CN101695489A - Aztreonam composition, powder injection and preparation method thereof - Google Patents
Aztreonam composition, powder injection and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an aztreonam composition. The composition comprises sterile aztreonam and arginine, and the weight ratio of the sterile aztreonam to the arginine is between 1:1 and 1.5:1. The weight of the sterile aztreonam is based on C13 compound. The aztreonam composition can be used for aztreonam powder injection with good stability and clarity and low water content. The invention also discloses a method for preparing the sterile aztreonam. The method is improved on the basis of the prior art to increase the purity and yield of prepared aztreonam compared with the prior art.
Description
Technical field
The invention belongs to the synthetic and formulation art of medicine, in particular, what the present invention relates to is a kind of aztreonam composition, its injectable powder and preparation method thereof.
Background technology
Aztreonam (Aztreonam) is a kind of antibacterials of U.S. Shi Guibao company exploitation, went on the market in Italy in 1984, it is that first is applied to clinical monocycle beta-lactam antibiotics, and gram negative bacilli is had stronger antibacterial activity, and is stable to β-Nei acyl ammonia enzyme.In recent years, along with the extensive use of antibacterials, gram negative bacilli infects proportion and obviously increases, and its Resistant strain is showed increased also, before the feasible head armful antibiotic clinical efficacy of bacteriums can not show a candle to.But aztreonam makes antibacterial to its sensitivity, thereby is widely used clinically because of its particular structure.
Aztreonam, English name is Aztreonam, chemical name is [2S-[2 α, 3 β (Z)]-2-[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfenyl-3-azetidinyl) amino]-2-oxo ethylidene] amino] oxo]-2-methyl-propanoic acid, its molecular formula is C
13H
17N
5O
8S
2, molecular weight is 435.44, chemical structural formula is as follows:
Its pharmacological action is: aztreonam has the antibacterial activity of height to most of aerobic gram-negative bacterias, belongs to, comprises the Enterobacter of enterobacter cloacae, bloodthirsty hemophilus influenza (comprising that anti-ampicillin and other produce the penicillinase bacterial strain), Pseudomonas aeruginosa and comprise the Serratia of serratia marcesens as: dust Xi Shi escherichia coli, pneumobacillus and Ao Kexituoke bacterium, proteus mirabilis that thunder gram diphtheria belongs to, the citrobacter that comprises the Fei Shi citrobacter.In vitro tests shows: aztreonam to Aeromonas hydrophila, morganella morganii, Neisseria gonorrhoeae (comprise and produce the penicillinase bacterial strain), kill Bath more and get bacterium, proteus vulgaris, providencia stuartii, providencia rettgeri etc. and also have good antibacterial action.Aztreonam by with the aerobic gram-negative bacteria cell membrane of sensitivity on penicillin-binding protein 3 (PBP3) height affinity suppress the synthetic of cell wall.Different with most of beta-lactam antibiotics is that it does not induce antibacterial to produce beta-lactamase, highly stable to bacteriogenic most of beta-lactamases simultaneously.
Aztreonam has multiple crystal structure form, is divided into α, β, γ, the δ type, wherein the dissolubility of α type in water is bigger, but moisture absorption easily, and mobile relatively poor, storage stability is poor, therefore can not be used for doing preparation, the β type is not easy moisture absorption, and good fluidity, and its solid-state stability is better, so medicinal aztreonam is generally the β type, but the dissolubility of β type aztreonam in water is very little.
Introduced a kind of method of the β of preparation type aztreonam among the U.S. Patent application US4946838, wherein, the α type is dissolved in dehydrated alcohol with the triethylamine salt form, just can obtain β type aztreonam to wherein adding the anhydrous chlorides of rase hydrogen solution afterwards.
