CN101265263B - Method for producing piperacillin sodium tazobactam sodium compound injection - Google Patents
Method for producing piperacillin sodium tazobactam sodium compound injection Download PDFInfo
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- CN101265263B CN101265263B CN2008100975379A CN200810097537A CN101265263B CN 101265263 B CN101265263 B CN 101265263B CN 2008100975379 A CN2008100975379 A CN 2008100975379A CN 200810097537 A CN200810097537 A CN 200810097537A CN 101265263 B CN101265263 B CN 101265263B
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- piperacillin
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Abstract
The invention provides a method for preparing high-purity piperacillin or tazobactam sodium, and a preparation method of piperacillin-tazobactam sodium compound injection. The method includes the following steps: (1) dissolving piperacillin or tazobactam sodium for injection into the water to obtain solution, performing gel chromatography in a gel column, and collecting eluting fraction with piperacillin or tazobactam sodium content of no smaller than 90%; and (2) separating in a reversed column chromatography, collecting eluting fraction with piperacillin or tazobactam sodium content of no smaller than 99%, freezing, drying and obtaining the high-purity piperacillin or tazobactam sodium material.
Description
Technical field
The invention provides a kind of method for preparing high purity piperacillin sodium or sodium-tazobactam, a kind of production method of piperacillin sodium tazobactam sodium compound injection also is provided, belong to medical technical field.
Background technology
Piperacillin is a kind of spectrum semi-synthetic penicillins microbiotic, has been widely used in clinical.Owing to reasons such as the life-time service of piperacillin and improper uses, the result of treatment of piperacillin just constantly descends, and this has influenced the application of piperacillin to a great extent.Sodium-tazobactam is a lactamase restrainer, belongs to the antibiotic strong synergistic agent of the third generation, share the drug effect that can strengthen the two and prolongs action time with piperacillin or cefoperazone.Sodium-tazobactam and piperacillin sodium are united when using, produce the obvious synergistic effect, be widely used in serious general of treatment and local infection, abdominal cavity infection, lower respiratory infection, soft tissue infection, septicemia etc., have antimicrobial spectrum and indication widely than other the antibiotic recombiner that has used, shown huge advantage aspect the resistance overcoming.
At present the piperacillin sodium and tazobactam sodium compound preparation that uses exists effective pure degree not high, and problem such as the side effect that causes thus is big.
Summary of the invention
The object of the present invention is to provide a kind of method for preparing high purity piperacillin sodium or sodium-tazobactam, and the production method that a kind of piperacillin sodium tazobactam sodium compound injection is provided.
The technical solution used in the present invention is as follows:
The invention provides the method for a kind of purifying piperacillin sodium or sodium-tazobactam, it is characterized in that comprising the steps:
(1) piperacillin sodium crude product or sodium-tazobactam crude product through gel filtration chromatography,, are collected piperacillin sodium or Tazobactam Sodium sodium content and are not less than 90% wash-out flow point as eluent with the low alkyl group alcohol solution;
(2) step (1) gained wash-out flow point through reverse column chromatography, is a filler with alkyl linked phase silica gel,, collects piperacillin sodium or Tazobactam Sodium sodium content and is not less than 99% wash-out flow point as eluent with water-containing organic solvent.
The present invention also provides a kind of production method of piperacillin sodium tazobactam sodium compound injection, it is characterized in that comprising the steps:
(1) piperacillin sodium crude product and sodium-tazobactam crude product as eluent, are collected piperacillin sodium or Tazobactam Sodium sodium content and are not less than 90% wash-out flow point with the low alkyl group alcohol solution respectively through gel filtration chromatography;
(2) step (1) gained wash-out flow point, through reverse column chromatography, with alkyl linked phase silica gel is filler, with water-containing organic solvent as eluent, collect piperacillin sodium or Tazobactam Sodium sodium content and be not less than 99% wash-out flow point, lyophilize makes the raw material of highly purified piperacillin sodium and highly purified sodium-tazobactam respectively;
(3) with the highly purified piperacillin sodium of step (2) gained and highly purified sodium-tazobactam by weight (4～8): 1 mixes, and freeze dried injection is made in packing.
Above-mentioned described method, wherein said piperacillin sodium crude product can be formed in the presence of sodium hydroxide, yellow soda ash, sodium bicarbonate or sodium oxide by the piperacillin crude product.
Above-mentioned described method, wherein gel column described in the step (1) is polyacrylamide gel post, cross-linked dextran gel column, sepharose post or polystyrene gel post, be preferably cross-linked dextran gel column, more preferably the gel column of Sephadex LH series most preferably is Sephadex LH-20 post.
