CN101348492A - High-purity ceftizoxime sodium and preparation thereof - Google Patents
High-purity ceftizoxime sodium and preparation thereof Download PDFInfo
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- CN101348492A CN101348492A CNA2008101396250A CN200810139625A CN101348492A CN 101348492 A CN101348492 A CN 101348492A CN A2008101396250 A CNA2008101396250 A CN A2008101396250A CN 200810139625 A CN200810139625 A CN 200810139625A CN 101348492 A CN101348492 A CN 101348492A
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Abstract
The invention provides a method for preparing high purity ceftizoxime or a ceftizoxime salt, a method for preparing a powder-injection of ceftizoxime or the ceftizoxime salt, and high purity ceftizoxime or ceftizoxime salt and corresponding powder-injections prepared according the methods.
Description
Technical field
The invention provides a kind of method for preparing high-purity ceftizoxime or its salt, preparation ceftizoxime or its salt powder injection method and according to high-purity ceftizoxime or its salt and corresponding powder injection that this method prepares, belong to medical technical field.
Background technology
Ceftizoxime, English by name: Ceftizoxime, molecular formula is: C
13H
13N
5O
5S
2Chemical name is: 7-[2-methoxyimino-2-(2-amino-1,3-thiazole-4-yl)-kharophen]-3-cephem-4-carboxylic acid, belong to third generation cephalosporin, the tool broad-spectrum antibacterial action, stable to the wide spectrum lactamase (comprising penicillinase and cephalosporinase) of multiple gram positive organism and gram-negative bacteria generation.Rhodopseudomonass such as this product has powerful anti-microbial effect to enterobacteriaceae lactobacteriaceaes such as escherichia coli, Klebsiella Pneumoniae, Proteus mirabilises, Pseudomonas aeruginosa and acinetobacter are poor to this product susceptibility.Ceftizoxime has good anti-microbial effect to hemophilus influenzae and neisseria gonorrhoeae.The ceftizoxime mechanism of action is for reaching germicidal action by the biosynthesizing that suppresses the bacteria cell wall mucopeptide.Be applicable to meningitis and simple property gonorrhoea due to lower respiratory infection, urinary tract infections, abdominal cavity infection, pelvic infection, septicemia, skin soft-tissue infection, bone and the infection of joint, streptococcus pneumoniae or the hemophilus influenzae due to the sensitive organism.
Ceftizoxime for inj has been widely used in clinically for the powder injection of its sodium salt (ceftizoxime sodium), is present most widely used antibiotic medicine, and its preparation all is to make by the ceftizoxime sodium raw materials is aseptic subpackaged.Most of ceftizoxime sodium raw materials exist purity not high, and dissolving back clarity is poor, poor stability in the aqueous solution, problem such as side effect is bigger.Thereby, had a strong impact on the application of ceftizoxime or its salt.
The applicant is through discovering in earnest for a long time, combine with recrystallization and be used for especially sodium salt of purifying ceftizoxime or its salt being generally used for species analysis and the medium pressure chromatography post of isolating technology, unexpectedly can obtain highly purified said medicine, thereby finish the present invention.
Summary of the invention:
The object of the present invention is to provide the method for the powder injection of a kind of method for preparing high-purity ceftizoxime or its salt, preparation high-purity ceftizoxime or its salt.The product purity that obtains according to method of the present invention significantly improves, and product stability significantly improves.
For achieving the above object, the present invention proposes following technical scheme:
In one embodiment, the invention provides a kind of method for preparing high-purity ceftizoxime or its salt, it comprises the steps:
(1) ceftizoxime or its salt aqueous solution of crude are changed into ceftizoxime acid under acidic conditions;
(2) obtain the ceftizoxime acid crude with organic solvent extraction step (1);
(3) with the filler of aluminum oxide as chromatography column, be eluent with the mixed solution of hydrocarbon solvent and chlorinated solvents, step (2) gained ceftizoxime acid crude is carried out chromatographic separation, collect the ceftizoxime acid content and be not less than 80% flow point;
(4) remove solvent in the ceftizoxime acid flow point of step (3) gained, add the lower alkyl alcohol dissolution with solvents then, add alkali to separating out precipitation;
(5) with the precipitation lower alkyl alcohol solvent recrystallization of step (4) gained, obtain high-purity ceftizoxime or its salt.
