CN101544661B - Cefobutazine sodium compound and pharmaceutical composition made therefrom - Google Patents
Cefobutazine sodium compound and pharmaceutical composition made therefrom Download PDFInfo
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- CN101544661B CN101544661B CN2009100151212A CN200910015121A CN101544661B CN 101544661 B CN101544661 B CN 101544661B CN 2009100151212 A CN2009100151212 A CN 2009100151212A CN 200910015121 A CN200910015121 A CN 200910015121A CN 101544661 B CN101544661 B CN 101544661B
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Abstract
The invention relates to a cefobutazine sodium compound and a purification method thereof. The invention adopts the combination of pH value adjustment and resin absorption so as to be capable of separating out high molecular polymers contained in the cefobutazine sodium compound and finally obtain high-purity cefobutazine sodium. The invention also relates to a product obtained according to the method and a pharmaceutical composition containing the product.
Description
Technical field
Product that the present invention relates to a kind of purification process of cefobutazine sodium, prepares according to this method and the pharmaceutical composition that comprises described product.
Background technology
Cefobutazine sodium, have another name called ceftezol sodium, English name, ceftezole sodium, chemical name is: (6R, 7R)-3-[(1,3,4-thiadiazoles-2-yl) sulphomethyl]-8-oxo-7-[2-(1H-tetrazolium-1-yl) kharophen]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2 sodium formiate, molecular formula: C
13H
11N
8NaO
4S
3, molecular weight: 462.45, structural formula is:
Cefobutazine sodium is semisynthetic cephalosporins derivatives, and its mechanism of action is by suppressing the synthetic anti-microbial activity of bringing into play of bacteria cell wall.Cefobutazine sodium has anti-microbial activity to following bacterium: 1. aerobic gram-positive microorganism: streptococcus aureus, streptococcus pneumoniae, micrococcus scarlatinae.2. aerobic gram-negative bacteria: intestinal bacteria, klebsiella pneumoniae, Bacillus proteus.Be applicable to respiratory system infection, urinary system infection, septicemia, peritonitis.
The listing kind of cefobutazine sodium mostly is the powder injection of the anhydride raw material direct packaging preparation of cefobutazine sodium greatly at present.Because cefobutazine sodium has and very strong draws moistly, has very big difficulty in the packing preparation process, and is mobile very poor, and ambient temperature and humidity is required very high, complicated operating process, not easy to operate.Because cefobutazine sodium is deposited in the process, particularly under the condition of high temperature (＞50 ℃), degraded and polyreaction often taking place, thereby causes active constituents of medicine content to reduce, color and luster is strengthened, and polymeric impurities content raises.In addition, out of date cefobutazine sodium because the shelf-time is long, also usually is that active constituents of medicine content reduces, and darkens, and polymer content raises.And in some cases, because controlling of production process is improper, resulting cefobutazine sodium polymer content is high especially.And polymer content easily makes human body produce anaphylaxis when high.In order to ensure the human body drug safety, for this cefobutazine sodium that class impurity is residual or foreign matter content is high, be necessary to be further purified, obtain the high ceftezole sodium crystal of purity.
The inventor is through long-term conscientious research, beyond thought discovery is by carrying out acid-alkali accommodation to it, and employing resin absorption, its high molecular polymer that contains is therefrom separated out, reached the purpose of purifying, solve problems such as the purity that exists in the prior art is on the low side, foreign matter content is high, product look level is high, thereby finished the present invention.
Summary of the invention
One object of the present invention is to provide a kind of purification process of cefobutazine sodium, and it comprises the steps:
1). the cefobutazine sodium crude product is water-soluble, add acidic solution and regulate the pH value, stir and separate out insolubles;
2). filter out the gained insolubles, washing obtains solid, adds organic solvent then and make its dissolving in this solid, with eluent wash-out purifying, collects elutriant through macroporous adsorbent resin;
3). with the pH value that basic solution is regulated the gained elutriant, separate out solid, centrifugal, washing, vacuum-drying gets the cefobutazine sodium highly finished product.
