CN101279979A - Separation and purification method of cefamandole nafate and preparation of cefathiamidine freeze-dried injectable powder - Google Patents
Separation and purification method of cefamandole nafate and preparation of cefathiamidine freeze-dried injectable powder Download PDFInfo
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- CN101279979A CN101279979A CNA2008101104572A CN200810110457A CN101279979A CN 101279979 A CN101279979 A CN 101279979A CN A2008101104572 A CNA2008101104572 A CN A2008101104572A CN 200810110457 A CN200810110457 A CN 200810110457A CN 101279979 A CN101279979 A CN 101279979A
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Abstract
Disclosed is a method to separate and purify cefamandole nafate, which is characterized in that cefamandole nafate is separated and purified for three times through a high-speed countercurrent chromatograph which adopts a solvent system composed of trichloromethane, ethyl acetate, carbinol and water, with the upper phase being stationary and the lower phase being mobile. The cefamandole nafate can be further froze and dried to prepare freeze-dried powder injection. The method greatly increases the purity of the material up to 99%, and the purification process causes no pollution; therefore the method is good for industrial continuous production.
Description
Technical field
The present invention relates to the separation purification method of Sodium O-formylcefamole, and the preparation method of Sodium O-formylcefamole freeze-dried powder.
Background technology
Sodium O-formylcefamole is a second generation cephalosporin class microbiotic, and Sodium O-formylcefamole enters and is hydrolyzed to Cefamandole in the body rapidly.Be applicable to pulmonary infection, urinary tract infections, biliary tract infection, skin soft-tissue infection, bone and the infection of joint due to the sensitive bacterial and septicemia, abdominal cavity infection etc.
The cefamandole nafate for inj powder injection has been widely used in clinical, determined curative effect, and market outlook are good, and its preparation all is to make by the Mandokef sodium raw materials is aseptic subpackaged.Most of Mandokef sodium raw materials exist purity not high, and dissolving back clarity is poor, the problem of poor stability in the aqueous solution, and this also is the common problem of all cephalosporins medicines.
Summary of the invention
Purpose of the present invention just is to provide a kind of separation purification method of Sodium O-formylcefamole, to be further purified Sodium O-formylcefamole, so that improve the solvability of the preparation of making thus.
Second purpose of the present invention also is to provide a kind of preparation method of Sodium O-formylcefamole freeze-dried powder.
In order to realize first purpose of the present invention, adopt following technical scheme: a kind of separation purification method of Sodium O-formylcefamole, carry out three separation and purification with high speed adverse current chromatogram, high speed adverse current chromatogram adopts the solvent system that constitutes stationary phase, moving phase with trichloromethane, ethyl acetate, first alcohol and water, on be stationary phase mutually, is moving phase mutually down.
With decolouring with activated carbon after the high speed adverse current chromatogram separation and purification, use the filtering with microporous membrane degerming again, can improve product color and sanitary condition.
For realizing second purpose of the present invention, technical scheme is: earlier the Mandokef sodium raw materials is carried out separation and purification with high speed adverse current chromatogram, high speed adverse current chromatogram adopts the solvent system that constitutes stationary phase, moving phase with trichloromethane, ethyl acetate, first alcohol and water, on be stationary phase mutually, is moving phase mutually down; Also decolour with activated carbon after with the high speed adverse current chromatogram separation and purification, use the filtering with microporous membrane degerming again, freeze-dried powder is made in lyophilize then.
In the above-mentioned high speed adverse current chromatogram separation and purification Mandokef process, comparative optimization be that solvent system is by trichloromethane, ethyl acetate, methyl alcohol, water by volume 1.0～2.5: 0.5～3.2 during separation and purification for the first time: 0.8～2.2: 1 forms.
Comparative optimization be for the second time separation and purification high speed adverse current chromatogram solvent for use system by trichloromethane, ethyl acetate, methyl alcohol, water by volume 0.8～2.4: 0.5～1.6: 1.0～2.0: 1 forms.