In another embodiment, the invention provides the method for preparing high-purity ceftizoxime or its salt,, it comprises the steps:
(1) ceftizoxime or its salt crude product are dissolved with purified water, add the pH regulator agent pH value of solution value is transferred to acidity;
(2) extract with organic solvent, separate organic phase, with organic phase with the siccative drying after reclaim under reduced pressure to doing, the upper prop product;
(3) with the filler of aluminum oxide as the medium pressure chromatography post, mixed solution with hydrocarbon solvent and chlorinated solvents is an eluent, and the upper prop product are dissolved back feed liquor, the flow point Fractional Collections behind the wash-out with eluent, collection and merging ceftizoxime acid content are not less than 85%, more preferably are not less than 90% flow point;
(4) flow point of concentrating under reduced pressure step (3) gained adds dissolve with ethanol afterwards, adds to separate out precipitation after alkali alkalizes;
(5) step (4) gained precipitation is used ethyl alcohol recrystallization, crystallisate obtains high-purity ceftizoxime or its salt through lyophilize.
In another embodiment, the present invention also provides a kind of method for preparing ceftizoxime or its salt powder injection, it comprises by the description of above-mentioned option and carries out step (1)-(5), carry out step (6) then: step (5) gained ceftizoxime or its salt are pulverized, carry out aseptic subpackagedly, obtain the powder injection of high-purity ceftizoxime or its salt.
In this article, the acidity in the step (1) refers to that the pH of solution is 1-5, preferred 2-4; The used organic solvent of step (2) extraction is a chlorinated solvents, preferably is selected from chloroform, monochloro methane, methylene dichloride, trichloromethane, 1, one or more in 2-ethylene dichloride, trichloroethane, trieline, zellon and the carrene; Hydrocarbon solvent described in the eluent of step (3) is selected from one or more in pentane, hexane, heptane, octane, nonane, decane, pentamethylene, hexanaphthene, suberane, cyclooctane, cyclononane, cyclodecane, 1-hexene, 1-heptene, 1-octene, 1-nonene, 1-decene, 1-hexin, 1-heptyne, 1-octyne, 1-n-heptylacetylene, 1-decine, sherwood oil and No. 6 solvent oils; Described chlorinated solvents is selected from chloroform, monochloro methane, methylene dichloride, trichloromethane, 1, one or more in 2-ethylene dichloride, trichloroethane, trieline, zellon and the carrene.In the described eluent, the amount ratio of hydrocarbon solvent and chlorinated solvents is restriction especially not, and preferably, the volume ratio of hydrocarbon solvent and chlorinated solvents is 1: 2～10, and more preferably 1: 4～7.
In this article, the described chromatography column column length of step (3) 20-500cm, preferred 30-350cm; Column diameter 5-100cm, preferred 5-50cm; Alumina particle is the 50-800 order, preferred 100-400 order; Post is pressed and is 0.1-5Mpa; The weight ratio of alumina amount is 1: 10～200 in upper prop sample size and the post, preferred 1: 15～100.
In this article, the used alkali of step (4) is oxide compound, oxyhydroxide, carbonate or the supercarbonate of basic metal or alkaline-earth metal; Be preferably sodium hydroxide, yellow soda ash, sodium bicarbonate, potassium hydroxide, salt of wormwood or saleratus; Alkalization back pH value of solution is 8-13, preferred 9-11.
In this article, in step (6), ceftizoxime or its salt are crushed to the 60-100 mesh sieve, packing under 100 grades of conditions in sterilisable chamber makes the powder injection of high-purity ceftizoxime or its salt.
In this article, in the step (3),, can collect the ceftizoxime acid content and be not less than 98% flow point in order to obtain more highly purified ceftizoxime or its salt.
In this article, described ceftizoxime salt is ceftizoxime sodium.
In one embodiment of the invention, also provide the high-purity ceftizoxime or its salt that prepare according to above-mentioned any method, or the powder injection of high-purity ceftizoxime or its salt.In the present invention, described high purity is meant that the purity of described ceftizoxime or its salt is up to 99%, preferably up to 99.5%, more preferably up to 99.8%.
In another embodiment of the invention, provide to comprise the high-purity ceftizoxime for preparing according to above-mentioned any method or about compositions of its salt.
The used alumina filled post of middle pressure of the present invention can be used dry column-packing, also can adopt wet method dress post, all can obtain good separating effect.The separation principle of the alumina filled post of middle pressure is gel-filtration, and promptly molecular sieve in order to obtain satisfied separating effect, can be adjusted the length of described packed column; The long more sample of packed column is long more by the time of packed column, can increase production cost because of disengaging time is long, therefore preferably, needs to select suitable column length.In the present invention, as preferably, pressing the column length of alumina filled post in described is 20-500cm, more preferably 30-350cm.And in order to obtain better treatment capacity, in the present invention, as preferably, the diameter of pressing aluminum oxide to complete post in described is 5-100cm, more preferably 5-50cm.The post of packed column is pressed purifying speed is had certain influence, and will be complementary with the intensity of filling alumina, in the present invention, as preferably, post is pressed and is 0.1-5MPa, and alumina particle is the 50-800 order, as further preferred, alumina particle is the 100-400 order.