Introduced a kind of preparation method of aztreonam among the U.S. Patent application US4775670; relate to 2-2-amino-4-thiazolyl)-2-(1-diphenyl methoxy carbonyl-1-methyl ethoxy) acetimidic acid hydrochlorate and (2S-is trans)-3-amino-2-methyl-4-oxo-1-azetidinyl sulfonic acid carries out dehydration with dicyclohexyl charcoal diimine, takes off that benzhydryl is protected and the method for preparing aztreonam with trifluoroacetic acid and methoxybenzene then.The used solvent of deprotection base is trifluoroacetic acid and methoxybenzene in this application, and the deprotection effect is bad, and the trifluoroacetic acid cost is higher, and can't reclaim, and environment is produced harm.
Introduced the production method of the anhydrous aztreonam of a kind of β type crystal among the Chinese patent application CN02816342.7, wherein, under-10 ℃～15 ℃ condition, α type aztreonam is dissolved in dehydrated alcohol, through after the aseptic filtration, solution is heated to 50-55 ℃ again, to form the crystallization of anhydrous beta type aztreonam.
Introduced a kind of production method of anhydrous beta crystal formation aztreonam among the Chinese patent application CN200610161071.5, be included under-10 ℃～25 ℃ the temperature, the alpha-crystal form aztreonam is dissolved in the mixed liquor of dehydrated alcohol and acetone, through after the aseptic filtration, again solution is heated to 30-55 ℃ or vigorous stirring, to form the crystallization of anhydrous beta type aztreonam.
International Application No. WO 2004/013133 discloses a kind of method for preparing aztreonam; under the condition of elevated temperature; react and hydrolysis [3S-[3 α (Z), 4 β] by ester and aqueous acid]-3-[[(2-amino-4-thiazolyl) [(1-tert-butoxy base-1-methyl ethoxy) imino group] acetyl group] amino]-ester group of 4-methyl-2-oxo-1-azo-cycle butane sulfonic acid.Step is various in this method, and the yield of resultant product is not high.
Introduced a kind of method for simplifying of one pot of preparation aztreonam among the Chinese patent application CN200680015648.X, described method uses azetidine and TAEM as initiation material, need not intermediate section from t-bu aztreonam.Though this method step is further simplified,, therefore cause the content of prepared product aztreonam not high because product and separation of by-products are not thorough.
Introduced a kind of preparation method of antibacterials aztreonam among the Chinese patent application CN200610165272.2, this method comprises the aztreonam of side chain protected and the reactant aqueous solution of formic acid or formic acid, obtains the step of aztreonam.
Disclose the preparation method of aztreonam amino acid salt among the patent application CN200710092994, this method is dissolved in organic solvent with aztreonam, drips amino acid whose aqueous solution, and after having reacted, cold filtration obtains aztreonam salt.Utilize organic solvent as reaction solution in this application, make the salt-forming reaction of aztreonam more thorough, the reaction yield height.But the product of gained is subjected to the pollution of organic solvent easily.
In sum; for this medicine of aztreonam; the research of prior art is mainly from the mode of deprotection and how unsettled alpha-crystal form aztreonam is converted into this two aspect of stable beta crystal aztreonam and studies; and the purity that the prior art ubiquity aztreonam is not high; yield is low and thereby solvent can't reclaim the defective that causes the harm of environment; in order to overcome above-mentioned defective; research worker of the present invention is passed through long term studies; in the hope of method and a kind of high-quality aztreonam composition that obtains a kind of synthesis of high purity and high yield aztreonam; in view of this, special this invention of proposition.
Summary of the invention
One of purpose of the present invention is to provide a kind of aztreonam composition, and described aztreonam for injection compositions can be used as the Injectable sterile injectable powder, its solubility and good stability.Described aztreonam by on the basis of existing technology its preparation method being improved, makes prepared aztreonam purity height, and described method raw material is easy to get, and step is simple, and is workable.
To achieve these goals, the technical solution used in the present invention is:
A kind of aztreonam composition comprises aseptic aztreonam and arginine in the described compositions, and aseptic aztreonam and arginic weight ratio be 1: 1～1.5: 1, and described aseptic aztreonam weight is with C
13H
17N
5O
8S
2Meter.