Above-mentioned described method, wherein the filler described in the step (2) is C
4, C
8Or C
18Filler, be preferably C
18Filler.
Above-mentioned described method, wherein the described lower alkyl alcohol of step (1) is methyl alcohol, ethanol or propyl alcohol, is preferably ethanol, more preferably eluent is 60%～95% ethanol.
Above-mentioned described method, wherein the described organic solvent of step (2) is selected from acetonitrile, methyl alcohol, ethanol, propyl alcohol, acetone, dioxane, tetrahydrofuran (THF), methylethylketone, propyl carbinol or vinyl acetic monomer, be preferably methyl alcohol or ethanol, ethanol more preferably, most preferably eluent is 60%～80% ethanol.
As one of specific embodiment of the invention, the method for a kind of purifying piperacillin sodium or sodium-tazobactam is provided, it is characterized in that comprising the steps:
(1) piperacillin sodium crude product or sodium-tazobactam crude product are water-soluble, through Sephadex LH-20 gel filtration chromatography,, collect piperacillin sodium or Tazobactam Sodium sodium content and are not less than 90% wash-out flow point as eluent with 60%～95% ethanol;
(2) step (1) gained wash-out flow point through medium pressure column chromatography, is used anti-phase C
18Filled column carries out gradient elution with 60%～80% ethanol, collects piperacillin sodium or Tazobactam Sodium sodium content and is not less than 99% wash-out flow point.
As another embodiment of the present invention, a kind of production method of piperacillin sodium tazobactam sodium compound injection is provided, it is characterized in that comprising the steps:
(1) piperacillin sodium crude product or sodium-tazobactam crude product are water-soluble, through Sephadex LH-20 gel filtration chromatography,, collect piperacillin sodium or Tazobactam Sodium sodium content and are not less than 90% wash-out flow point as eluent with 60%～95% ethanol;
(2) step (1) gained wash-out flow point through medium pressure column chromatography, is used anti-phase C
18Filled column carries out gradient elution with 60%～80% ethanol, collects piperacillin sodium or Tazobactam Sodium sodium content and is not less than 99% wash-out flow point, and lyophilize makes the raw material of highly purified piperacillin sodium and highly purified sodium-tazobactam respectively;
(3) highly purified piperacillin sodium of step (2) gained and highly purified sodium-tazobactam were mixed by weight 4: 1 or 8: 1, be ground into 60-100 order powder, in sterilisable chamber, be distributed into the injection of (1.125～4.5 gram)/bottle specification then under 100 grades of conditions.
The principle that adopts gel column to carry out purifying is to utilize the difference of the molecular weight of different substances to separate.Gel column of the present invention can be any one in polyacrylamide gel post, cross-linked dextran gel column, sepharose post or the polystyrene gel post.As preferably, can use the gel column of Sephadex LH series.The Sephadex gel column is a cross-linked dextran gel column, and the commercially available prod of various models is arranged.In the gel column of Sephadex LH series, the present invention preferably uses Sephadex LH-20 or Sephadex LH-60.
At present, oppositely the used filling kind of chromatography column is various, and the present invention preferably uses C
4, C
8Or C
18Be filler, more preferably use C
18Be filler.
In order to realize purpose of the present invention, obtain highly purified piperacillin sodium or sodium-tazobactam, collect piperacillin sodium or Tazobactam Sodium sodium content and be not less than 99% wash-out flow point.Obtain more highly purified piperacillin sodium or sodium-tazobactam, can collect the higher wash-out flow point of piperacillin sodium or Tazobactam Sodium sodium content.Simultaneously, in suitability for industrialized production, not only to consider the purity of products therefrom, will consider the yield of product simultaneously.The raising of product purity will certainly cause the reduction of yield, therefore need take all factors into consideration this two factors.Among the present invention,, collect piperacillin sodium or Tazobactam Sodium sodium content and be not less than 99.5% wash-out flow point, most preferably collect piperacillin sodium or Tazobactam Sodium sodium content and be not less than 99.8% wash-out flow point as preferably.So both can guarantee to obtain highly purified piperacillin sodium or sodium-tazobactam, and can not cause yield low excessively again.