A key character of the present invention is that ceftizoxime or the preferred ceftizoxime sodium of its salt are transformed into ceftizoxime acid, and acid extracts to ceftizoxime with organic solvent more on this basis.Ceftizoxime or the preferred ceftizoxime sodium of its salt need just can be transformed into ceftizoxime acid under sour environment, therefore the ceftizoxime sodium crude product is dissolved usefulness with purified water, need add the pH regulator agent in solution the pH value of solution value is transferred to acidity.The present invention is to not restriction especially of described pH regulator agent, and described pH regulator agent can be selected one or more in hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, boric acid, citric acid, lactic acid, the acetylsalicylic acid for use, the preferred hydrochloric acid that uses separately.As long as under acidic conditions (pH is less than 7), ceftizoxime sodium can be transformed into ceftizoxime acid, and as preferably, after the pH regulator agent was regulated, pH value of solution was 1-5, more preferably 2-4.
In this article, the middle used organic solvent range of choice of ceftizoxime acid that extracts of step (2) is very extensive, can be varsol, halogenated hydrocarbon solvent, alcoholic solvent, ether solvent, ketones solvent, lipid solvent, phenol solvent.As preferably, described organic solvent is a chlorinated solvents, more preferably chloroform, monochloro methane, methylene dichloride, trichloromethane, 1, one or more in 2-ethylene dichloride, trichloroethane, trieline, zellon and the carrene.After extraction finishes, with organic phase and aqueous phase separation, for moisture remaining in the organic phase is removed, need the moisture in the organic phase to be removed with siccative, used siccative also has no special requirements, in the present invention, as preferably, used siccative is one or more in Calcium Chloride Powder Anhydrous, anhydrous magnesium sulfate, anhydrous cupric sulfate, calcium oxide, barium oxide, activated alumina, anhydrous sodium sulphate, calcium sulfate, discolour silica gel, molecular sieve, solid caustic soda, lime and the soda-lime, the further preferred anhydrous sodium sulphate of using.Can reduce pressure to reclaim organic solvent to dried organic phase, institute's recovered solvent can continue on for extraction.After the whole reclaim under reduced pressure of the organic solvent in the organic phase, can obtain exsiccant upper prop product.
Should determine the quality of the upper prop product that each upper prop added according to the treatment capacity of used chromatography column.The treatment capacity of chromatography column is that the quality of aluminum oxide is big more by the decision of the quality of aluminum oxide in the chromatography column, and the treatment capacity of chromatography column is big more.In the present invention, as preferably, the mass ratio of aluminum oxide is 1 in each used upper prop product of upper prop and the chromatography column: 10-200, the mass ratio of further preferably upper prop product and aluminum oxide is 1: 15-100.The upper prop product of step (2) gained are dissolved with eluent, the consumption of eluent dissolves the upper prop product fully as long as satisfy, after treating that the upper prop product all dissolve, feed liquor is in chromatography column, can use plunger tpe solvent pump feed liquor, also can use other mode feed liquors, in chromatography column, add eluent then, flow point Fractional Collections behind the wash-out, the content difference of ceftizoxime in the flow point of different sections, in order to obtain highly purified ceftizoxime sodium (purity is more than or equal to 99.5%), need the ceftizoxime acid content is merged more than or equal to 80% flow point, as preferably, can be with the ceftizoxime acid content more than or equal to 85%, preferably the ceftizoxime acid content is merged more than or equal to 90% flow point further, the purity of the ceftizoxime sodium of so final acquisition can be more than or equal to 99.5%.The enriched material that the ceftizoxime acid content obtains after less than 80% flow point reclaim under reduced pressure eluent can be used as the raw material of next column chromatography.Flow point after being combined carries out concentrating under reduced pressure, can obtain enriched material, and is reusable after thin-layer chromatography is proofreaied and correct through the eluent of reclaim under reduced pressure simultaneously.The thin-layer chromatography of eluent proofread and correct be the eluent that will reclaim as the thin-layer developing agent, ceftizoxime acid reference substance put on thin layer chromatography board, launches, according to unfolded Rf value, interpolation hydrocarbon solvent or chlorinated solvents make close with the Rf value of original proportioning.With the enriched material dissolve with ethanol of gained behind the concentrating under reduced pressure, add alkali after the dissolving and alkalize, promptly separate out precipitation after the alkalization.Used alkali can be oxide compound, oxyhydroxide, carbonate or the supercarbonate of basic metal or alkaline-earth metal; Be preferably sodium hydroxide, yellow soda ash, sodium bicarbonate, potassium hydroxide, salt of wormwood or saleratus; Be more preferably use sodium hydroxide, both can use sodium hydrate solid, also can use sodium hydroxide solution,, use the sodium hydroxide solution of 5%-20% to alkalize as further preferred.Solution