In purification process of the present invention, described acidic solution is selected from one or more in hydrochloric acid, phosphoric acid, sulfuric acid, formic acid, acetate, hydrosulfate, bitartrate, hydrophosphate, the Citric Acid hydrogen salt; Adding acidic solution adjusting pH value is 3.0-6.0, is preferably 4.0-5.0.Described hydrosulfate, bitartrate, hydrophosphate, Citric Acid hydrogen salt are meant the salt that sulfuric acid, tartrate, phosphoric acid or Citric Acid and basic metal, alkaline-earth metal etc. form.
In purification process of the present invention, described macroporous adsorbent resin is a styrene tyle macroporous adsorption resin; Preferred described macroporous adsorbent resin is D101 type macroporous adsorbent resin or AB-8 type macroporous adsorbent resin.
In purification process of the present invention, described eluent is selected from one or more in trichloromethane, methylene dichloride, ethyl acetate, acetone, the sherwood oil, preferred trichloromethane.
In purification process of the present invention, described basic solution is selected from one or more in sodium hydroxide, potassium hydroxide, sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, sodium acetate, Sodium isooctanoate, ammoniacal liquor, triethylamine, the n-Butyl Amine 99; Regulating the pH value with basic solution is 7.0-10.0, is preferably 8.0-9.0.
In purification process of the present invention, organic solvent is selected from one or more in methylene dichloride, ethanol, methyl alcohol, trichloromethane, ethyl acetate, acetone, the sherwood oil, preferred alcohol.
In purification process of the present invention, used water is preferably purified water, distilled water or deionized water.
In purification process of the present invention, when the cefobutazine sodium crude product is soluble in water in the step 1), spore is for there not being limited proportion especially between the consumption of azoles sodium crude product and water, as long as the consumption of water can satisfy the cefobutazine sodium crude product be dissolved in fully wherein (such as, by weight/volume ratio is cefobutazine sodium (weight): water (volume)=1: 10, i.e. 1g/10ml); Similarly, step 2) in solid, add organic solvent in when making its dissolving, also limited proportion especially not between the consumption of described solid and organic solvent, the consumption that needs only organic solvent can satisfy can be dissolved in wherein described solid.
In a preferred embodiment of the invention, the purification process of cefobutazine sodium provided by the invention comprises the steps: the cefobutazine sodium crude product water-soluble, add acidic solution, regulating the pH value is 4.0～5.0, stirs and separates out solid insoluble, filter, obtain solid after the purified water washing, in the gained solid, add organic solvent then and make its dissolving, through D101 macroporous adsorbent resin or AB-8 macroporous adsorbent resin, with trichloromethane wash-out purifying, collect elutriant; The pH value of regulating this elutriant with basic solution is 8.0-9.0, separates out solid, uses washing with alcohol behind the centrifugal 10-30min, 30～40 ℃ of vacuum-drying 8～10 hours, the cefobutazine sodium highly finished product.
According to purification process of the present invention, the purity of the cefobutazine sodium that finally prepares is reached more than 99.5%.
Another object of the present invention is to provide the product for preparing according to purification process of the present invention, to make various pharmaceutical dosage forms according to the ceftezole sodium crystal that purification process purifying of the present invention obtains, the preferred powder injection, in ceftezole, every bottle contains cefobutazine sodium 0.25～4.0g.
In one embodiment of the invention, the powder injection of described cefobutazine sodium is prepared as follows: the cefobutazine sodium of purifying is crossed 60-100 mesh sieve (preferred 70-90 mesh sieve, more preferably 80 mesh sieves) pulverize, 100 grades of cleaning conditions are aseptic subpackaged in sterilisable chamber, tamponade, roll lid, get the Ceftezole sodium used for injection powder injection.
The present invention also provides a kind of pharmaceutical composition, and it comprises the product that the purification process purifying according to cefobutazine sodium of the present invention obtains, and promptly comprises highly purified ceftezole sodium crystal.
