CN101265265B - Method for producing high-purity azlocillin sodium and powder injection thereof - Google Patents
Method for producing high-purity azlocillin sodium and powder injection thereof Download PDFInfo
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- CN101265265B CN101265265B CN2008100975398A CN200810097539A CN101265265B CN 101265265 B CN101265265 B CN 101265265B CN 2008100975398 A CN2008100975398 A CN 2008100975398A CN 200810097539 A CN200810097539 A CN 200810097539A CN 101265265 B CN101265265 B CN 101265265B
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Abstract
The invention provided a method for preparing high-purity Mezlocillin sodium, and a method for preparing the Mezlocillin sodium powder injection. The method includes (1) dissolving Mezlocillin sodium crude product in purified water, and adjusting the pH value to less than 7 with the pH regulator; (2) extracting with organic solvent, separating the organic phase, drying with desiccant, and vacuum recovering to dry to obtain the product; (3) dissolving the product with eluting agent of mixed solution of hydrocarbon solvent and chlorine-containing solvent, eluting with alumina as filler of medium-pressure chromatography column, and collecting the fraction in a sectional manner; (4) mixing fractions with the Mezlocillin acid content of no smaller than 80%, vacuum concentrating, dissolving into ethanol, and basifying with base to separate precipitate; and (5) re-crystallizing the precipitate with ethanol, and freeze drying to obtain the high-purity Mezlocillin sodium.
Description
Technical field
The present invention relates to the method that a kind of continuous medium pressure column chromatography prepares the high purity azlocillin sodium, also relate to a kind of high purity azlocillin sodium and prepare azlocillin sodium injection and preparation method thereof, belong to medical technical field by described method preparation.
Background technology
The azlocillin is a Penicillin antibiotics, to streptococcuses such as streptococcus pneumoniae, Hemolytic streptococcuss, do not produce aerobic gram positive coccus such as penicillinase staphylococcus, enterococcus faecalis, aerobic gram-negative bacterias such as escherichia coli, Proteus mirabilis, Salmonella, hemophilus influenzae, Diplococcus gonorrhoeae do not produce the beta lactamase bacterial strain and helicobacter pylori has good antibacterial activity.Bacteria cell wall is synthetic brings into play germicidal action by suppressing in the azlocillin, can make bacterium become spherule rapidly and dissolves, breaks.
The azlocillin is applicable to due to the sensitive organism (not producing the beta lactamase bacterial strain) that the state of an illness in the following infection is heavier needs hospital care or patient that can not be oral.1. upper respiratory tract infection such as otitis media, sinusitis paranasal sinusitis, pharyngitis, tonsillitis due to Streptococcus hemolyticus, streptococcus pneumoniae, staphylococcus or the hemophilus influenzae.2. the urogenital infections due to escherichia coli, Proteus mirabilis or the enterococcus faecalis.3. the skin soft-tissue infection due to Streptococcus hemolyticus, staphylococcus or the escherichia coli.4. lower respiratory infections such as acute bronchitis, pneumonia due to Streptococcus hemolyticus, streptococcus pneumoniae, staphylococcus or the hemophilus influenzae.5. this product still can be used for treating typhoid fever and leptospirosis.
The azlocillin sodium for injection powder injection has been widely used in clinical, is present most widely used antibiotic medicine, and its preparation all is to make by the azlocillin sodium raw materials is aseptic subpackaged.Most of azlocillins sodium raw materials exists 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 antibiotics.
Summary of the invention:
The object of the present invention is to provide a kind of method for preparing the high purity azlocillin sodium, a kind of method for preparing the azlocillin sodium injection also is provided simultaneously.The product purity that the inventive method obtains significantly improves, and product stability significantly improves.