is after alkalization, and pH becomes alkalescence (greater than 7) and get final product, and as preferably, alkalization back pH value of solution is 8-13, and as further preferred, pH value of solution is 9-11 after the alkalization.Filter, the precipitation of separating out is separated from liquid, precipitation is carried out recrystallization, can be used as column chromatography raw material purifying once more behind the mother liquor decompression recycling ethanol behind the recrystallization with ethanol.Recrystallization is this area common technology means, and concrete implementation step is: add the alcohol reflux dissolving in precipitation, cooling crystallization, crystallisate are used ethyl alcohol recrystallization 1 time again.The crystallisate of gained promptly gets high-purity ceftizoxime sodium through lyophilize behind the recrystallization, and the purity of gained ceftizoxime sodium is more than or equal to 99.5%.As preferably, dissolving enriched material and the used ethanol of recrystallization are mass percent more than or equal to 90% ethanol.
Can reuse after regeneration and balance through the alumina chromatographic column behind the chromatography purification.Wherein chlorinated solvents is that regenerator is regenerated to described alumina chromatographic column, and hydrocarbon solvent is that poiser carries out balance to described alumina chromatographic column; The consumption of regenerator is a 1-10 times of column volume, and the poiser consumption is a 5-20 times of column volume.Alumina chromatographic column through above-mentioned processing can directly use.
In this manual, if not explanation especially, the device that is adopted, equipment, instrument, technology, technology, raw material, method, step etc. all are that art technology is known, and perhaps those skilled in the art can obtain according to known technology.
Compared with prior art, the continuous medium pressure column chromatography provided by the present invention method for preparing high-purity ceftizoxime or its salt has following advantage:
1. gained ceftizoxime or its salt sodium salt purity height particularly, its purity is not less than 99%.
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 the solvability of ceftizoxime sodium in water, improved the stability of its aqueous solution simultaneously.
4. alumina chromatographic column is reusable, and access times reach more than 20 times, have reduced production cost.
Overcome by defectives such as clarity difference and aqueous stability difference after the not high dissolving that causes of material purity by the ceftizoxime of method of the present invention preparation or the ceftizoxime of its salt preparation or the powder injection of its salt.Described ceftizoxime or its salt especially clarity after the powder injection dissolving of sodium salt and its aqueous stability improve a lot than the powder injection of clinical used ceftizoxime or its salt at present.
Specific embodiments
Further set forth the present invention with reference to specific embodiment below, should be appreciated that these embodiment only are the explanations to preferred version of the present invention, and also limit protection scope of the present invention never in any form.
Embodiment 1:
(1) gets 500g ceftizoxime sodium dissolving crude product in the 2L purified water, add sulphur acid for adjusting pH value to 4;
(2) use the 6L n-butanol extraction, separate organic phase, organic phase is flow through the dehydration of anhydrous magnesium sulfate post, be evaporated to then dried, the upper prop product;
(3) be that 800 order aluminum oxide 20kg of II level are with behind the normal hexane suspendible with activity, drive away bubble, evenly join effective column length 400cm, in the glass chromatography column of internal diameter 20cm, above-mentioned being concentrated in the dried ceftizoxime sodium crude product adding 800ml eluent (suberane and trichloromethane volume ratio are 1: 7) dissolved, use on the plunger tpe solvent pump behind the filtering insolubles in column cap, pump into eluent (suberane and trichloromethane volume ratio are 1: 7) wash-out then, post is pressed and is 3MPa, the Fractional Collections flow point, TLC and HPLC detect, and merge the ceftizoxime acid content more than or equal to 85% effluent liquid, behind the reclaim under reduced pressure eluent enriched material 428.8g;
(4) acid of gained ceftizoxime is joined among the 98% ethanol 500ml dissolve, adding 20% sodium hydroxide solution adjust pH is 12, separates out precipitation, filters;
(5) step (4) gained precipitation is added the dissolving that refluxes among the 98% ethanol 7000ml, cooling crystallization, crystallisate are used ethyl alcohol recrystallization 1 time again, filtration under diminished pressure, and lyophilize gets ceftizoxime sodium pure product 414.4g, purity 99.7%, yield is 82.88%;
(6) get the raw material of enriched material behind the mother liquor decompression and solvent recovery as next column chromatography, the ceftizoxime acid content after less than 85% effluent liquid reclaim under reduced pressure eluent enriched material also as the raw material of next column chromatography, the eluent that reclaims is reused next time after thin-layer chromatography is proofreaied and correct, alumina column behind the wash-out pumps into the regeneration of 30L methylene dichloride, and then pumping into 40L normal hexane balance, the alumina column after the balance can directly use next time.