Aseptic aztreonam and arginic weight ratio are 1.25: 1 in the compositions of the present invention, and described aseptic aztreonam weight is with C
13H
17N
5O
8S
2Meter.
Aseptic aztreonam of the present invention is prepared by following method:
(1) aztreonam is synthetic:
Earlier with triethylamine and dimethyl sulfoxide mix homogeneously, obtain the triethylamine mixed solution, MSA is added in the above-mentioned mixed solution again, obtain the MSA mixed solution, under stirring condition, TAEM is dropped in the above-mentioned MSA mixed solution, dropwise the back and continue reaction 5-10 hour, TLC check reaction finishes, and obtains reactant liquor;
Reactant liquor is cooled off, add entry and concentrated hydrochloric acid successively, 0 ℃ of-5 ℃ of stirring, centrifugalize, washing obtains the aztreonam crude product after the drying;
(2) aztreonam is refining
The aztreonam crude product is made with extra care, obtained the aztreonam elaboration;
(3) preparation of aseptic aztreonam
Aztreonam elaboration at step (2) gained carries out aseptic process, obtains aseptic aztreonam.
In the step of the present invention (1), when dropping to TAEM in the above-mentioned MSA mixed solution, described dropping is at the uniform velocity dripping, and the speed of dropping is that the TAEM that per minute drips is 1/360～1/120 of a TAEM total amount.
Step of the present invention (2) specifically comprises:
The aztreonam crude product is added in the reactor, adds dehydrated alcohol, be cooled to 0 ℃-5 ℃, add triethylamine again, after the stirring and dissolving, obtain the aztreonam crude product solution, the aztreonam crude product solution is crossed the HP-20 resin column at ambient temperature, solution temperature rises to room temperature, to 1.5-2.5, and then slowly be cooled to 0 ℃-5 ℃ with the hydrochloric acid adjust pH, behind the crystallize, washing is drying to obtain the aztreonam elaboration.
Among the present invention when crossing the HP-20 resin column eluant be water.
Slow cooling of the present invention is that per minute descends 1 ℃-3 ℃, and preferred described slow cooling is that per minute descends 1 ℃-2 ℃.
Step of the present invention (3) specifically comprises:
In the aztreonam elaboration of step (2) gained, add dehydrated alcohol, cooling, add triethylamine again, treat aztreonam dissolving after, add active carbon and handle, carry out sucking filtration through 0.22 μ m filter membrane then, the filtrate that obtains is transferred in the aseptic reactor, regulates pH value to 1.5-2.5 with hydrochloric acid, cooling, in the time of 0 ℃-5 ℃, under stirring condition, separate out crystal, will promptly obtain described aseptic aztreonam after crystal washing, the drying.
Triethylamine consumption of the present invention is the 20-30% of aztreonam elaboration weight, and the consumption of preferred described triethylamine is the 22-24% of aztreonam elaboration weight.Described percentage ratio is mass percent.
The consumption of active carbon of the present invention is the 1-2% of aztreonam elaboration weight, and the consumption of preferred described active carbon is 1.5% of an aztreonam elaboration weight.Described percentage ratio is mass percent.
Among the present invention, with the aztreonam dissolving crude product time, its mixing speed is 150-180 rev/min.
Another object of the present invention is to, a kind of aztreonam sterile powder injection is provided.
To achieve these goals, the technical solution used in the present invention is:
A kind of aztreonam sterile powder injection, described sterile powder injection comprises aztreonam composition.
The present invention also has a purpose to be, a kind of preparation method of aztreonam sterile powder injection is provided.
To achieve these goals, the technical solution used in the present invention is:
A kind of method for preparing the aztreonam sterile powder injection, described method comprises: indoor in the sterile working, take by weighing aseptic aztreonam according to recipe quantity, aseptic subpackaged in antibiotic glass bottle, and jump a queue, roll lid promptly.