In the present invention, if do not mention especially, device that is adopted or instrument, raw material, material, consumption (or concentration), method, time, temperature and other condition etc. all are well-known in the art, or those skilled in the art can obtain in conjunction with prior art according to the application's description.
Purification process of the present invention has following advantage:
(1) method of the present invention has adopted acid-alkali accommodation, and adopts resin absorption, is particularly conducive to separating out of the high molecular polymer that wherein comprises, is particularly useful for the purifying of the high cefobutazine sodium of polymeric impurities content or its cefobutazine sodium pharmaceutical preparation;
(2) it is moist that method of the present invention has been improved drawing of cefobutazine sodium and preparation thereof, solves the difficulty of dividing the flowability difference that exists in the process of assembling;
(3) operation is simple, accurate, quick, good reproducibility for method of the present invention;
(4) crystal purity height, the polymer content of the cefobutazine sodium that obtains of method purifying of the present invention are low, color and luster good;
(5) cefobutazine sodium that obtains of method purifying of the present invention and adopt that its dosage form stability for preparing is good, validity period is longer has improved clinical application safety.
Embodiment
The present invention will adopt following specific embodiment to be described in detail, and should be appreciated that the purpose that these embodiment are only used for setting forth, and also limit protection scope of the present invention never in any form.Those skilled in the art can make multiple modification or change to embodiment of the present invention under spirit of the present invention and purport under the instruction of this specification sheets, these all will comprise within the scope of the invention.
Used D101 macroporous resin of following examples and AB-8 macroporous resin are available from Liaoyuan, Bengbu novel material company limited; Cefobutazine sodium is available from Guangdong Bo Zhou pharmaceutcal corporation, Ltd (lot number 20081214), and purity is 98.5%; Ceftezole sodium used for injection is available from Guangdong Bo Zhou pharmaceutcal corporation, Ltd (lot number 20081028), and purity is 98.4%.
Embodiment 1
Purifying cefobutazine sodium as follows:
1). 100g cefobutazine sodium crude product is dissolved in 1000ml water, adds the 2mol/L hydrochloric acid soln, regulating the pH value is 3.0, stirs and separates out insolubles;
2). filter out this insolubles, obtain solid after the purified water washing, in the gained solid, add 1000ml ethanol then and make its dissolving,,, collect elutriant with 500ml trichloromethane wash-out purifying through the D101 absorption with macroporous adsorbent resin;
3). the pH value of regulating this elutriant with 10% sodium hydroxide solution is 8.0, separates out solid, uses the 300ml washing with alcohol behind the centrifugal 30min, 30 ℃ of vacuum-dryings 10 hours, get cefobutazine sodium highly finished product 95.5g, yield is 95.5%, and adopting HPLC to measure purity is 99.5%.
Embodiment 2
100g cefobutazine sodium crude product is dissolved in 1000ml water, add the 5mol/L formic acid solution, regulating the pH value is 5.0, insolubles is separated out in stirring, filters, and obtains solid after the purified water washing, in the gained solid, add the 800ml methylene dichloride then and make its dissolving, through the AB-8 macroporous resin adsorption,, collect elutriant with 800ml acetone wash-out purifying; The pH value of regulating this elutriant with 20% sodium acetate solution is 8.0 again, separates out solid, uses the 300ml washing with alcohol behind the centrifugal 20min, 40 ℃ of vacuum-drying 8 hours, cefobutazine sodium highly finished product 94.7g, yield is 94.7%, adopting HPLC to measure purity is 99.7%.
Embodiment 3
100g cefobutazine sodium crude product is dissolved in 1000ml water, add 5% sodium dihydrogen phosphate, regulating the pH value is 4.5, insolubles is separated out in stirring, filters, and obtains solid after the purified water washing, in the gained solid, add 1000ml methyl alcohol then and make its dissolving, through the AB-8 macroporous resin adsorption,, collect elutriant with 500ml sherwood oil wash-out purifying; The pH value of regulating this elutriant with 10% ammonia soln is 9.0 again, separates out solid, uses the 300ml washing with alcohol behind the centrifugal 10min, 35 ℃ of vacuum-drying 10 hours, cefobutazine sodium highly finished product 96.3g, yield is 96.3%, adopting HPLC to measure purity is 99.6%.