For achieving the above object, technical solution of the present invention is as follows:
The invention provides a kind of method for preparing the high purity azlocillin sodium, it is characterized in that comprising the steps: that (1) azlocillin sodium crude product solution changes into azlocillin acid under acidic conditions; (2) obtain the azlocillin 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 azlocillin acid crude is carried out chromatographic separation, collect the azlocillin acid content and be not less than 70% flow point; (4) azlocillin of step (3) gained acid stream part adds the lower alkyl alcohol dissolution with solvents except that after desolvating, and adds alkali to separating out precipitation; (5) step (4) gained precipitation is used the lower alkyl alcohol solvent recrystallization, obtains the high purity azlocillin sodium.
The above-mentioned described method for preparing the high purity azlocillin sodium is characterized in that comprising the steps: that (1) azlocillin sodium crude product dissolves with purified water, adds 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, the upper prop product dissolve the back feed liquor with eluent, the flow point Fractional Collections behind the wash-out, and collection and merging azlocillin acid content are not less than the flow point of 80% (more preferably being not less than 90%); (4) add dissolve with ethanol behind stream part concentrating under reduced pressure of step (3) gained, add and separate out precipitation after alkali alkalizes; (5) step (4) gained precipitation is used ethyl alcohol recrystallization, and crystallisate obtains the high purity azlocillin sodium through lyophilize.
The present invention also provides a kind of method for preparing the azlocillin sodium injection, it is characterized in that comprising the steps: that (1) azlocillin sodium crude product solution changes into azlocillin acid under acidic conditions; (2) obtain the azlocillin 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 azlocillin acid crude is carried out chromatographic separation, collect the azlocillin acid content and be not less than 70% flow point; (4) azlocillin of step (3) gained acid stream part adds the lower alkyl alcohol dissolution with solvents except that after desolvating, and adds alkali to separating out precipitation; (5) step (4) gained precipitation is used the lower alkyl alcohol solvent recrystallization, obtains the high purity azlocillin sodium; (6) after step (5) gained azlocillin sodium is pulverized, carry out aseptic subpackagedly, make the azlocillin sodium injection.
The above-mentioned described method for preparing the azlocillin sodium injection is characterized in that comprising the steps: that (1) azlocillin sodium crude product dissolves with purified water, adds 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, the upper prop product dissolve the back feed liquor with eluent, the flow point Fractional Collections behind the wash-out, and collection and merging azlocillin acid content are not less than the flow point of 80% (more preferably being not less than 90%); (4) add dissolve with ethanol behind stream part concentrating under reduced pressure of step (3) gained, add and separate out precipitation after alkali alkalizes; (5) step (4) gained precipitation is used ethyl alcohol recrystallization, and crystallisate obtains the high purity azlocillin sodium through lyophilize; (6) after step (5) gained azlocillin sodium is pulverized, carry out aseptic subpackagedly, make the azlocillin sodium injection.
Wherein, the above-mentioned described method of the present invention is characterized in that: pH value of solution is 1-6 in the step (1), preferred 2-4.
Wherein, above-mentioned described method, it is characterized in that: the used organic solvent of step (2) extraction is a chlorinated solvents, preferred chloroform, monochloro methane, methylene dichloride, trichloromethane, 1, one or more in 2-ethylene dichloride, trichloroethane, trieline, zellon and the carrene.
Wherein, above-mentioned described method is characterized in that: 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 in upper prop sample size and the post: (10～200), preferred 1: (15～100).
Wherein, above-mentioned described method is characterized in that: 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; The volume ratio of hydrocarbon solvent and chlorinated solvents is 1 in the described eluent: (2～10) are preferably 1: (4～7).
Wherein, above-mentioned described method is characterized in that: 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.
The above-mentioned described method of the present invention is characterized in that azlocillin sodium is crushed to the 60-100 mesh sieve in the step (6), and packing under 100 grades of conditions in sterilisable chamber then makes the azlocillin sodium injection.