Embodiment 2:
(1) gets 800g ceftizoxime sodium dissolving crude product in the 3L purified water, add phosphorus acid for adjusting pH value to 3;
(2) with the extraction of 10L cyclooctane, separate organic phase, organic phase flow through the dehydration of Calcium Chloride Powder Anhydrous post, be evaporated to then dried, the upper prop product;
(3) be that 100 order aluminum oxide 10kg of II level are with behind the normal hexane suspendible with activity, drive away bubble, evenly join effective column length 200cm, in the glass chromatography column of internal diameter 10cm, above-mentionedly be concentrated into dried ceftizoxime sodium crude product and add 1000ml eluent (1-nonene and 1,2-ethylene dichloride volume ratio is 1: 4) dissolving, use on the plunger tpe solvent pump behind the filtering insolubles in column cap, pump into eluent (1-nonene and 1,2-ethylene dichloride volume ratio is 1: 4) wash-out then, post is pressed and is 2.6MPa, the Fractional Collections flow point, TLC and HPLC detect, and merge the ceftizoxime acid content more than or equal to 90% effluent liquid, behind the reclaim under reduced pressure eluent enriched material 666.4g;
(4) acid of gained ceftizoxime adds dehydrated alcohol 600ml dissolving, and adding 10% sodium hydroxide solution to pH value is 10, separates out precipitation, filters;
(5) step (4) gained precipitation adds 98% ethanol 7000ml backflow dissolving, and cooling crystallization, crystallisate are used ethyl alcohol recrystallization 1 time again, filtration under diminished pressure, and lyophilize gets ceftizoxime sodium pure product 636.0g, purity 99.6%, yield is 79.5%.
(6) get the raw material of enriched material behind the mother liquor decompression and solvent recovery as next column chromatography, the ceftizoxime acid content after less than 85% effluent liquid reclaim under reduced pressure eluent enriched material also as the raw material of next column chromatography, the eluent that reclaims is reused next time after thin-layer chromatography is proofreaied and correct, alumina column behind the wash-out pumps into the regeneration of 100L methylene dichloride, and then pumping into 210L normal hexane balance, the alumina column after the balance can directly use next time.
Embodiment 3
(1) gets 600g ceftizoxime sodium dissolving crude product in the 2L purified water, add salt acid for adjusting pH value to 2.5;
(2) divide three extractions with the 5L trichloromethane, separate organic phase, organic phase is flow through the dehydration of anhydrous sodium sulphate post, be evaporated to then dried, the upper prop product;
(3) be that 50 order aluminum oxide 5kg of II level are with behind the normal hexane suspendible with activity, drive away bubble, evenly join effective column length 20cm, in the glass chromatography column of internal diameter 5cm, above-mentionedly be concentrated into dried ceftizoxime sodium crude product and add 600ml eluent (normal hexane is 1: 10 with the methylene chloride volume ratio) dissolving, use on the plunger tpe solvent pump behind the filtering insolubles in column cap, pump into eluent (normal hexane is 1: 10 with the methylene chloride volume ratio) wash-out then, post is pressed and is 0.1MPa, the Fractional Collections flow point, TLC and HPLC detect, and merge the ceftizoxime acid content more than or equal to 85% effluent liquid, behind the reclaim under reduced pressure eluent enriched material 513.3g;
(4) acid of gained ceftizoxime adds 95% ethanol 500ml dissolving, and adding 5% sodium hydroxide solution to pH value is 9.8, separates out precipitation, filters;
(5) step (4) gained precipitation adds 95% ethanol 8000ml backflow dissolving, and cooling crystallization, crystallisate are used ethyl alcohol recrystallization 1 time again, filtration under diminished pressure, and lyophilize gets ceftizoxime sodium pure product 487.5g, purity 99.6%, yield is 81.25%.
