CN101322701B - Amoxicillin sodium and sulbactam sodium for injection and preparation of freeze-dried injection thereof - Google Patents
Amoxicillin sodium and sulbactam sodium for injection and preparation of freeze-dried injection thereof Download PDFInfo
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- CN101322701B CN101322701B CN2008101348276A CN200810134827A CN101322701B CN 101322701 B CN101322701 B CN 101322701B CN 2008101348276 A CN2008101348276 A CN 2008101348276A CN 200810134827 A CN200810134827 A CN 200810134827A CN 101322701 B CN101322701 B CN 101322701B
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Abstract
The invention discloses a preparation method of amoxicillin sodium and sulbactam sodium used for injection and a freeze-dried powder injection thereof as well as a separating and purifying method of the amoxicillin sodium and sulbactam sodium used for injection. By adopting high speed countercurrent chromatography, a solvent system of an immobile phase and a mobile phase prepared from trichloromethane, ethyl acetate, methanol and water is used for separating and purifying amoxicillin sodium and sulbactam sodium to obtain the amoxicillin sodium and sulbactam sodium used for injection; the purity of the obtained product can reach more than 98% and the prepared injection has improved stability.
Description
Technical field
The invention provides a kind of Amoxicillin Sodium of injection and the isolation and purification method of sulbactam sodium, and the preparation method of amoxicillin sodium and sulbactam sodium injectable powder.Belong to field of medicaments.
Background technology
The amoxicillin is the bactericidal properties broad ectrum antibiotic, and sulbactam sodium is irreversible wide spectrum beta-lactamase inhibitor, can suppress the beta-lactamase that fastbacteria produces effectively.Many clinically Grain-positives and gram-negative bacteria produce beta-lactamase, and this enzyme can make the amoxicillin lose antibacterial activity.Because the existence of sulbactam sodium can make the amoxicillin exempt from the destruction of p-lactamase, thereby make the amoxicillin drug resistance and produce the antibacterial of beta-lactamase, still to the amoxicillin sensitivity.This product is a bactericidal antibiotic, can kill multiple Grain-positive and gram-negative bacteria clinically, and is particularly effective in cure to the fastbacteria that produces beta-lactamase.
The drug combination of Amoxicillin Sodium and sulbactam sodium is applicable to respiratory system infection, urogenital infections, the infection of serious system, otorhinolaryngology infection, skin and soft tissue infection and other infection etc.
The clinical consumption of this product is big, determined curative effect, and market prospect is good.This product is the same with most of cephalosporinses, and its preparation all is to be made by Amoxicillin Sodium and the aseptic raw material packing of sulbactam sodium or lyophilizing.Most of Amoxicillin Sodiums and sulbactam sodium exist purity low, and dissolving back visible foreign matters is many, aqueous solution utmost point problem of unstable.
High speed adverse current chromatogram (High-Speed Countercurrent Chromatography) is a kind of liquid luquid partition chromatography isolation technics of continuous high-efficient, do not need the solid support thing owing to adopt liquid immobile phase, thereby avoided because of sample loss that Irreversible Adsorption causes, inactivation degeneration etc., very rapid development in nearly 20～30 years.But prior art does not have the report that high speed adverse current chromatogram is used for the separation and purification of Amoxicillin Sodium and sulbactam sodium as yet, does not provide to use the report that high speed adverse current chromatogram prepares the amoxicillin sodium and sulbactam sodium lyophilized injectable powder yet.
Summary of the invention
One of purpose of the present invention is to provide a kind of Amoxicillin Sodium of injection and the isolation and purification method of sulbactam sodium, to improve the injection stability of Amoxicillin Sodium and sulbactam sodium.
Two of purpose of the present invention is to provide a kind of preparation method of amoxicillin sodium and sulbactam sodium injectable powder, in this way Zhi Bei injectable powder good stability.
For achieving the above object, technical solution of the present invention is as follows:
The invention provides a kind of preparation method of amoxicillin sodium and sulbactam sodium injection, it is characterized in that comprising that the raw material of Amoxicillin Sodium or sulbactam sodium carries out the step of purification with high speed adverse current chromatogram, the condition of wherein said high speed adverse current chromatogram is with chloroform, methanol, water and ethyl acetate preparation constitute immobile phase, the dicyandiamide solution of mobile phase, on be immobile phase mutually, be mobile phase mutually down, make in the whole cylinder of high-speed counter-current chromatograph and be full of immobile phase, again mobile phase is pumped in the post, the raw material of Amoxicillin Sodium or sulbactam sodium with mobile phase as dissolution with solvents after by the injection valve sample introduction.