The used alumina filled post of middle pressure of preparation the present invention can be used dry column-packing, also can adopt wet method dress post, no matter adopt which kind of dress column method, all can obtain good separating effect.The separation principle of the alumina filled post of middle pressure is gel-filtration, i.e. molecular sieve, so described packed column need possess certain length, to reach satisfied separating effect; But the long more sample of packed column is long more by the time of packed column, though also can reach the purpose of preparation high purity azlocillin, can increase production cost because of disengaging time is long, so need to select suitable column length, and this can be definite by testing.In the present invention, as preferably, pressing the column length of alumina filled post in described is 20-500cm, more preferably 30-350cm.The chromatography column diameter increases the chromatography column diameter and can increase treatment capacity, but can increase floor space not influence of purification effect.Therefore select the diameter of chromatography column only need consider that production task and production plant real space size get final product.In the present invention, as preferably, pressing the diameter of alumina filled post in described is 5-100cm, more preferably 5-50cm.It is in order to ensure certain purifying speed that the post of packed column is pressed, and will be complementary with the intensity of filling alumina simultaneously, 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.
Realize that one of key of the present invention is azlocillin sodium to be transformed into azlocillin acid, with organic solvent azlocillin acid is extracted again on this basis.Azlocillin sodium need just can be transformed into azlocillin acid under sour environment, therefore the azlocillin 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 of described pH regulator agent, as long as reach the purpose of regulating pH, 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), azlocillin sodium can be transformed into azlocillin acid, and as preferably, after the pH regulator agent was regulated, pH value of solution was 1-6, more preferably 2-4.
In step (2), the used organic solvent range of choice of extraction azlocillin acid 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 with siccative the moisture in the organic phase to be removed, used siccative also has no special requirements, as long as reach the purpose of removing moisture.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.
In column chromatography process of the present invention, be eluent with the mixed solution of hydrocarbon solvent and chlorinated solvents.Hydrocarbon solvent described in the described eluent is a kind of 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 chloroform, monochloro methane, methylene dichloride, trichloromethane, 1, a kind of in 2-ethylene dichloride, trichloroethane, trieline, zellon and the carrene.Described eluent to the amount ratio of hydrocarbon solvent and chlorinated solvents without limits, so long as the mixing solutions of hydrocarbon solvent and chlorinated solvents gets final product.As preferably, the mass ratio of hydrocarbon solvent and chlorinated solvents is 1 in the described eluent: 2-10, further the mass ratio of preferred hydrocarbons solvent and chlorinated solvents is 1: 4-7.
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 azlocillin in the flow point of different sections, in order to obtain highly purified azlocillin sodium (purity is more than or equal to 99.5%), need the azlocillin acid content is merged more than or equal to 70% flow point, as preferably, can be with the azlocillin acid content more than or equal to 80%, preferably the azlocillin acid content is merged more than or equal to 90% flow point further, the purity of the azlocillin sodium of so final acquisition can be more than or equal to 99.8%.The enriched material that the azlocillin acid content obtains after less than 70% 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, azlocillin 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 the high purity azlocillin sodium through lyophilize behind the recrystallization, and the purity of gained azlocillin 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.
Adopt the high purity azlocillin sodium of method for preparing to can be used as the raw material for preparing the azlocillin sodium injection.The preparation technology of described azlocillin sodium injection is this area common technology, the azlocillin sodium that obtains is crossed the 50-200 mesh sieve pulverize, the preferred 60-100 mesh sieve of crossing, then in sterilisable chamber under hundred grades of conditions packing promptly get the azlocillin sodium injection.
The high purity azlocillin sodium injection prepared to each embodiment 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 conformance with standard requirement that the present invention makes, and every quality index does not have considerable change after quickening June and long-term 18 months, all meets quality standard, and the good quality stability of sample of preparation of the present invention has been described effectively.
Compared with prior art, the continuous medium pressure column chromatography provided by the present invention method for preparing the high purity azlocillin sodium has following advantage:
1. gained azlocillin sodium purity height, its purity is more than or equal to 99.5%.