Describe the present invention below:
A kind of aztreonam composition comprises aseptic aztreonam and arginine in the described compositions, and aseptic aztreonam and arginic weight ratio be 1: 1～1.5: 1, and described aseptic aztreonam weight is with C
13H
17N
5O
8S
2Meter.
Aseptic aztreonam and arginic weight ratio are 1.25: 1 in the described compositions, and described aseptic aztreonam weight is with C
13H
17N
5O
8S
2Meter.
In the present invention, because the dissolubility of aseptic aztreonam in water for injection is very little, therefore when preparation aztreonam for injection compositions, need to add arginine, make said composition can in official hour, be dissolved in the water for injection in use as cosolvent and stabilizing agent.In addition, because prepared aseptic aztreonam adds water and makes the solution that contains 5mg among every 1ml, its pH value is 2.2～2.8, and the pH tolerance range of human body is 4.0-9.0, therefore add after the arginine, can regulate the pH value of aseptic aztreonam, make its pH value be in the human body tolerance range.Research worker is found through experiment, at aseptic aztreonam and arginic weight ratio is 1.25: 1 o'clock, aseptic aztreonam is well dissolved, can make its pH value be in suitable scope again, and the clarity of the prepared aztreonam composition product that goes out and stability are better.
Among the present invention, the preparation method of aseptic aztreonam mainly may further comprise the steps:
(1) aztreonam is synthetic;
Earlier with triethylamine and dimethyl sulfoxide mix homogeneously, obtain the triethylamine mixed solution, MSA is added in the above-mentioned mixed solution again, obtain the MSA mixed solution, under stirring condition, TAEM is dropped in the above-mentioned MSA mixed solution, dropwise the back and continue reaction 5-10 hour, TLC check reaction finishes, and obtains reactant liquor;
Reactant liquor is cooled off, add entry and concentrated hydrochloric acid successively, 0 ℃ of-5 ℃ of stirring, centrifugalize, washing obtains the aztreonam crude product after the drying;
Among the present invention in the building-up process of aztreonam crude product, earlier triethylamine is mixed with dimethyl sulfoxide, MSA is added in the above-mentioned mixed solution again, obtain the MSA mixed solution, then toward this MSA mixed solution and dripping TAEM, described dropping is at the uniform velocity dripping, and the speed of dropping is that the TAEM that per minute drips is 1/360～1/120 of a TAEM total amount.TAEM is added dropwise in the MSA mixed solution with such speed, make the reaction of aztreonam to carry out smoothly, TAEM can fully contact with reactant MSA, so just can effectively avoid the generation of side reaction, prevents to react the not high problem of purity that too acutely causes the aztreonam crude product.
In the building-up process of aztreonam crude product, after dropwising, at room temperature stirring reaction 5-10 hour, preferably the speed of its stirring was 120-150 rev/min.In order to guarantee fully carrying out of this primary response, need stir reactant liquor, but the speed that stirs needs control, the reactant mixing speed is too fast, can't contact fully between the reactant, makes reaction not exclusively, the reactant mixing speed is too low, make that then to have significant concentration between the reactant poor, thereby cause the generation of side reaction, make that the yield of prepared product is not high.Research worker of the present invention is through test of many times, finds that its mixing speed in the time of 120-150 rev/min, fully reacts between the reactant, makes that the purity of resulting aztreonam crude product and yield are all high.
(2) aztreonam is refining
The aztreonam crude product is added in the reactor, adds dehydrated alcohol, the addition of dehydrated alcohol is 3-6 a times of aztreonam crude product weight; The addition of preferred dehydrated alcohol is 5 times of aztreonam crude product weight.It is cooled to 0 ℃-5 ℃, stirs, add triethylamine again and make its dissolving, the consumption of described triethylamine is the 20-30% of aztreonam crude product weight, and the consumption of preferred described triethylamine is the 22-24% of aztreonam crude product weight; Obtain the aztreonam crude product solution, the aztreonam crude product solution is crossed the HP-20 resin column at ambient temperature, the temperature of solution rises to room temperature afterwards, to 1.5-2.5, and then slowly be cooled to 0 ℃-5 ℃ with the hydrochloric acid adjust pH, behind the crystallize, washing is drying to obtain the aztreonam elaboration.Used eluant is a water when crossing the HP-20 resin column.Slow cooling of the present invention is that per minute descends 1 ℃-3 ℃, and preferred described slow cooling is that per minute descends 1 ℃-2 ℃.