Above-mentioned described method, the consumption volume ratio of chloroform, methanol, water and ethyl acetate is 1～3 in the wherein said dicyandiamide solution: 0.8～2.5: 1.2～2: 1; The consumption volume ratio that is more preferably chloroform, methanol, water and ethyl acetate in the described dicyandiamide solution is 2: 1: 1.5: 1.
The above-mentioned described method of the present invention, the engine speed of high speed adverse current chromatogram, flow velocity etc. are not particularly limited.As the specific embodiment of the invention, the present invention is preferably with behind immobile phase and the mobile phase ultrasonic degas, earlier be full of whole cylinder with immobile phase, open high-speed counter-current chromatograph then, rotating speed is 1000～2000rpm, with 1.0～2.0ml/min flow velocity mobile phase is pumped in the post, treat that whole system is set up dynamic equilibrium after, carry out sample introduction again.The engine speed that is more preferably high speed adverse current chromatogram is 1500rpm, with the flow velocity of 1.5ml/min mobile phase is pumped in the post.
The above-mentioned described method of the present invention can make purity at least at amoxicillin sodium for injection more than 98% and injection sulbactam sodium.Prepared amoxicillin sodium for injection and injection sulbactam sodium can be mixed with various injections as required.As preferred version of the present invention, described method, wherein said injection is a freeze-dried powder, the raw material of Amoxicillin Sodium or sulbactam sodium separates with high speed adverse current chromatogram, collect respectively Amoxicillin Sodium 98% with top and sulbactam sodium 98% with top, after lyophilization, the pulverizing, carry out aseptic subpackaged in proportion.
If desired, above-mentioned described method, wherein collect 98% with top, before carrying out lyophilization, use activated carbon decolorizing earlier, use microporous filter membrane (for example 0.22um microporous filter membrane) filtration sterilization then, carry out lyophilization again, make injectable powder.
The above-mentioned described method of the present invention, the weight ratio of Amoxicillin Sodium and sulbactam sodium is in the wherein said injection, can mix by a certain percentage as required.As optimal way, the weight ratio of Amoxicillin Sodium and sulbactam sodium is (1～2) in the described injection: (1～2); More preferably the weight ratio of Amoxicillin Sodium and sulbactam sodium is 2: 1.
Wherein, in the above-mentioned described method, the preparation specification of described freeze-dried powder can be determined as required, and the preferred every bottled amount of the present invention is 0.375g～3.0g.
Further, the present invention also provides the purification process of a kind of amoxicillin sodium for injection or injection sulbactam sodium, it is characterized in that comprising that the raw material of Amoxicillin Sodium or sulbactam sodium carries out the step of purification with high speed adverse current chromatogram, the condition of wherein said high speed adverse current chromatogram is with chloroform, methanol, water and ethyl acetate preparation constitute immobile phase, the dicyandiamide solution of mobile phase, on be immobile phase mutually, be mobile phase mutually down, make in the whole cylinder of high-speed counter-current chromatograph and be full of immobile phase, again mobile phase is pumped in the post, the raw material of Amoxicillin Sodium or sulbactam sodium with mobile phase as dissolution with solvents after by the injection valve sample introduction.
Above-mentioned described method, the consumption volume ratio of chloroform, methanol, water and ethyl acetate is 1～3: 0.8～2.5 in the wherein said dicyandiamide solution: 1.2～2: 1; The consumption volume ratio of chloroform, methanol, water and ethyl acetate is 2: 1: 1.5 in the preferred described dicyandiamide solution: 1.
As the specific embodiment of the invention, the present invention is preferably with behind immobile phase and the mobile phase ultrasonic degas, earlier be full of whole cylinder with immobile phase, open high-speed counter-current chromatograph then, rotating speed is 1000～2000rpm, with 1.0～2.0ml/min flow velocity mobile phase is pumped in the post, treat that whole system is set up dynamic equilibrium after, carry out sample introduction again; Preferred rotating speed is 1500rpm, with the flow velocity of 1.5ml/min mobile phase is pumped in the post.
The present invention adopts high speed adverse current chromatogram, constitute the dicyandiamide solution of immobile phase, mobile phase with chloroform, ethyl acetate, methanol, water preparation, Amoxicillin Sodium and sulbactam sodium are carried out separation and purification, obtain amoxicillin sodium for injection and sulbactam sodium, products obtained therefrom purity is at least more than 98%, and prepared injection has the stability of improvement.
Advantage of the present invention is:
1, the present invention has adopted the high speed adverse current chromatogram separation method, high-speed countercurrent chromatography has been avoided the chemical modification because of the sample loss that adsorption causes, sample component, separation efficiency can be compared with preparation HPLC with capacity, and does not generally have the conditions of streaking at peak.