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 azlocillin 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.
The azlocillin sodium injection that the azlocillin sodium that is prepared by described method prepares has overcome by defectives such as clarity difference and aqueous stability difference after the not high dissolving that causes of material purity.The requirement that clarity after the sodium injection dissolving of described azlocillin and its aqueous stability all reach clinical application.
Embodiment:
Embodiment 1:
500g azlocillin sodium crude product stirring and dissolving adds hydrochloric acid and regulates pH to 1 in the 2L purified water, divides 3 extractions with the 6L methylene dichloride, and extraction liquid flows through the dehydration of anhydrous sodium sulphate post, is evaporated to dried then.The 50 order aluminum oxide 5kg that with activity are the II level are with behind the normal hexane suspendible, drive away bubble, evenly join effective column length 20cm, in the glass chromatography column of internal diameter 5cm, above-mentioned concentrate as for the azlocillin sodium crude product add 600ml eluent (normal hexane and methylene dichloride mass ratio are 1: 99) and dissolve, use on the plunger tpe solvent pump behind the filtering insolubles in column cap, pump into eluent (normal hexane and methylene dichloride mass ratio are 1: 99) wash-out then, post is pressed and is 0.1MPa, Fractional Collections flow point, TLC and HPLC detect, merge the azlocillin acid content more than or equal to 80% effluent liquid, behind the reclaim under reduced pressure eluent enriched material 422g, add 95% ethanol 500ml dissolving, add 5% sodium hydroxide and regulate pH to 7.1, sedimentation and filtration adds 95% ethanol 9000ml backflow dissolving, cooling crystallization, crystallisate is used ethyl alcohol recrystallization 1 time again, filtration under diminished pressure, lyophilize gets azlocillin sodium pure product 403g, purity 99.5%, yield are 80.6%.Get the raw material of enriched material behind the mother liquor decompression and solvent recovery as next column chromatography, the azlocillin acid content after less than 80% 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 40L methylene dichloride, and then pumping into 60L normal hexane balance, the alumina column after the balance can directly use next time.
Embodiment 2:
500g azlocillin sodium crude product stirring and dissolving adds sulfuric acid and regulates pH to 6 in the 2L purified water, uses the 8L n-butanol extraction, and extraction liquid flows through the dehydration of anhydrous magnesium sulfate post, is evaporated to dried then.The 800 order aluminum oxide 100kg that with activity are the II level are with behind the normal hexane suspendible, drive away bubble, evenly join effective column length 2000cm, in the glass chromatography column of internal diameter 100cm, above-mentionedly be concentrated into dried azlocillin sodium crude product and add 700ml eluent (suberane and trichloromethane mass ratio are 100: 1) and dissolve, use on the plunger tpe solvent pump behind the filtering insolubles in column cap, pump into eluent (suberane and trichloromethane mass ratio are 100: 1) wash-out then, post is pressed and is 5MPa, Fractional Collections flow point, TLC and HPLC detect, merge the azlocillin acid content more than or equal to 85% effluent liquid, behind the reclaim under reduced pressure eluent enriched material 408g, add 98% ethanol 500ml dissolving, add 20% sodium hydroxide and regulate pH to 13, sedimentation and filtration adds 98% ethanol 9000ml backflow dissolving, cooling crystallization, crystallisate is used ethyl alcohol recrystallization 1 time again, filtration under diminished pressure, lyophilize gets azlocillin sodium pure product 397g, purity 99.7%, yield are 79.4%.Get the raw material of enriched material behind the mother liquor decompression and solvent recovery as next column chromatography, the azlocillin 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 800L methylene dichloride, and then pumping into 1200L normal hexane balance, the alumina column after the balance can directly use next time.