Another object of the present invention provides a kind of preparation method of piperacillin sodium tazobactam sodium compound injection.Piperacillin sodium is a microbiotic commonly used clinically, belongs to penicillins.But because the appearance of resistant organism, the result of treatment of piperacillin sodium has been greatly diminished, and resistant organism makes piperacillin sodium forfeiture antibacterial ability by the secretion β-Nei Xiananmei.Sodium-tazobactam is a beta-lactamase inhibitor, and piperacillin sodium and sodium-tazobactam are united use, can produce the obvious synergistic effect.In order to reach best synergy, the weight ratio of piperacillin sodium and sodium-tazobactam is 4-8 in the described compound preparation: 1.As preferably, the weight ratio of piperacillin sodium and sodium-tazobactam is 4: 1 or 8: 1 in the described compound preparation.For the ease of using recipe comprising piperacillin sodium and sodium-tazobactam 1.125g-4.5g in the preferred per unit preparation clinically.
Beneficial effect below by description of test technical scheme provided by the present invention.The piperacillin sodium and tazobactam sodium powder injection prepared to embodiment 1-4 carries out quality examination.Carried out under 40 ℃ of high temperature, relative humidity 75% ± 5% condition accelerated test simultaneously 6 months and 25 ℃ of temperature, relative humidity 60% ± 10% condition under 18 months investigation of test of long duration, detect the variation of every quality index, the gained data are shown in table 1-3:
0 day quality detected result of table 1
Accelerated test is 6 months under 40 ℃ of table 2 high temperature, relative humidity 75% ± 5% condition
Test of long duration is 18 months under 25 ℃ of table 3 temperature, relative humidity 60% ± 10% condition
By above data results as can be seen, the piperacillin sodium and tazobactam sodium powder injection quality conformance with standard requirement that the present invention makes, and through acceleration to wait in 6 months and long-term 18 months test after, every quality index does not have considerable change, all meet quality standard, illustrated that the sample quality stability of preparation of the present invention is fine.
Compared with prior art, the method for preparing high purity piperacillin sodium or sodium-tazobactam provided by the present invention has following advantage:
1. prepared piperacillin sodium or sodium-tazobactam purity height, its purity is more than or equal to 99.0%.
2. purge process is pollution-free, cost is low, and all solvents are all recyclable, is convenient to industrial continuous production.
3. remove a lot of water-insoluble impurity, improved piperacillin sodium or the sodium-tazobactam solvability in water, improved the stability of its aqueous solution simultaneously.
4. used chromatography column is reusable, and access times reach more than 20 times, have reduced production cost.
Embodiment
Embodiment 1
The piperacillin sodium injection raw material is water-soluble, gained solution is carried out gel chromatography, the filler of used chromatography column is Sephadex LH-20, carries out wash-out with the 60%-95% ethanolic soln, collects the piperacillin sodium content and is not less than 90% wash-out flow point.Gained wash-out flow point is equipped with the chromatographic instrument chromatography with compacting among the BUCHI, and the filler of used reverse chromatography column is C
18Alkyl linked phase silica gel.Carry out wash-out with the 60%-80% ethanolic soln, collect the piperacillin sodium content and be not less than 99% wash-out flow point, reclaim solvent, get highly purified piperacillin sodium raw materials after the lyophilize, yield is 85.2%.
Injection Tazobactam Sodium sodium raw materials is water-soluble, gained solution is carried out gel chromatography, the filler of used chromatography column is Sephadex LH-20, carries out wash-out with the 60%-95% ethanolic soln, collects the Tazobactam Sodium sodium content and is not less than 90% wash-out flow point.Gained wash-out flow point is equipped with the chromatographic instrument chromatography with compacting among the BUCHI, and the filler of used reverse chromatography column is C
18Alkyl linked phase silica gel.Carry out wash-out with the 60%-80% ethanolic soln, collect the Tazobactam Sodium sodium content and be not less than 99% wash-out flow point, reclaim solvent, get highly purified Tazobactam Sodium sodium raw materials after the lyophilize, yield is 84.0%.
Prepared highly purified piperacillin sodium and Tazobactam Sodium sodium raw materials are mixed by 4: 1 weight ratio, pulverized 50 mesh sieves, packing under hundred grades of conditions of sterilisable chamber, every bottle contains 1.125g, promptly gets piperacillin sodium and tazobactam sodium compound powder injection.
Embodiment 2
The piperacillin sodium injection raw material is water-soluble, gained solution is carried out gel chromatography, the filler of used chromatography column is Sephadex LH-60, carries out wash-out with the 60%-95% ethanolic soln, collects the piperacillin sodium content and is not less than 90% wash-out flow point.Gained wash-out flow point is equipped with the chromatographic instrument chromatography with compacting among the BUCHI, and the filler of used reverse chromatography column is C
4Alkyl linked phase silica gel.Carry out wash-out with the 60%-80% ethanolic soln, collect the piperacillin sodium content and be not less than 99% wash-out flow point, reclaim solvent, get highly purified piperacillin sodium raw materials after the lyophilize, yield is 81.0%.