Aztreonam is a multi-crystalline compounds, comprises α, beta, gamma, the δ type, and be used for pharmaceutical preparation best be β type crystal, in order to obtain the best aztreonam of the higher medicine of purity, aztreonam is made with extra care, in the hope of obtaining highly purified β type aztreonam crystal.In purified process, earlier the aztreonam crude product is put into reactor, add dehydrated alcohol again, be cooled to 0 ℃-5 ℃, and adding triethylamine hydrotropy, also contain some unreacteds reactant and some byproducts of reaction completely after the stirring and dissolving in the resulting aztreonam crude product solution, therefore described crude product solution is crossed the HP-20 resin, and the HP-20 resin has the adsorbance height, uniform particles, mechanical strength is good, be difficult for broken, the advantage that residue is few, at aztreonam crude product solution of the present invention, research worker finds through being after eluant is crossed the HP-20 resin with this crude product solution with water, the purity height of the recrystallization method that the purity of described aztreonam is used than prior art.
After crossing the HP-20 resin, the temperature of aztreonam crude product solution rises to room temperature, regulate pH value to 1.5-2.5 with hydrochloric acid, through slowly cooling, select per minute to descend 1 ℃-3 ℃ among the present invention again, under such cooling rate, carry out crystallize, make that crystalline speed of separating out is moderate, can not cause other impurity molecule of parcel in the crystal structure because crystallize is too fast, therefore, the purity height of aztreonam of the present invention.
(3) preparation of aseptic aztreonam
Add dehydrated alcohol in the aztreonam elaboration of step (2) gained, the addition of dehydrated alcohol is 3-6 a times of aztreonam elaboration weight; The addition of preferred dehydrated alcohol is 5 times of aztreonam elaboration weight.It is carried out freezing, the triethylamine of Jia Ruing again, described triethylamine consumption is the 20-30% of aztreonam elaboration weight, described percentage ratio is weight percentage.After treating that the aztreonam elaboration dissolves fully, adding active carbon handles, carry out sucking filtration through 0.22 μ m filter membrane then, the filtrate that obtains is transferred in the aseptic reactor, regulate pH value to 1.5-2.5 with hydrochloric acid, cooling is separated out crystal under stirring condition in the time of 0 ℃-5 ℃, will promptly obtain described aseptic aztreonam after crystal washing, the drying.The consumption of described active carbon is the 1-2% of aztreonam elaboration weight, and the consumption of preferred described active carbon is 1.5% of an aztreonam elaboration weight.The preparation of aseptic aztreonam is carried out under aseptic condition.Percentage ratio of the present invention is weight percentage.
Of the present invention being cooled to is cooled to 0-5 ℃, and during dissolving, used cosolvent is a triethylamine.When regulating pH value to 1.5-2.5 with hydrochloric acid, the concentration of used hydrochloric acid is 1-3mol/L, when crystal is washed, washes with water, wash 2 times, and when carrying out drying, described drying temperature under the condition of vacuum is 30-35 ℃ of dry 18-36 hour.Under such drying condition, neither can cause destruction to crystal and composition thereof, thereby stability and clarity when influencing its aztreonam composition and using as injectable powder, and moisture contained in the aseptic aztreonam can also be reduced to below 1%, thereby satisfy the requirement of its quality standard (moisture is lower than 2%).
TAEM of the present invention is
MSA of the present invention is (3S-is trans)-4-methyl-2-oxo-3 amino-1-nitrogen-containing heterocyclic ring butyl sulfonic acid
The invention has the beneficial effects as follows:
(1) aztreonam for injection compositions of the present invention, its stability and clarity are good, and moisture is low, is a kind of high-quality aztreonam for injection compositions, can be used as the aztreonam for injection injectable powder and uses.