Embodiment 3
500g azlocillin sodium crude product stirring and dissolving adds phosphoric acid and regulates pH to 2 in the 2L purified water, and with the extraction of 7L cyclooctane, extraction liquid flows through the dehydration of Calcium Chloride Powder Anhydrous post, is evaporated to dried then.The 100 order aluminum oxide 7.5kg that with activity are the II level are with behind the normal hexane suspendible, drive away bubble, evenly join effective column length 30cm, in the glass chromatography column of internal diameter 10cm, above-mentionedly be concentrated into dried azlocillin sodium crude product and add 650ml eluent (1-nonene and 1,2-ethylene dichloride mass ratio is 1: 4) dissolving, behind the filtering insolubles on the usefulness plunger tpe solvent pump in column cap, pump into eluent (1-nonene and 1 then, 2-ethylene dichloride mass ratio is 1: 4) wash-out, post is pressed and is 2.5MPa, Fractional Collections flow point, TLC and HPLC detect, merge the azlocillin acid content more than or equal to 90% effluent liquid, behind the reclaim under reduced pressure eluent enriched material 362g, add dehydrated alcohol 500ml dissolving, add 10% sodium hydroxide and regulate pH to 9, sedimentation and filtration adds dehydrated alcohol 9000ml backflow dissolving, cooling crystallization, crystallisate is used ethyl alcohol recrystallization 1 time again, filtration under diminished pressure, lyophilize gets azlocillin sodium pure product 353g, purity 99.8%, yield are 70.6%.Get the raw material of enriched material behind the mother liquor decompression and solvent recovery as next column chromatography, the azlocillin acid content after less than 90% 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 60L methylene dichloride, and then pumping into 90L normal hexane balance, the alumina column after the balance can directly use next time.
Embodiment 4:
500g azlocillin sodium crude product stirring and dissolving adds nitric acid and phosphoric acid and regulates pH to 4 in the 2L purified water, uses 7L1, the extraction of 2-ethylene dichloride, and extract flow calcium peroxide and the dehydration of calcium sulfate post are evaporated to dried then.The 400 order aluminum oxide 50kg that with activity are the II level are with behind the normal hexane suspendible, drive away bubble, evenly join effective column length 350cm, in the glass chromatography column of internal diameter 50cm, above-mentionedly be concentrated into dried azlocillin sodium crude product and add 600ml eluent (octane and trichloroethane mass 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 mass ratio are 1: 7) wash-out then, post is pressed and is 3.0MPa, Fractional Collections flow point, TLC and HPLC detect, merge the azlocillin acid content more than or equal to 80% effluent liquid, behind the reclaim under reduced pressure eluent enriched material 419g, add dehydrated alcohol 500ml dissolving, add 15% sodium hydroxide and regulate pH to 11, sedimentation and filtration adds dehydrated alcohol 9000ml backflow dissolving, cooling crystallization, crystallisate is used ethyl alcohol recrystallization 1 time again, filtration under diminished pressure, lyophilize gets azlocillin sodium pure product 401g, purity 99.5%, yield are 80.2%.Get the raw material of enriched material behind the mother liquor decompression and solvent recovery as next column chromatography, the azlocillin acid content after less than 80% 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:
500g azlocillin sodium crude product stirring and dissolving adds hydrochloric acid and regulates pH to 3 in the 2L purified water, uses the 7L extracted with diethyl ether, and extraction liquid flows through the dehydration of anhydrous sodium sulphate post, is evaporated to dried then.The 300 order aluminum oxide 25kg that with activity are the II level are with behind the normal hexane suspendible, drive away bubble, evenly join effective column length 300cm, in the glass chromatography column of internal diameter 40cm, above-mentionedly be concentrated into dried azlocillin sodium crude product and add 600ml eluent (octane and trichloroethane mass 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 mass ratio are 1: 5) wash-out then, post is pressed and is 4.0MPa, Fractional Collections flow point, TLC and HPLC detect, merge the azlocillin acid content more than or equal to 80% effluent liquid, behind the reclaim under reduced pressure eluent enriched material 421g, add dehydrated alcohol 500ml dissolving, add 8% sodium hydroxide and regulate pH to 10, sedimentation and filtration adds dehydrated alcohol 9000ml backflow dissolving, cooling crystallization, crystallisate is used ethyl alcohol recrystallization 1 time again, filtration under diminished pressure, lyophilize gets azlocillin sodium pure product 405g, purity 99.5%, yield are 81.0%.Get the raw material of enriched material behind the mother liquor decompression and solvent recovery as next column chromatography, the azlocillin acid content after less than 80% 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 99.5% azlocillin sodium pure product and cross 50 mesh sieves and pulverize, be distributed into the azlocillin sodium injection under 100 grades of conditions in sterilisable chamber, 0.5g/ props up.