Injection Tazobactam Sodium sodium raw materials is water-soluble, gained solution is carried out gel chromatography, the filler of used chromatography column is Sephadex LH-60, carries out wash-out with the 60%-95% ethanolic soln, collects the Tazobactam Sodium sodium content and is not less than 90% wash-out flow point.Gained wash-out flow point is equipped with the chromatographic instrument chromatography with compacting among the BUCHI, and the filler of used reverse chromatography column is C
4Alkyl linked phase silica gel.Carry out wash-out with the 60%-80% ethanolic soln, collect the Tazobactam Sodium sodium content and be not less than 99% wash-out flow point, reclaim solvent, get highly purified Tazobactam Sodium sodium raw materials after the lyophilize, yield is 81.6%.
Prepared highly purified piperacillin sodium and Tazobactam Sodium sodium raw materials are mixed by 8: 1 weight ratio, pulverized 80 mesh sieves, packing under hundred grades of conditions of sterilisable chamber, every bottle contains 2.25g, promptly gets piperacillin sodium and tazobactam sodium compound powder injection.
Embodiment 3
Press embodiment 1 prepared highly purified piperacillin sodium and Tazobactam Sodium sodium raw materials, mix by 4: 1 weight ratios, pulverized 100 mesh sieves, packing under hundred grades of conditions of sterilisable chamber, promptly get piperacillin sodium and tazobactam sodium compound powder injection, the per unit powder injection contains 3.375g piperacillin sodium and sodium-tazobactam.
Embodiment 4
Press embodiment 1 prepared highly purified piperacillin sodium and Tazobactam Sodium sodium raw materials, mix by 8: 1 weight ratios, pulverized 80 mesh sieves, packing under hundred grades of conditions of sterilisable chamber, promptly get piperacillin sodium and tazobactam sodium compound powder injection, the per unit powder injection contains 4.5g piperacillin sodium and sodium-tazobactam.
The present invention is described according to preferred embodiment.Should be understood that the description of front and embodiment are just to illustrating the present invention.Under prerequisite without departing from the spirit and scope of the present invention, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (5)
1. the method for purifying piperacillin sodium or sodium-tazobactam is characterized in that comprising the steps:
(1) piperacillin sodium crude product or sodium-tazobactam crude product, cross-linked dextran gel column chromatography through Sephadex LH-20 or Sephadex LH-60,, collect piperacillin sodium or Tazobactam Sodium sodium content and be not less than 90% wash-out flow point as eluent with 60%～95% ethanol;
(2) step (1) gained wash-out flow point is through reverse column chromatography, with C
4Alkyl linked phase silica gel or C
18Alkyl linked phase silica gel is filler,, collects piperacillin sodium or Tazobactam Sodium sodium content and is not less than 99% wash-out flow point as eluent with 60%～80% ethanol.
2. the production method of a piperacillin sodium tazobactam sodium compound injection is characterized in that comprising the steps:
(1) piperacillin sodium crude product and sodium-tazobactam crude product are respectively through the cross-linked dextran gel column chromatography of Sephadex LH-20 or Sephadex LH-60,, collect piperacillin sodium or Tazobactam Sodium sodium content and be not less than 90% wash-out flow point as eluent with 60%～95% ethanol;
(2) step (1) gained wash-out flow point is through reverse column chromatography, with C
4Alkyl linked phase silica gel or C
18Alkyl linked phase silica gel is filler, with 60%～80% ethanol as eluent, collect piperacillin sodium or Tazobactam Sodium sodium content and be not less than 99% wash-out flow point, lyophilize makes the raw material of highly purified piperacillin sodium and highly purified sodium-tazobactam respectively;
(3) with the highly purified piperacillin sodium of step (2) gained and highly purified sodium-tazobactam by weight (4～8): 1 mixes, and injection is made in packing.
3. according to each described method of claim 1-2, wherein said piperacillin sodium crude product is formed in the presence of sodium hydroxide, yellow soda ash, sodium bicarbonate or sodium oxide by the piperacillin crude product.