(2) preparation method of aseptic aztreonam of the present invention, it improves on the basis of existing technology, makes the purity of prepared suitable medicinal aztreonam and yield be improved than prior art.
The specific embodiment
Embodiment 1
(1) aztreonam is synthetic
Elder generation is mix homogeneously in the 50L reactor with triethylamine 1.8Kg and dimethyl sulfoxide (DMSO) 10L, obtain the triethylamine mixed solution, MSA1.1Kg is added in the above-mentioned mixed solution again, obtain the MSA mixed solution, under stirring condition, TAEM3.8Kg is dropped in the above-mentioned MSA mixed solution, and the speed of dropping is that the TAEM that per minute drips is 1/240 of a TAEM total amount.Dropwise the back and continue reaction 5 hours, TLC check reaction finishes, and developing solvent is that volume ratio is an acetonitrile: the solution of water=4: 1 obtains reactant liquor;
Reactant liquor is cooled to 0 ℃, adds entry and concentrated hydrochloric acid successively, stirred 2 hours at 0 ℃, centrifugalize with the 10L washing, obtains aztreonam crude product 2.23Kg behind 30 ℃ of vacuum dryings, and productive rate is 83.5%; Be no more than 10% with the assorted speckle of TLC control.(developing solvent is the volume ratio acetonitrile: water=4: 1.5)
(2) aztreonam is refining
Aztreonam crude product 2.23Kg is added in the 50L reactor, add dehydrated alcohol, the addition of dehydrated alcohol is that 5 times of aztreonam crude product weight are 11.15Kg, be cooled to 0 ℃, add triethylamine again, the addition of triethylamine is 25% of an aztreonam crude product weight, be 0.5575Kg, with 180 rev/mins mixing speeds stir make its dissolving after, obtain the aztreonam crude product solution, the aztreonam crude product solution is crossed the HP-20 resin column at ambient temperature, is eluant with water, and the temperature of solution rises to room temperature afterwards, with hydrochloric acid adjust pH to 1.5, and then slowly being cooled to 0 ℃-5 ℃ and stirred simultaneously 5 hours, the speed of described slow cooling is 1 ℃ of per minute, behind the crystallize, centrifuge is centrifugal, with 5L washing twice, promptly get aztreonam elaboration 2.11Kg at 30 ℃ of vacuum dryings, consistent through the infrared Absorption collection of illustrative plates of infrared discriminating this product with the reference substance collection of illustrative plates.
(3) preparation of aseptic aztreonam
In the 50L in ten thousand grades of workshops reactor, add the resulting aztreonam elaboration of step (2), add dehydrated alcohol again, the addition of dehydrated alcohol is 4 times of aztreonam elaboration weight, be cooled to 0 ℃, add triethylamine again, the addition of triethylamine is 30% of an aztreonam elaboration weight, after treating the dissolving of aztreonam elaboration, add active carbon and handle, the consumption of active carbon is 0.15% of an aztreonam elaboration weight, carries out sucking filtration through 0.22 μ m filter membrane then, the filtrate that obtains is transferred in the aseptic reactor, regulate pH value to 1.5 with hydrochloric acid, 5 hours crystallize processes are carried out in cooling under stirring condition in the time of 0 ℃-5 ℃, carry out centrifugal with centrifuge, the crystal that the obtains water washing twice of 2L, the reuse absolute ethanol washing promptly obtains described aseptic aztreonam 1.85Kg behind 30 ℃ of vacuum dryings.