(6) get the raw material of enriched material behind the mother liquor decompression and solvent recovery as next column chromatography, the ceftizoxime acid content after less than 85% effluent liquid reclaim under reduced pressure eluent enriched material also as the raw material of next column chromatography, the eluent that reclaims is reused next time after thin-layer chromatography is proofreaied and correct, alumina column behind the wash-out pumps into the regeneration of 90L methylene dichloride, and then pumping into 50L normal hexane balance, the alumina column after the balance can directly use next time.
Embodiment 4:
(1) gets 500g ceftizoxime sodium dissolving crude product in the 2L purified water, add phosphorus acid for adjusting pH value to 3.1;
(2) divide three extractions with the 7L ether, separate organic phase, with organic phase fluid calcium peroxide and the dehydration of calcium sulfate post, be evaporated to then dried, the upper prop product;
(3) be that 400 order aluminum oxide 50kg of II level are with behind the normal hexane suspendible with activity, drive away bubble, evenly join effective column length 350cm, in the glass chromatography column of internal diameter 50cm, above-mentionedly be concentrated into dried ceftizoxime sodium crude product and add 600ml eluent (octane and trichloroethane volume ratio are 1: 7) and dissolve, use on the plunger tpe solvent pump behind the filtering insolubles in column cap, pump into eluent (octane and trichloroethane volume ratio are 1: 7) wash-out then, post is pressed and is 3.0MPa, the Fractional Collections flow point, TLC and HPLC detect, and merge the ceftizoxime acid content more than or equal to 90% effluent liquid, behind the reclaim under reduced pressure eluent enriched material 408.8g;
(4) acid of gained ceftizoxime adds dehydrated alcohol 500ml dissolving, and adding 15% sodium hydroxide solution to pH value is 11, separates out precipitation, filters;
(5) step (4) gained precipitation adds dehydrated alcohol 9000ml backflow dissolving, and cooling crystallization, crystallisate are used ethyl alcohol recrystallization 1 time again, filtration under diminished pressure, and lyophilize gets ceftizoxime sodium pure product 397.6g, purity 99.7%, yield is 79.52%.
(6) get the raw material of enriched material behind the mother liquor decompression and solvent recovery as next column chromatography, the ceftizoxime acid content after less than 85% effluent liquid reclaim under reduced pressure eluent enriched material also as the raw material of next column chromatography, the eluent that reclaims is reused next time after thin-layer chromatography is proofreaied and correct, alumina column behind the wash-out pumps into the regeneration of 400L methylene dichloride, and then pumping into 600L normal hexane balance, the alumina column after the balance can directly use next time.
Embodiment 5:
(1) gets 800g ceftizoxime sodium dissolving crude product in the 3L purified water, add phosphorus acid for adjusting pH value to 2.4;
(2) with 10L 1, the 2-ethylene dichloride divides three extractions, separates organic phase, and organic phase is flow through the dehydration of anhydrous sodium sulphate post, be evaporated to then dried, must the upper prop product;
(3) be that 300 order aluminum oxide 25kg of II level are with behind the normal hexane suspendible with activity, drive away bubble, evenly join effective column length 300cm, in the glass chromatography column of internal diameter 40cm, above-mentionedly be concentrated into dried ceftizoxime sodium crude product and add 800ml eluent (octane and trichloroethane volume ratio are 1: 5) and dissolve, use on the plunger tpe solvent pump behind the filtering insolubles in column cap, pump into eluent (octane and trichloroethane volume ratio are 1: 5) wash-out then, post is pressed and is 4.0MPa, the Fractional Collections flow point, TLC and HPLC detect, and merge the ceftizoxime acid content more than or equal to 85% effluent liquid, behind the reclaim under reduced pressure eluent enriched material 675.8g;
(4) acid of gained ceftizoxime adds dehydrated alcohol 800ml dissolving, and adding 8% sodium hydroxide solution to pH value is 10, separates out precipitation, filters;
(5) step (4) gained precipitation adds dehydrated alcohol 9000ml backflow dissolving, and cooling crystallization, crystallisate are used ethyl alcohol recrystallization 1 time again, filtration under diminished pressure, and lyophilize gets ceftizoxime sodium pure product 640.2g, purity 99.6%, yield is 80.02%.