Embodiment 7:
Get 300g embodiment 2 gained purity and be 99.7% azlocillin sodium pure product and cross 200 mesh sieves and pulverize, be distributed into the azlocillin sodium injection under 100 grades of conditions in sterilisable chamber, 1.0g/ props up.
Embodiment 8:
Get 300g embodiment 3 gained purity and be 99.8% azlocillin sodium pure product and cross 60 mesh sieves and pulverize, be distributed into the azlocillin sodium injection under 100 grades of conditions in sterilisable chamber, 2.0g/ props up.
Embodiment 9:
Get 300g embodiment 4 gained purity and be 99.5% azlocillin sodium pure product and cross 100 mesh sieves and pulverize, be distributed into the azlocillin sodium injection under 100 grades of conditions in sterilisable chamber, 1.0g/ props up.
Embodiment 10:
Get 300g embodiment 5 gained purity and be 99.5% azlocillin sodium pure product and cross 80 mesh sieves and pulverize, be distributed into the azlocillin sodium injection under 100 grades of conditions in sterilisable chamber, 2.0g/ props up.
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 (15)
1. a method for preparing azlocillin sodium is characterized in that comprising the steps: that (1) azlocillin sodium crude product solution changes into azlocillin acid under acidic conditions; (2) obtain the azlocillin 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 azlocillin acid crude is carried out chromatographic separation, collect the azlocillin acid content and be not less than 70% flow point; (4) azlocillin of step (3) gained acid stream part adds dissolve with ethanol except that after desolvating, and adds alkali to separating out precipitation; (5) step (4) gained precipitation is used ethyl alcohol recrystallization, obtains azlocillin sodium; Wherein, described hydrocarbon solvent 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, the zellon; Described alkali is oxide compound, oxyhydroxide, carbonate or the supercarbonate of basic metal or alkaline-earth metal.
2. the method for preparing azlocillin sodium according to claim 1 is characterized in that comprising the steps: that (1) azlocillin sodium crude product dissolves with purified water, adds 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, be eluent with the mixed solution of hydrocarbon solvent and chlorinated solvents, the upper prop product are with eluent dissolving back feed liquor, and the flow point Fractional Collections behind the wash-out is collected and is merged the azlocillin acid content and is not less than 80% flow point; (4) add dissolve with ethanol behind stream part concentrating under reduced pressure of step (3) gained, add and separate out precipitation after alkali alkalizes; (5) step (4) gained precipitation is used ethyl alcohol recrystallization, and crystallisate obtains azlocillin sodium through lyophilize; Wherein, described hydrocarbon solvent 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, the zellon; Described alkali is oxide compound, oxyhydroxide, carbonate or the supercarbonate of basic metal or alkaline-earth metal.
3. the method for preparing azlocillin sodium according to claim 2, wherein middle collection of step (3) and merging azlocillin acid content are not less than 90% flow point.