4. one kind according to the purifying piperacillin sodium of claim 1 or the method for sodium-tazobactam, it is characterized in that comprising the steps:
(1) piperacillin sodium crude product or sodium-tazobactam crude product are water-soluble, through the SephadexLH-20 gel filtration chromatography,, collect piperacillin sodium or Tazobactam Sodium sodium content and are not less than 90% wash-out flow point as eluent with 60%～95% ethanol;
(2) step (1) gained wash-out flow point through medium pressure column chromatography, is used anti-phase C
18Filled column carries out gradient elution with 60%～80% ethanol, collects piperacillin sodium or Tazobactam Sodium sodium content and is not less than 99% wash-out flow point.
5. the production method according to the piperacillin sodium tazobactam sodium compound injection of claim 2 is characterized in that comprising the steps:
(1) piperacillin sodium crude product or sodium-tazobactam crude product are water-soluble, through Sephadex LH-20 gel filtration chromatography,, collect piperacillin sodium or Tazobactam Sodium sodium content and are not less than 90% wash-out flow point as eluent with 60%～95% ethanol;
(2) step (1) gained wash-out flow point through medium pressure column chromatography, is used anti-phase C
18Filled column carries out gradient elution with 60%～80% ethanol, collects piperacillin sodium or Tazobactam Sodium sodium content and is not less than 99% wash-out flow point, and lyophilize makes the raw material of highly purified piperacillin sodium and highly purified sodium-tazobactam respectively;
(3) highly purified piperacillin sodium of step (2) gained and highly purified sodium-tazobactam were mixed by weight 4: 1 or 8: 1, be ground into 60-100 order powder, in sterilisable chamber, be distributed into the injection of (1.125～4.5 gram)/bottle specification then under 100 grades of conditions.
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101696212B (en) * | 2009-08-28 | 2012-01-11 | 海南美大制药有限公司 | High-purity tazobactam sodium compound |
| CN102018713B (en) * | 2009-09-11 | 2013-01-23 | 北京四环新盛医药科技有限公司 | Medicinal composition |
| WO2013014544A1 (en) * | 2011-07-25 | 2013-01-31 | Vardhman Chemtech Limited | Method for preparation of composition of piperacillin sodium and tazobactam sodium |
| BR112015023523B8 (en) * | 2013-03-15 | 2023-03-07 | Merck Sharp & Dohme | PHARMACEUTICAL COMPOSITIONS AND SINGLE DOSAGE FORM CONTAINER |
| CN103340866B (en) * | 2013-07-11 | 2014-08-06 | 四川省惠达药业有限公司 | Piperacillin sodium-tazobactam sodium medicine composition and preparation method thereof |
| CN104856997A (en) * | 2014-02-21 | 2015-08-26 | 杭州长典医药科技有限公司 | Special piperacillin sodium-tazobactam sodium ultra-fine powder preparation and preparation method thereof |
| CN104644637B (en) * | 2015-01-27 | 2017-11-10 | 华北制药股份有限公司 | A kind of piperacillin sodium and tazobactam sodium for injection preparation and preparation method thereof |
| CN112409381B (en) * | 2020-12-03 | 2022-03-01 | 山东安信制药有限公司 | Piperacillin sodium and tazobactam sodium co-amorphous substance and preparation method thereof |
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| US4534977A (en) * | 1981-03-26 | 1985-08-13 | American Cyanamid Company | Composition of matter comprising a low bulk density lyophilized preparation of Sodium Piperacillin |
| US4562073A (en) * | 1982-12-24 | 1985-12-31 | Taiho Pharmaceutical Company Limited | Penicillin derivatives |
| CN1802179A (en) * | 2003-04-14 | 2006-07-12 | 惠氏控股公司 | Compositions containing piperacillin and tazobactam useful for injection |
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2008
- 2008-05-12 CN CN2008100975379A patent/CN101265263B/en not_active Expired - Fee Related
Patent Citations (4)
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|---|---|---|---|---|
| US4477452A (en) * | 1981-03-26 | 1984-10-16 | American Cyanamid Company | Composition of matter comprising a lyophilized preparation of a penicillin derivative |
| US4534977A (en) * | 1981-03-26 | 1985-08-13 | American Cyanamid Company | Composition of matter comprising a low bulk density lyophilized preparation of Sodium Piperacillin |
| US4562073A (en) * | 1982-12-24 | 1985-12-31 | Taiho Pharmaceutical Company Limited | Penicillin derivatives |
| CN1802179A (en) * | 2003-04-14 | 2006-07-12 | 惠氏控股公司 | Compositions containing piperacillin and tazobactam useful for injection |
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