2, adopt the high speed adverse current chromatogram purification process, the purity of raw material is greatly improved, product purity reaches more than 98% at least, and purge process is pollution-free, is convenient to industrial continuous production.
3, the effective theoretical plate number of this method purification Amoxicillin Sodium and sulbactam sodium is 1300～2500, has efficient, quick, the characteristics such as fractional dose is big, sample free of losses, response rate height, isolating environment gentleness, saving solvent of separating.
4, remove a lot of water-insoluble impurity, improved the dissolubility in water.
The method for preparing the amoxicillin sodium and sulbactam sodium injectable powder provided by the invention, the injectable powder purity height of preparation, dissolubility is good, stable in properties.
The specific embodiment
The invention will be further described below in conjunction with specific embodiment, to help understanding content of the present invention.
Used Amoxicillin Sodium and sulbactam sodium raw material in the following examples provides by Shangdong Ruiyang Pharmaceutical Co., Ltd, and purity is respectively 96.1% and 95.9%.
Embodiment 1
Use half countercurrent chromatography instrument, be furnished with constant flow pump, the 15ml injection valve, politef post, column volume are 200ml, the UV UV-detector.With volume ratio is 2: 1: 1.5: 1 chloroform, methanol, water, ethyl acetate is miscible in separatory funnel, shake up the back standing demix, get its upper solution (going up phase) and be immobile phase, lower floor's solution (following phase) is mobile phase, behind the ultrasonic degas, earlier be full of whole cylinder with immobile phase, open high-speed counter-current chromatograph then, the adjustment engine speed is 1500rpm, in the flow velocity of 1.5ml/min mobile phase being pumped into, treat that whole system is set up dynamic equilibrium after, in being dissolved in the amoxicillin sodium raw materials mutually, by the injection valve sample introduction,, collect 98% with top then according to the detector uv-spectrogram, activated carbon decolorizing, 0.22 after the degerming of μ m filtering with microporous membrane, lyophilization gets the purified feed stock powder.
Analyze through HPLC, the purity of Amoxicillin Sodium is 99.2%, and effective theoretical plate number is 2042.
With method purification sulbactam sodium raw material, lyophilization gets sulbactam sodium purified feed stock powder.Analyze through HPLC, the purity of sulbactam sodium is 99.5%, and effective theoretical plate number is 1668.
Amoxicillin Sodium after the lyophilization and sulbactam sodium pure product are crossed 60 mesh sieves respectively pulverize, then by weight 2: 1 mix homogeneously, packing under 100 grades of conditions in sterilizing room, amoxicillin sodium for injection sulbactam sodium powder injection formulation, every bottled amount is 0.375g.
Embodiment 2
Press high-speed countercurrent chromatography operating procedure purification Amoxicillin Sodium and the sulbactam sodium raw material of embodiment 1, the consumption volume ratio of chloroform, methanol, water, ethyl acetate is 1: 0.8: 1.2: 1, analyze through HPLC, the purity of Amoxicillin Sodium is 99.3%, effective theoretical plate number is 1870, the purity of sulbactam sodium is 99.2%, and effective theoretical plate number is 2230.
The Amoxicillin Sodium of purification and sulbactam sodium raw material are crossed 80 mesh sieves respectively pulverize, then by weight 2: 1 mix homogeneously, packing under 100 grades of conditions in sterilizing room, amoxicillin sodium for injection sulbactam sodium powder injection formulation, every bottle of packing 3.0g.
Embodiment 3
Press high-speed countercurrent chromatography operating procedure purification Amoxicillin Sodium and the sulbactam sodium raw material of embodiment 1, the consumption volume ratio of chloroform, methanol, water, ethyl acetate is 3: 2.5: 2: 1, analyze through HPLC, Amoxicillin Sodium is 99.0%, effective theoretical plate number is 2042, the purity of sulbactam sodium is 99.4%, and effective theoretical plate number is 1955.
The Amoxicillin Sodium of purification and sulbactam sodium raw material are crossed 100 mesh sieves respectively pulverize, then by weight 2: 1 mix homogeneously, packing under 100 grades of conditions in sterilizing room, amoxicillin sodium for injection sulbactam sodium powder injection formulation, every bottle of packing 1.5g.
Embodiment 4 (contrast)
Press high-speed countercurrent chromatography operating procedure purification Amoxicillin Sodium and the sulbactam sodium raw material of embodiment 1, the consumption volume ratio of chloroform, methanol, water, ethyl acetate is 0.9: 2: 2.1: 1, analyze through HPLC, Amoxicillin Sodium is 97.5%, effective theoretical plate number is 1836, the purity of sulbactam sodium is 97.6%, and effective theoretical plate number is 2278.