Embodiment 4
100g cefobutazine sodium crude product is dissolved in 1000ml water, add 10% phosphoric acid solution, regulating the pH value is 6.0, insolubles is separated out in stirring, filters, and obtains solid after the purified water washing, in the gained solid, add the 500ml trichloromethane then and make its dissolving, through the D101 absorption with macroporous adsorbent resin,, collect elutriant with 1000ml methylene dichloride wash-out purifying; The pH value of regulating this elutriant with 5% sodium carbonate solution is 8.8 again, separates out solid, uses the 300ml washing with alcohol behind the centrifugal 15min, 40 ℃ of vacuum-drying 10 hours, cefobutazine sodium highly finished product 93.9g, yield is 93.9%, adopting HPLC to measure purity is 99.7%
Embodiment 5
The cefobutazine sodium crystal 5 0g of embodiment 1 purifying is crossed the pulverizing of 60 mesh sieves, and 100 grades of conditions are aseptic subpackaged in sterilisable chamber, and lid is rolled in tamponade, gets Ceftezole sodium used for injection powder pin, and every bottle contains cefobutazine sodium in ceftezole 0.25g.
Embodiment 6
The ceftezole sodium crystal 80g of embodiment 2 purifying is crossed the pulverizing of 100 mesh sieves, and 100 grades of conditions are aseptic subpackaged in sterilisable chamber, and lid is rolled in tamponade, gets Ceftezole sodium used for injection powder pin, and every bottle contains cefobutazine sodium in ceftezole 0.75g.
Embodiment 7
The cefobutazine sodium crystal 6 0g of embodiment 3 purifying is crossed the pulverizing of 80 mesh sieves, and 100 grades of conditions are aseptic subpackaged in sterilisable chamber, and lid is rolled in tamponade, gets Ceftezole sodium used for injection powder pin, and every bottle contains cefobutazine sodium in ceftezole 1.5g.
Embodiment 8
The cefobutazine sodium crystal 5 0g of embodiment 4 purifying is crossed the pulverizing of 100 mesh sieves, and 100 grades of conditions are aseptic subpackaged in sterilisable chamber, and lid is rolled in tamponade, gets Ceftezole sodium used for injection powder pin, and every bottle contains cefobutazine sodium in ceftezole 4.0g.
Stability test
The present invention carries out quality examination to the prepared ceftezole sodium injection of embodiment 5～embodiment 8 and the powder injection of list marketing, 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 18 months investigation of test of long duration, 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
Annotate: " Y1, Y2, the Y3 ... " in the above form represents yellow No. 1, yellow No. 2, yellow No. 3, yellow respectively ... number standard color solution; "＜Y1 " expression is not deeper than yellow No. 1 standard color solution, and "＜Y2 " expression is not deeper than yellow No. 1 standard color solution, successively roughly the same.
By above data results as can be seen, the sample quality conformance with standard requirement that the present invention makes, and also every quality index does not have considerable change after quickening June and long-term 18 months, all meets quality standard; List marketing powder injection every quality index after quickening June and long-term 18 months alters a great deal, and has exceeded the quality standard scope, has confirmed the good quality stability of sample of preparation of the present invention effectively.
Claims (12)
1. the purification process of the cefobutazine sodium of structure shown in the formula (I),
It comprises the steps:
1). the cefobutazine sodium crude product is water-soluble, add acidic solution and regulate the pH value, stir and separate out insolubles;
2). filter out the gained insolubles, washing obtains solid, adds organic solvent then and make its dissolving in this solid, with eluent wash-out purifying, collects elutriant through macroporous adsorbent resin;
3). with the pH value that basic solution is regulated the gained elutriant, separate out solid, centrifugal, washing, vacuum-drying gets the cefobutazine sodium highly finished product.