(6) get the raw material of enriched material behind the mother liquor decompression and solvent recovery as next column chromatography, the ceftizoxime acid content after less than 85% effluent liquid reclaim under reduced pressure eluent enriched material also as the raw material of next column chromatography, the eluent that reclaims is reused next time after thin-layer chromatography is proofreaied and correct, alumina column behind the wash-out pumps into the regeneration of 200L methylene dichloride, and then pumping into 300L normal hexane balance, the alumina column after the balance can directly use next time.
Embodiment 6:
Get 300g embodiment 1 gained purity and be 99.7% ceftizoxime sodium pure product and cross 60 mesh sieves and pulverize, be distributed into the ceftizoxime sodium injection under 100 grades of conditions in sterilisable chamber, 0.5g/ props up.
Embodiment 7:
Get 300g embodiment 2 gained purity and be 99.6% ceftizoxime sodium pure product and cross 100 mesh sieves and pulverize, be distributed into the ceftizoxime sodium injection under 100 grades of conditions in sterilisable chamber, 0.75g/ props up.
Embodiment 8:
Get 300g embodiment 3 gained purity and be 99.6% ceftizoxime sodium pure product and cross 80 mesh sieves and pulverize, be distributed into the ceftizoxime sodium injection under 100 grades of conditions in sterilisable chamber, 1.0g/ props up.
Embodiment 9:
Get 300g embodiment 4 gained purity and be 99.7% ceftizoxime sodium pure product and cross 100 mesh sieves and pulverize, be distributed into the ceftizoxime sodium injection under 100 grades of conditions in sterilisable chamber, 1.5g/ props up.
Embodiment 10:
Get 300g embodiment 5 gained purity and be 99.6% ceftizoxime sodium pure product and cross 80 mesh sieves and pulverize, be distributed into the ceftizoxime sodium injection under 100 grades of conditions in sterilisable chamber, 2.0g/ props up.
Stability test
The high-purity ceftizoxime sodium powder injection that embodiment 6-10 is prepared carries 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 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
By above data results as can be seen, the sample quality that the present invention prepares is better than standard-required, and quicken after June and long-term 18 months every quality index especially purity do not have considerable change, all be better than quality standard, confirmed that the quality stability of sample of preparation of the present invention is very good.
Above-mentionedly the present invention is described according to preferred embodiment.Should be appreciated that 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, it all should be understood to be within protection scope of the present invention.
Claims (10)
1. method for preparing high-purity ceftizoxime or its salt, it comprises the steps:
(1) ceftizoxime or its salt aqueous solution of crude are changed into ceftizoxime acid under acidic conditions;
(2) obtain the ceftizoxime acid crude with organic solvent extraction step (1);
(3) with the filler of aluminum oxide as chromatography column, be eluent with the mixed solution of hydrocarbon solvent and chlorinated solvents, step (2) gained ceftizoxime acid crude is carried out chromatographic separation, collect the ceftizoxime acid content and be not less than 80% flow point;
(4) remove solvent in the ceftizoxime acid flow point of step (3) gained, add the lower alkyl alcohol dissolution with solvents then, add alkali to separating out precipitation.
(5) with the precipitation lower alkyl alcohol solvent recrystallization of step (4) gained, obtain high-purity ceftizoxime or its salt.
2. method according to claim 1, it comprises the steps:
(1) ceftizoxime or its salt crude product are dissolved with purified water, add the pH regulator agent pH value of solution value is transferred to acidity;
(2) extract with organic solvent, separate organic phase, with organic phase with the siccative drying after reclaim under reduced pressure to doing, the upper prop product;
(3) with the filler of aluminum oxide as the medium pressure chromatography post, mixed solution with hydrocarbon solvent and chlorinated solvents is an eluent, and the upper prop product are dissolved back feed liquor, the flow point Fractional Collections behind the wash-out with eluent, collection and merging ceftizoxime acid content are not less than 85%, more preferably are not less than 90% flow point;
(4) flow point of concentrating under reduced pressure step (3) gained adds dissolve with ethanol afterwards, adds to separate out precipitation after alkali alkalizes;
(5) step (4) gained precipitation is used ethyl alcohol recrystallization, crystallisate obtains high-purity ceftizoxime or its salt through lyophilize.
3. method for preparing ceftizoxime or its salt powder injection, it comprises by the description of claim 1 or 2 and carries out step (1)-(5), carry out step (6) then: step (5) gained ceftizoxime or its salt are pulverized, carried out aseptic subpackagedly, obtain the powder injection of high-purity ceftizoxime or its salt.