The Amoxicillin Sodium of purification and sulbactam sodium raw material are crossed 60 mesh sieves respectively pulverize, then by weight 2: 1 mix homogeneously, packing under 100 grades of conditions in sterilizing room, amoxicillin sodium for injection sulbactam sodium powder injection formulation, every bottle of packing 0.375g.
Embodiment 5 (contrast)
Press high-speed countercurrent chromatography operating procedure purification Amoxicillin Sodium and the sulbactam sodium raw material of embodiment 1, the consumption volume ratio of chloroform, methanol, water, ethyl acetate is 3.1: 0.7: 1.1: 1, analyze through HPLC, Amoxicillin Sodium is 97.0%, effective theoretical plate number is 2244, the purity of sulbactam sodium is 97.7%, and effective theoretical plate number is 1996.
The Amoxicillin Sodium of purification and sulbactam sodium raw material are crossed 80 mesh sieves respectively pulverize, then by weight 2: 1 mix homogeneously, packing under 100 grades of conditions in sterilizing room, amoxicillin sodium for injection sulbactam sodium powder injection formulation, every bottle of packing 3.0g.
Experimental example 6 quality researches
Respectively will more than the sample that makes under 60 ℃ of high temperature, illumination 4500Lx condition, place and carried out the influence factor in 10 days and test investigation, it the results are shown in Table 1; Under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 months, carry out accelerated test and investigate, the results are shown in Table 2; Under 25 ℃ of high temperature, relative humidity 60% ± 10% condition 18 months, carry out long term test and investigate, detect the variation of every quality index, the results are shown in Table 3.
Table 1 influence factor result
Table 2 accelerated test result
Table 3 long-term test results
Annotate: " Y1, Y2, the Y3 ... " in the above form represents yellow No. 1, yellow No. 2, yellow No. 3 standard color solutions respectively, and "＜Y1 " expression is not deeper than yellow No. 1 standard color solution.
By above data result as can be seen, the sample purity that the embodiment of the invention 1, embodiment 2, embodiment 3 make is fine, and influence factor 10 days, quicken June and long-term 18 months after every quality index do not have significant change, all meet quality standard.Having proved absolutely in the technology of the present invention scope can well purification Amoxicillin Sodium and sulbactam sodium raw material, the amoxicillin sodium for injection sulbactam sodium preparation that preparation quality is qualified.
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 (13)
1. the preparation method of an amoxicillin sodium and sulbactam sodium injection, it is characterized in that comprising that the raw material of Amoxicillin Sodium and sulbactam sodium carries out the step of purification respectively with high speed adverse current chromatogram, the condition of wherein said high speed adverse current chromatogram is with chloroform, methanol, water and ethyl acetate preparation constitute immobile phase, the dicyandiamide solution of mobile phase, on be immobile phase mutually, be mobile phase mutually down, make in the whole cylinder of high-speed counter-current chromatograph and be full of immobile phase, again mobile phase is pumped in the post, after the raw material of Amoxicillin Sodium and sulbactam sodium uses mobile phase as dissolution with solvents respectively by the injection valve sample introduction, wherein, chloroform in the described dicyandiamide solution, methanol, the consumption volume ratio of water and ethyl acetate is 1～3: 0.8～2.5: 1.2～2: 1.
2. the method for claim 1, the consumption volume ratio that it is characterized in that chloroform, methanol, water and ethyl acetate in the described dicyandiamide solution is 2: 1: 1.5: 1.
3. as each described method of claim 1-2, after it is characterized in that immobile phase and mobile phase ultrasonic degas, earlier be full of whole cylinder with immobile phase, open high-speed counter-current chromatograph then, rotating speed is 1000～2000rpm, with 1.0～2.0ml/min flow velocity mobile phase is pumped in the post, treat that whole system is set up dynamic equilibrium after, carry out sample introduction again.
4. method as claimed in claim 3, wherein said rotating speed are 1500rpm, with the flow velocity of 1.5ml/min mobile phase are pumped in the post.
5. as each described method of claim 1-2, wherein said injection is a freeze-dried powder, the raw material of Amoxicillin Sodium and sulbactam sodium is used the high speed adverse current chromatogram purification respectively, collect respectively Amoxicillin Sodium purity 98% with top and sulbactam sodium purity 98% with top, after lyophilization, the pulverizing, carry out aseptic subpackaged in proportion.