4. a method for preparing the azlocillin sodium injection is characterized in that comprising the steps: that (1) azlocillin sodium crude product solution changes into azlocillin acid under acidic conditions; (2) obtain the azlocillin 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 azlocillin acid crude is carried out chromatographic separation, collect the azlocillin acid content and be not less than 70% flow point; (4) azlocillin of step (3) gained acid stream part adds dissolve with ethanol except that after desolvating, and adds alkali to separating out precipitation; (5) step (4) gained precipitation is used ethyl alcohol recrystallization, obtains azlocillin sodium; (6) after step (5) gained azlocillin sodium is pulverized, carry out aseptic subpackagedly, make the azlocillin sodium injection; Wherein, described hydrocarbon solvent 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, the zellon; Described alkali is oxide compound, oxyhydroxide, carbonate or the supercarbonate of basic metal or alkaline-earth metal.
5. the method for preparing the azlocillin sodium injection according to claim 4 is characterized in that comprising the steps: that (1) azlocillin sodium crude product dissolves with purified water, adds 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, be eluent with the mixed solution of hydrocarbon solvent and chlorinated solvents, the upper prop product are with eluent dissolving back feed liquor, and the flow point Fractional Collections behind the wash-out is collected and is merged the azlocillin acid content and is not less than 80% flow point; (4) add dissolve with ethanol behind stream part concentrating under reduced pressure of step (3) gained, add and separate out precipitation after alkali alkalizes; (5) step (4) gained precipitation is used ethyl alcohol recrystallization, and crystallisate obtains the high purity azlocillin sodium through lyophilize; (6) after step (5) gained azlocillin sodium is pulverized, carry out aseptic subpackagedly, make the azlocillin sodium injection; Wherein, described hydrocarbon solvent 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, the zellon; Described alkali is oxide compound, oxyhydroxide, carbonate or the supercarbonate of basic metal or alkaline-earth metal.
6. the method for preparing the azlocillin sodium injection according to claim 5, wherein middle collection of step (3) and merging azlocillin acid content are not less than 90% flow point.
7. according to each described method of claim 1-6, it is characterized in that: pH value of solution is 1-6 in the step (1).
8. method according to claim 7 is characterized in that described pH is 2-4.
9. according to each described method of claim 1-6, it is characterized in that: the used organic solvent of step (2) extraction is a chlorinated solvents, be selected from chloroform, monochloro methane, methylene dichloride, trichloromethane, 1, one or more in 2-ethylene dichloride, trichloroethane, trieline, the zellon.
10. according to each described method of claim 1-6, it is characterized in that: the described chromatography column column length of step (3) 20-500cm; Column diameter 5-100cm; Alumina particle is the 50-800 order; Post is pressed and is 0.1-5Mpa; The weight ratio of alumina amount is 1 in upper prop sample size and the post: (10～200).
11., it is characterized in that according to each described method of claim 1-6: described in the step (3) in the eluent volume ratio of hydrocarbon solvent and chlorinated solvents be 1: (2～10).
12. method according to claim 11 is characterized in that: described in the step (3) in the eluent volume ratio of hydrocarbon solvent and chlorinated solvents be 1: (4～7).
13. according to each described method of claim 1-6, it is characterized in that: the used alkali of step (4) is sodium hydroxide, yellow soda ash, sodium bicarbonate, potassium hydroxide, salt of wormwood or saleratus, and alkalization back pH value of solution is 8-13.
14. method according to claim 13 is characterized in that described pH is 9-11.
15. according to each described method of claim 4-6, it is characterized in that azlocillin sodium is crushed to the 60-100 mesh sieve in the step (6), packing under 100 grades of conditions in sterilisable chamber then makes the azlocillin sodium injection.
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| CN103622822A (en) * | 2013-12-30 | 2014-03-12 | 华北制药股份有限公司 | Preparation method and product of azlocillin sodium powder injection |
| CN104910181A (en) * | 2015-05-28 | 2015-09-16 | 浙江长典医药有限公司 | Children azlocillin sodium compound entity and drug preparation thereof |
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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: Method for producing high-purity azlocillin sodium and powder injection thereof Granted publication date: 20100609 License type: Exclusive License Open date: 20080917 Record date: 20110928 |
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