Comparative optimization be for the third time separation and purification high speed adverse current chromatogram solvent for use system by trichloromethane, ethyl acetate, methyl alcohol, water by volume 0.6～1.8: 0.5～2.0: 0.8～1.5: 1 forms.
The present invention has following beneficial effect:
1, adopts the high speed adverse current chromatogram purification process, solvent system with trichloromethane, ethyl acetate, first alcohol and water formation stationary phase, moving phase is greatly improved the purity of raw material, reaches more than 99%, and purge process is pollution-free, is convenient to industrial continuous production.
2, removed a lot of water-insoluble impurity, improved the solvability in water, built in the fast and good stability of freeze-dried powder rehydration dissolving.
Embodiment
The invention will be further described below in conjunction with specific embodiment, to help understanding content of the present invention.
Mandokef sodium raw materials used in the following examples is to be provided by Hainan Prov Lingkang Pharmaceutical Co., Ltd, and purity is 95.8%.
Embodiment 1
(1) Mandokef sodium raw materials applied sample amount 200mg, purity 95.8%.Solvent system: trichloromethane, ethyl acetate, methyl alcohol, water volume ratio 2: 2.5: 1.8: 1 (volume ratio), column volume: 200ml, rotating speed 800rpm, on be stationary phase mutually, is moving phase mutually down, flow velocity 2ml/min, stationary phase retention value: 52%.
Pressed trichloromethane, ethyl acetate, methyl alcohol, water volume ratio 2: 2.5: 1.8: 1 preparation solvent system, standing demix is told upper and lower phase, gets to be stationary phase mutually, is moving phase mutually down.Make in the high-speed counter-current chromatograph pillar to be full of stationary phase, its main frame is clockwise rotated, in moving phase being pumped into, using the Mandokef sodium raw materials down, phase solvent dissolves the back by the sampling valve sample introduction, according to detector spectrogram receiving target composition again.
(2) will do separation and purification for the second time with high-speed counter-current chromatograph by the isolate that (1) obtains, the retention time scope is 2.5～3.3 hours, chromatographic condition: column volume 200ml, rotating speed 800rpm, solvent system: trichloromethane: ethyl acetate: methyl alcohol: water=2: 1.3: 1.6: 1 (volume ratio), applied sample amount: 100mg, on be stationary phase mutually, is moving phase mutually down, flow velocity 2ml/min, operation steps is with (1), stationary phase retention value 58%.
(3) do separation and purification for the third time with high-speed counter-current chromatograph again by the isolate that obtains in (2), retention time is 5.3～6.5 hours, chromatographic condition: column volume 200ml, rotating speed 800rpm, solvent system: trichloromethane: ethyl acetate: methyl alcohol: water=1.5: 1: 1.2: 1 (volume ratio), applied sample amount: 80mg, on be stationary phase mutually, is moving phase mutually down, flow velocity 2ml/min, operation steps is with (1), stationary phase retention value 58%.
(4) with the isolate activated carbon decolorizing of gained in (3), after the 0.22 μ m filtering with microporous membrane degerming, lyophilize gets the purified feed stock powder.
(5) detecting purity with high performance liquid chromatograph is 99.4%.
(6) Mandokef sodium pure product after the lyophilize is crossed 80～100 mesh sieves and is pulverized, packing under 100 grades of conditions in sterilisable chamber, cefamandole nafate for inj freeze-dried powder sterile preparation.
Embodiment 2
Get the Mandokef sodium raw materials, operation steps is pressed embodiment 1, difference is: solvent system in the step (1): the volume ratio of trichloromethane, ethyl acetate, methyl alcohol, water is 1.5: 1.8: 1: 1, solvent system in the step (2): trichloromethane: ethyl acetate: methyl alcohol: the volume ratio of water is 1.0: 0.8: 1.3: 1, and solvent system in the step (3): trichloromethane: ethyl acetate: methyl alcohol: the volume ratio of water is 0.8: 0.5: 1.0: 1.Detecting purity with high performance liquid chromatograph behind the purifying is 99.3%.Aseptic subpackaged, get cefamandole nafate for inj freeze-dried powder sterile preparation.