Embodiment 2
(1) aztreonam is synthetic
Elder generation is mix homogeneously in the 50L reactor with triethylamine 2.2Kg and dimethyl sulfoxide (DMSO) 10L, obtain the triethylamine mixed solution, MSA1.8Kg is added in the above-mentioned mixed solution again, obtain the MSA mixed solution, under stirring condition, TAEM4.1Kg is dropped in the above-mentioned MSA mixed solution, and the speed of dropping is that the TAEM that per minute drips is 1/120 of a TAEM total amount.Dropwise the back and continue reaction 8 hours, TLC check reaction finishes, and developing solvent is that volume ratio is an acetonitrile: the solution of water=4: 1 obtains reactant liquor;
Reactant liquor is cooled to 3 ℃, adds entry and concentrated hydrochloric acid successively, stirred 2 hours at 3 ℃, centrifugalize with the 10L washing, obtains aztreonam crude product 2.4Kg behind 30 ℃ of vacuum dryings, and productive rate is 83.3%; Be no more than 10% with the assorted speckle of TLC control.(developing solvent is the volume ratio acetonitrile: water=4: 1.5)
(2) aztreonam is refining
Aztreonam crude product 2.4Kg is added in the 50L reactor, add dehydrated alcohol, the addition of dehydrated alcohol is 3 times of aztreonam crude product weight, be cooled to 5 ℃, add triethylamine again, the addition of triethylamine is 20% of an aztreonam crude product weight, with 150 rev/mins mixing speeds stir make its dissolving after, obtain the aztreonam crude product solution, the aztreonam crude product solution is crossed the HP-20 resin column at ambient temperature, with water is eluant, the temperature of solution rises to room temperature afterwards, with hydrochloric acid adjust pH to 2.5, and then slowly is cooled to 3 ℃ and stirred simultaneously 5 hours, the speed of described slow cooling is 3 ℃ of per minutes, behind the crystallize, centrifuge is centrifugal, with twice of 5L washing, promptly get aztreonam elaboration 2.27Kg at 30 ℃ of vacuum dryings, consistent through the infrared Absorption collection of illustrative plates of infrared discriminating this product with the reference substance collection of illustrative plates.
(3) preparation of aseptic aztreonam
In the 50L in ten thousand grades of workshops reactor, add the resulting aztreonam elaboration of step (2), add dehydrated alcohol, the addition of dehydrated alcohol is 6 times of aztreonam elaboration weight, be cooled to 0 ℃, add triethylamine again, the addition of triethylamine is 30% of an aztreonam elaboration weight, after treating the aztreonam dissolving, add active carbon and handle, the consumption of active carbon is 0.1% of an aztreonam elaboration weight, carries out sucking filtration through 0.22 μ m filter membrane then, the filtrate that obtains is transferred in the aseptic reactor, regulate pH value to 2.5 with hydrochloric acid, cooling is carried out 6 hours crystallize processes at 0 ℃ under stirring condition, carry out centrifugal with centrifuge, the crystal that the obtains water washing twice of 2L, the reuse absolute ethanol washing promptly obtains described aseptic aztreonam 2.05Kg behind 32 ℃ of vacuum dryings.
Embodiment 3
(1) aztreonam is synthetic
Elder generation is mix homogeneously in the 50L reactor with triethylamine 1.6Kg and dimethyl sulfoxide (DMSO) 10L, obtain the triethylamine mixed solution, MSA1.1Kg is added in the above-mentioned mixed solution again, obtain the MSA mixed solution, under stirring condition, TAEM3.5Kg is dropped in the above-mentioned MSA mixed solution, and the speed of dropping is that the TAEM that per minute drips is 1/360 of a TAEM total amount.Dropwise the back and continue reaction 10 hours, TLC check reaction finishes, and developing solvent is that volume ratio is an acetonitrile: the solution of water=4: 1 obtains reactant liquor;
Reactant liquor is cooled to 5 ℃, adds entry and concentrated hydrochloric acid successively, stirred 2 hours at 5 ℃, centrifugalize with the 10L washing, obtains aztreonam crude product 2.06Kg, productive rate 84.0% behind 30 ℃ of vacuum dryings; Be no more than 10% with the assorted speckle of TLC control.(developing solvent is the volume ratio acetonitrile: water=4: 1.5)
(2) aztreonam is refining
The aztreonam crude product is added in the 50L reactor, add dehydrated alcohol, the addition of dehydrated alcohol is 6 times of aztreonam crude product weight, be cooled to 0 ℃, add triethylamine again, the addition of triethylamine is 25% of an aztreonam crude product weight, with 170 rev/mins mixing speeds stir make its dissolving after, obtain the aztreonam crude product solution, the aztreonam crude product solution is crossed the HP-20 resin column at ambient temperature, with water is eluant, the temperature of solution rises to room temperature afterwards, with hydrochloric acid adjust pH to 2.5, and then slowly is cooled to 0 ℃ and stirred simultaneously 5 hours, the speed of described slow cooling is 2 ℃ of per minutes, behind the crystallize, centrifuge is centrifugal, with twice of 5L washing, promptly get aztreonam elaboration 1.97Kg at 35 ℃ of vacuum dryings, consistent through the infrared Absorption collection of illustrative plates of infrared discriminating this product with the reference substance collection of illustrative plates.