6. method as claimed in claim 5 is characterized in that: use activated carbon decolorizing earlier before carrying out lyophilization, use the filtering with microporous membrane degerming then.
7. as each described method of claim 1-2, the weight ratio of Amoxicillin Sodium and sulbactam sodium is (1～2) in the wherein said injection: (1～2).
8. method as claimed in claim 7, the weight ratio of Amoxicillin Sodium and sulbactam sodium is 2: 1 in the wherein said injection.
9. method as claimed in claim 5, the every bottled amount that it is characterized in that described freeze-dried powder is 0.375g～3.0g.
10. the purification process of amoxicillin sodium for injection or injection sulbactam sodium, it is characterized in that comprising that the raw material of Amoxicillin Sodium or sulbactam sodium carries out the step of purification with high speed adverse current chromatogram, the condition of wherein said high speed adverse current chromatogram is with chloroform, methanol, water and ethyl acetate preparation constitute immobile phase, the dicyandiamide solution of mobile phase, on be immobile phase mutually, be mobile phase mutually down, make in the whole cylinder of high-speed counter-current chromatograph and be full of immobile phase, again mobile phase is pumped in the post, the raw material of Amoxicillin Sodium or sulbactam sodium with mobile phase as dissolution with solvents after by the injection valve sample introduction, chloroform in the wherein said dicyandiamide solution, methanol, the consumption volume ratio of water and ethyl acetate is 1～3: 0.8～2.5: 1.2～2: 1.
11. method as claimed in claim 10, the consumption volume ratio that it is characterized in that chloroform, methanol, water and ethyl acetate in the described dicyandiamide solution is 2: 1: 1.5: 1.
12. as each described method of claim 10-11, after it is characterized in that immobile phase and mobile phase ultrasonic degas, earlier be full of whole cylinder with immobile phase, open high-speed counter-current chromatograph then, rotating speed is 1000～2000rpm, with 1.0～2.0ml/min flow velocity mobile phase is pumped in the post, treat that whole system is set up dynamic equilibrium after, carry out sample introduction again.
13. method as claimed in claim 12, wherein said rotating speed are 1500rpm, with the flow velocity of 1.5ml/min mobile phase are pumped in the post.
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| CN2008101348276A CN101322701B (en) | 2008-08-01 | 2008-08-01 | Amoxicillin sodium and sulbactam sodium for injection and preparation of freeze-dried injection thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2632708C1 (en) * | 2016-11-14 | 2017-10-09 | Лонг Шенг Фарма Лимитед | Method for combined antibacterial preparation production |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101822669B (en) * | 2010-04-23 | 2012-06-13 | 海南美兰史克制药有限公司 | Liposome injection of amoxicillin sodium sulbactam sodium medicinal composition |
| CN103012429B (en) * | 2012-12-28 | 2014-12-31 | 吴秋萍 | Novel amoxicillin sodium compound and composition of amoxicillin sodium compound and sulbactam sodium compound |
| CN103432121A (en) * | 2013-06-17 | 2013-12-11 | 四川制药制剂有限公司 | Preparation method of amoxicillim sodium and sulbactam sodium for injection |
| CN103301123A (en) * | 2013-06-17 | 2013-09-18 | 四川制药制剂有限公司 | Preparation method for controlling pH (Potential of Hydrogen) of amoxicillin sodium/sulbactam sodium |
| CN104147004A (en) * | 2014-02-21 | 2014-11-19 | 杭州长典医药科技有限公司 | Specific amoxicillin sodium and sulbactam sodium superfine powdered preparation and preparation method thereof |
| CN106946908A (en) * | 2017-04-25 | 2017-07-14 | 四川制药制剂有限公司 | A kind of production technology of amoxicillin sodium for injection sulbactam |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1623544A (en) * | 2003-12-01 | 2005-06-08 | 沈阳华泰药物研究有限公司 | Preparation of injection amoxicillin subaton |
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| CN1623544A (en) * | 2003-12-01 | 2005-06-08 | 沈阳华泰药物研究有限公司 | Preparation of injection amoxicillin subaton |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2632708C1 (en) * | 2016-11-14 | 2017-10-09 | Лонг Шенг Фарма Лимитед | Method for combined antibacterial preparation production |
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Assignee: SHANDONG WEIFANG PHARMACEUTICAL FACTORY CO., LTD. Assignor: Hainan Baina Pharmaceutical Development Co., Ltd. Contract record no.: 2011990000938 Denomination of invention: Amoxicillin sodium and sulbactam sodium for injection and preparation of freeze-dried injection thereof Granted publication date: 20100818 License type: Exclusive License Open date: 20081217 Record date: 20110928 |
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