Embodiment 3
Get the Mandokef sodium raw materials, operation steps is pressed embodiment 1, difference is: solvent system in the step (1): the volume ratio of trichloromethane, ethyl acetate, methyl alcohol, water is 3.0: 3.5: 2.5: 1, solvent system in the step (2): trichloromethane: ethyl acetate: methyl alcohol: the volume ratio of water is 2.5: 2.0: 1.5: 1, and solvent system in the step (3): trichloromethane: ethyl acetate: methyl alcohol: the volume ratio of water is 0.5: 1.0: 0.7: 1.Detecting purity with high performance liquid chromatograph behind the purifying is 97.2%.Aseptic subpackaged, get cefamandole nafate for inj freeze-dried powder sterile preparation.
The experimental example quality approach
The sample that makes among above three embodiment is carried out quality examination, and 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 test of long duration test in 18 months investigate, obtain data results as table 1-table 3:
0 day quality detected result of table 1
| Sample | Proterties | Acidity | Clarity | Related substance (%) | Content (%) |
| Embodiment 1 | White powder | 5.5 | Up to specification | 0.86 | 102.2 |
| Embodiment 2 | White powder | 5.7 | Up to specification | 0.89 | 99.7 |
| Embodiment 3 | White powder | 5.6 | Up to specification | 2.83 | 100.4 |
Table 2 accelerated test result
Table 3 long-term test results
By the data results of above table 1-table 3 as can be seen, the sample purity that the embodiment of the invention 1, embodiment 2 make is fine, and every quality index does not have considerable change after quickening June and long-term 18 months, all meets quality standard; The sample purity of embodiment 3 preparations is relatively poor, and every quality index changes greatly after quickening June and long-term 18 months, exceeds the quality standard requirement.Having proved absolutely in the technology of the present invention scope can well purifying Mandokef sodium raw materials, the cefamandole nafate for inj preparation that preparation quality is qualified.
Claims (10)
1, a kind of separation purification method of Sodium O-formylcefamole, it is characterized in that: be to carry out three separation and purification with high speed adverse current chromatogram, high speed adverse current chromatogram adopts the solvent system that constitutes stationary phase, moving phase with trichloromethane, ethyl acetate, first alcohol and water, on be stationary phase mutually, is moving phase mutually down.
2, the separation purification method of Sodium O-formylcefamole according to claim 1 is characterized in that: with also decolouring with activated carbon after the high speed adverse current chromatogram separation and purification, use the filtering with microporous membrane degerming again.
3, the separation purification method of Sodium O-formylcefamole as claimed in claim 1 or 2 is characterized in that: for the first time separation and purification high speed adverse current chromatogram solvent for use system is by trichloromethane, ethyl acetate, methyl alcohol, water by volume 1.0～2.5: 0.5～3.2: 0.8～2.2: 1 forms.
4, the separation purification method of Sodium O-formylcefamole as claimed in claim 1 or 2 is characterized in that: for the second time separation and purification high speed adverse current chromatogram solvent for use system is by trichloromethane, ethyl acetate, methyl alcohol, water by volume 0.8～2.4: 0.5～1.6: 1.0～2.0: 1 forms.
5, the separation purification method of Sodium O-formylcefamole as claimed in claim 1 or 2 is characterized in that: separation and purification high speed adverse current chromatogram solvent for use system is by trichloromethane, ethyl acetate, methyl alcohol, water by volume 0.6～1.8: 0.5～2.0 for the third time: 0.8～1.5: 1 forms.
6, a kind of preparation method of Sodium O-formylcefamole freeze-dried powder, it is characterized in that: earlier the Mandokef sodium raw materials is carried out separation and purification with high speed adverse current chromatogram, high speed adverse current chromatogram is the solvent system that constitutes stationary phase, moving phase with trichloromethane, ethyl acetate, first alcohol and water, on be stationary phase mutually, is moving phase mutually down; Also decolour with activated carbon after with the high speed adverse current chromatogram separation and purification, use the filtering with microporous membrane degerming again, freeze-dried powder is made in lyophilize then.