2. purification process according to claim 1 is characterized in that described acidic solution is selected from one or more in hydrochloric acid, phosphoric acid, sulfuric acid, formic acid, acetate, hydrosulfate, bitartrate, hydrophosphate, the Citric Acid hydrogen salt; Adding acidic solution adjusting pH value is 3.0-6.0.
3. purification process according to claim 2 wherein adds acidic solution adjusting pH value and is 4.0-5.0.
4. purification process according to claim 1 is characterized in that described macroporous adsorbent resin is a styrene tyle macroporous adsorption resin.
5. purification process according to claim 4 is characterized in that described macroporous adsorbent resin is D101 type macroporous adsorbent resin or AB-8 type macroporous adsorbent resin.
6. purification process according to claim 1 is characterized in that described eluent is selected from one or more in trichloromethane, methylene dichloride, ethyl acetate, acetone, the sherwood oil.
7. purification process according to claim 6 is characterized in that described eluent is selected from trichloromethane.
8. purification process according to claim 1 is characterized in that described basic solution is selected from one or more in sodium hydroxide, potassium hydroxide, sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, sodium acetate, Sodium isooctanoate, ammoniacal liquor, triethylamine, the n-Butyl Amine 99; Regulating the pH value with basic solution is 7.0-10.0.
9. purification process according to claim 8 is characterized in that regulating the pH value with basic solution is 8.0-9.0.
10. purification process according to claim 1 is characterized in that described organic solvent is selected from one or more in methylene dichloride, ethanol, methyl alcohol, trichloromethane, ethyl acetate, acetone, the sherwood oil.
11. the preparation method of a ceftezole sodium injection, it comprises the steps:
1). the cefobutazine sodium crude product is water-soluble, add acidic solution and regulate the pH value, stir and separate out insolubles;
2). filter out the gained insolubles, washing obtains solid, adds organic solvent then and make its dissolving in this solid, with eluent wash-out purifying, collects elutriant through macroporous adsorbent resin;
3). with the pH value that basic solution is regulated the gained elutriant, separate out solid, centrifugal, washing, vacuum-drying gets the cefobutazine sodium highly finished product;
The highly finished product of purifying are crossed 60～100 mesh sieves pulverize, 100 grades of conditions are aseptic subpackaged in sterilisable chamber, and lid is rolled in tamponade, get the Ceftezole sodium used for injection powder injection.
12. the preparation method of the ceftezole sodium injection of claim 11 wherein crosses the highly finished product of purifying the 70-90 mesh sieve and pulverizes.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102219795A (en) * | 2011-07-28 | 2011-10-19 | 哈药集团制药总厂 | Method for preparing ceftezole sodium |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101787039B (en) * | 2010-01-26 | 2012-05-09 | 陶灵刚 | High-purified cefmetazole sodium compound |
| CN102010431B (en) * | 2010-12-02 | 2012-08-01 | 胡建荣 | Ceftezole sodium compound and novel method thereof |
| CN102190667B (en) * | 2011-03-24 | 2013-05-29 | 海南灵康制药有限公司 | New method for purifying cefotiam hydrochloride |
| CN102824309B (en) * | 2011-06-15 | 2013-09-25 | 悦康药业集团有限公司 | Cefmetazole sodium powder for injection and preparation method thereof |
| CN105055423A (en) * | 2015-09-16 | 2015-11-18 | 青岛华之草医药科技有限公司 | Medicine ceftezole sodium composition for curing infectious diseases |
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2009
- 2009-05-12 CN CN2009100151212A patent/CN101544661B/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102219795A (en) * | 2011-07-28 | 2011-10-19 | 哈药集团制药总厂 | Method for preparing ceftezole sodium |
| CN102219795B (en) * | 2011-07-28 | 2014-12-24 | 哈药集团制药总厂 | Method for preparing ceftezole sodium |
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