4. each described method among the claim 1-3, wherein the acidity in the step (1) refers to that the pH of solution is 1-5, preferred 2-4; The used organic solvent of step (2) extraction is varsol, halogenated hydrocarbon solvent, alcoholic solvent, ether solvent, ketones solvent, lipid solvent, phenol solvent, preferred chlorinated solvents, preferably be selected from chloroform, monochloro methane, methylene dichloride, trichloromethane, 1, one or more in 2-ethylene dichloride, trichloroethane, trieline, zellon and the carrene; Hydrocarbon solvent described in the eluent of step (3) is selected from one or more in pentane, hexane, heptane, octane, nonane, decane, pentamethylene, hexanaphthene, suberane, cyclooctane, cyclononane, cyclodecane, 1-hexene, 1-heptene, 1-octene, 1-nonene, 1-decene, 1-hexin, 1-heptyne, 1-octyne, 1-n-heptylacetylene, 1-decine, sherwood oil and No. 6 solvent oils; Described chlorinated solvents is selected from chloroform, monochloro methane, methylene dichloride, trichloromethane, 1, one or more in 2-ethylene dichloride, trichloroethane, trieline, zellon and the carrene; In the described eluent volume ratio of hydrocarbon solvent and chlorinated solvents be preferably 1: 2～10, more preferably 1: 4～7.。
5. each described method among the claim 1-3,, the described chromatography column column length of step (3) 20-500cm wherein, preferred 30-350cm; Column diameter 5-100cm, preferred 5-50cm; Alumina particle is the 50-800 order, preferred 100-400 order; Post is pressed and is 0.1-5Mpa; The weight ratio of alumina amount is 1: 10～200 in upper prop sample size and the post, preferred 1: 15～100.
6. each described method among the claim 1-3,, wherein the used alkali of step (4) is oxide compound, oxyhydroxide, carbonate or the supercarbonate of basic metal or alkaline-earth metal; Be preferably sodium hydroxide, yellow soda ash, sodium bicarbonate, potassium hydroxide, salt of wormwood or saleratus; Alkalization back pH value of solution is 8-13, preferred 9-11.
7. the described method of claim 3 wherein in step (6), is crushed to the 60-100 mesh sieve with ceftizoxime or its salt, and packing under 100 grades of conditions in sterilisable chamber makes the powder injection of high-purity ceftizoxime or its salt.
8. each described method in the claim 1 to 7, wherein said ceftizoxime salt is ceftizoxime sodium.
9. high-purity ceftizoxime or its salt that each method prepares among the 1-8 as requested, or the powder injection of high-purity ceftizoxime or its salt.
10. pharmaceutical composition wherein comprises each method prepares among the claim 1-8 high-purity ceftizoxime or its salt.
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| CN102079750A (en) * | 2010-12-02 | 2011-06-01 | 郝志艳 | Cefuroxime sodium compound and new preparation method thereof |
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| CN102180889A (en) * | 2010-03-17 | 2011-09-14 | 刘力 | Ceftizoxime sodium crystalline hydrate and preparation method and application thereof |
| WO2013010297A1 (en) * | 2011-07-15 | 2013-01-24 | 海南灵康制药有限公司 | Method for purifying ceftizoxime sodium |
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Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1600735A (en) * | 1977-03-14 | 1981-10-21 | Fujisawa Pharmaceutical Co | Cephem and cephem compounds and processes for preparation thereof |
| CN1712008A (en) * | 2004-06-14 | 2005-12-28 | 天津新丰制药有限公司 | Ceftizoxime sodium compound preparation |
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| WO2011113361A1 (en) * | 2010-03-17 | 2011-09-22 | Liu Li | Ceftizoxime sodium crystalline hydrate, preparation methods and uses thereof |
| CN102079750A (en) * | 2010-12-02 | 2011-06-01 | 郝志艳 | Cefuroxime sodium compound and new preparation method thereof |
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| CN102093392A (en) * | 2011-01-28 | 2011-06-15 | 海南灵康制药有限公司 | New method for preparing Cefamandole Nafate |
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| CN105646474A (en) * | 2016-01-15 | 2016-06-08 | 成都大学 | Preparation and structure confirmation method of impurities in ceftizoxime sodium |
| CN105646474B (en) * | 2016-01-15 | 2019-01-29 | 成都大学 | The preparation and structural identification method of impurity in a kind of ceftizoxime sodium |
| CN105622635A (en) * | 2016-03-10 | 2016-06-01 | 重庆福安药业集团庆余堂制药有限公司 | Ceftizoxime sodium novel crystal form capable of reducing anaphylactic reactions and preparation thereof |
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