7, the preparation method of Sodium O-formylcefamole freeze-dried powder as claimed in claim 6 is characterized in that: for the first time separation and purification high speed adverse current chromatogram solvent for use system is by trichloromethane, ethyl acetate, methyl alcohol, water by volume 1.0～2.5: 0.5～3.2: 0.8～2.2: 1 forms.
8, the preparation method of Sodium O-formylcefamole freeze-dried powder as claimed in claim 7 is characterized in that: for the second time separation and purification high speed adverse current chromatogram solvent for use system is by trichloromethane, ethyl acetate, methyl alcohol, water by volume 0.8～2.4: 0.5～1.6: 1.0～2.0: 1 forms.
9, the preparation method of Sodium O-formylcefamole freeze-dried powder as claimed in claim 7 is characterized in that: separation and purification high speed adverse current chromatogram solvent for use system is by trichloromethane, ethyl acetate, methyl alcohol, water by volume 0.6～1.8: 0.5～2.0 for the third time: 0.8～1.5: 1 forms.
10, as the preparation method of described Sodium O-formylcefamole freeze-dried powder one of in the claim 7 to 9, it is characterized in that: after pulverizing drying also with the pure product of Sodium O-formylcefamole after 80～100 mesh sieves pulverize, packing under 100 grades of conditions in sterilisable chamber.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101856333A (en) * | 2010-06-10 | 2010-10-13 | 湖北济生医药有限公司 | Freeze-dried powder injection of cefamandole nafate and preparation method thereof |
| CN101891755A (en) * | 2010-07-27 | 2010-11-24 | 海南永田药物研究院有限公司 | Cefsulodin sodium compound and novel preparation method thereof |
| CN102093392A (en) * | 2011-01-28 | 2011-06-15 | 海南灵康制药有限公司 | New method for preparing Cefamandole Nafate |
| CN102702232A (en) * | 2012-04-17 | 2012-10-03 | 山东鲁抗医药股份有限公司 | Method for preparation of fine cefamandole nafate |
| CN104892637A (en) * | 2015-06-16 | 2015-09-09 | 海南灵康制药有限公司 | Novel industrial crystallization technology for cefamandole nafate |
| CN105566351A (en) * | 2016-02-18 | 2016-05-11 | 海南灵康制药有限公司 | New crystal form cefamandole nafate compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100554271C (en) * | 2007-07-27 | 2009-10-28 | 苏州中联化学制药有限公司 | The synthetic method of antibiotics cefamandole nafate |
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2008
- 2008-06-03 CN CN2008101104572A patent/CN101279979B/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101856333A (en) * | 2010-06-10 | 2010-10-13 | 湖北济生医药有限公司 | Freeze-dried powder injection of cefamandole nafate and preparation method thereof |
| CN101856333B (en) * | 2010-06-10 | 2012-02-22 | 湖北济生医药有限公司 | Freeze-dried powder injection of cefamandole nafate and preparation method thereof |
| CN101891755A (en) * | 2010-07-27 | 2010-11-24 | 海南永田药物研究院有限公司 | Cefsulodin sodium compound and novel preparation method thereof |
| CN102093392A (en) * | 2011-01-28 | 2011-06-15 | 海南灵康制药有限公司 | New method for preparing Cefamandole Nafate |
| US8859761B2 (en) | 2011-01-28 | 2014-10-14 | Hainan Lingkang Pharmaceutical Co., Ltd. | Refining process of Cefamandole sodium |
| CN102702232A (en) * | 2012-04-17 | 2012-10-03 | 山东鲁抗医药股份有限公司 | Method for preparation of fine cefamandole nafate |
| CN104892637A (en) * | 2015-06-16 | 2015-09-09 | 海南灵康制药有限公司 | Novel industrial crystallization technology for cefamandole nafate |
| CN105566351A (en) * | 2016-02-18 | 2016-05-11 | 海南灵康制药有限公司 | New crystal form cefamandole nafate compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation |
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| CN101279979B (en) | 2010-07-28 |
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