minutes to stir, static phase-splitting, after two-phase interface is clear, get the heavy phase ionic liquid with transfer pipet and measure its optical value, the dissolving standard optically-active curve of reference penicillin in ionic liquid draws the concentration of penicillin in the ionic liquid, accurately measures the ionic liquid phase volume.Calculate total percentage extraction and be respectively 92.89%, 90.01%, 87.45%, 87.15%.Show that cross current solvent extraction compares the relation with percentage extraction.
Claims (4)
1. the method for an ion liquid abstraction separating penicillin, it is characterized in that: described method may further comprise the steps:
(1). get benzylpenicillin sodium solution, the water penicillin concn is controlled in 5000u/ml～80000u/ml scope, ionic liquid and benzylpenicillin sodium solution are added in the tempering tank, comparing and being controlled at O/W is 1: 1～1: 4 scope, open and stir, make the two-phase thorough mixing, temperature is controlled at 5 ℃～30 ℃ scope;
(2). slowly add souring agent in the solution of step (1), control pH stirs in 1.5～4.0 scope, reacts fully and carries out, and stops stirring static phase-splitting;
Or
Get the ionic liquid of penicillin, penicillin concn is controlled at 57000u/ml, and system is cooled to below 10 ℃, opens and stirs, and slowly adds the aqueous solution of basifier, and control pH is 6.5,7.0,7.5, stirs, and the reextraction process is finished in static then phase-splitting;
Described ionic liquid is 1-butyl-3-Methylimidazole phosphofluoric acid;
Described souring agent is sulfuric acid, hydrochloric acid, phosphoric acid or their any mixed solution;
The aqueous solution of described basifier is the aqueous solution of carbonate.
2. the method for claim 1, it is characterized in that: the aqueous solution of described carbonate is the aqueous solution of salt of wormwood, yellow soda ash, volatile salt, saleratus, sodium bicarbonate or bicarbonate of ammonia or their any mixed solution.
3. the method for claim 1, it is characterized in that: described extraction mode is single-stage extraction, cross current solvent extraction or counter-current extraction.
4. the method for claim 1, it is characterized in that: described tempering tank has whipping appts.
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| CN 200410009007 CN1247580C (en) | 2004-04-13 | 2004-04-13 | Method of ion liqid extraction for separating penicillin |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100522974C (en) * | 2006-07-14 | 2009-08-05 | 中国科学院过程工程研究所 | Device and method for continuously back extracting penicillin |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1944357B (en) * | 2005-10-09 | 2010-05-12 | 中国科学院过程工程研究所 | Recovery method for ionic liquid |
| CN100543026C (en) * | 2005-10-14 | 2009-09-23 | 中国科学院过程工程研究所 | Ion liquid extraction penicillin and enzymic catalytic reaction coupling prepare the method for semisynthetic antibiotic 6-amino penicillanic acid |
| CN100460404C (en) * | 2006-05-10 | 2009-02-11 | 中国科学院过程工程研究所 | Method for extracting penicillin by magnetic ion liquid and reactor |
| CN100469428C (en) * | 2006-06-28 | 2009-03-18 | 中国科学院过程工程研究所 | Extractor with circumrotating and stabilizing type magnetic stirring |
| CN104316620B (en) * | 2014-11-12 | 2016-01-20 | 吉林大学 | A kind of detection method of trace triazine herbicide |
| CN107129438A (en) * | 2017-04-28 | 2017-09-05 | 华南理工大学 | A kind of method of glyoxaline ion liquid double-aqueous phase system multitple extraction tetracycline |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100522974C (en) * | 2006-07-14 | 2009-08-05 | 中国科学院过程工程研究所 | Device and method for continuously back extracting penicillin |
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Assignee: North China Pharmaceutical Group Xiantai Pharmaceutical Co., Ltd. Assignor: Institute of Process Engineering, Chinese Academy of Sciences Contract fulfillment period: 2008.11.21 to 2013.10.20 contract change Contract record no.: 2008130000143 Denomination of invention: Method of ion liqid extraction for separating penicillin Granted publication date: 20060329 License type: Exclusive license Record date: 2008.12.4 |
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Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2008.11.21 TO 2013.10.20; CHANGE OF CONTRACT Name of requester: NORTH CHINA PHARMACUETICAL GROUP XIANTAI PHARMACEU Effective date: 20081204 |
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