(3) preparation of aseptic aztreonam
In the 50L in ten thousand grades of workshops reactor, add the resulting aztreonam elaboration of step (2), add dehydrated alcohol, the addition of dehydrated alcohol is 5 times of aztreonam elaboration weight, be cooled to 0 ℃, add triethylamine again, the addition of triethylamine is 28% of an aztreonam elaboration weight, after treating the aztreonam dissolving, add active carbon and handle, the consumption of active carbon is 0.2% of an aztreonam elaboration weight, carries out sucking filtration through 0.22 μ m filter membrane then, the filtrate that obtains is transferred in the aseptic reactor, regulate pH value to 2.5 with hydrochloric acid, 4 hours crystallize processes are carried out in cooling under stirring condition in the time of 5 ℃, carry out centrifugal with centrifuge, the crystal that the obtains water washing twice of 2L, the reuse absolute ethanol washing promptly obtains described aseptic aztreonam 1.69Kg behind 30 ℃ of vacuum dryings.
Embodiment 4
One, prescription is formed (1000 bottles)
This product is the sterilized powder that aztreonam is made; Press aztreonam (C
13H
17N
5O
8S
2) calculate, labelled amount is respectively 0.5g.
1, specification: 0.5g/ bottle
Aztreonam 500g is (with C
13H
17N
5O
8S
2Meter)
Arginine 400g
Make 1000 bottles
Two, preparation technology
Indoor in the sterile working, take by weighing the qualified aseptic aztreonam of chemical examination according to recipe quantity, press aztreonam (C
13H
17N
5O
8S
2) calculate and to be respectively the 0.5g/ bottle, aseptic subpackaged in antibiotic glass bottle, and jump a queue, roll lid promptly.
1, the processing of packaging material:
(1) after antibiotic glass bottle was used the ordinary water previous cleaning, the filterable water for injection recoil of reuse 0.2um was qualified, and aseptic compressed air dries up, and 320 ℃ of dry heat sterilizations are more than 25 minutes, and are standby;
(2) butyl rubber plug adds acid and boiled 30 minutes, is washed till neutrality with ordinary water, and the filterable water for injection recoil of reuse 0.2um is qualified, and aseptic compressed air dries up, and 120 ℃ of pressure sterilizings were dried after 2 hours, and are standby.
(3) 115 ℃ of-125 ℃ of dry heat sterilizations of aluminium-plastic cap are 2 hours.
2, sample preparation:
(1) indoorly in the sterile working accurately takes by weighing aseptic aztreonam and arginine by recipe quantity.
(2) press aztreonam (C
13H
17N
5O
8S
2) calculate the 0.5g/ bottle, arginine 0.4g/ bottle, aseptic subpackaged respectively in antibiotic glass bottle.
(3) jump a queue, roll lid.
(4) finished product packing warehouse-in and censorship.
Embodiment 5
One, prescription is formed
This product is the sterilized powder that aztreonam is made; Press aztreonam (C
13H
17N
5O
8S
2) calculate, labelled amount is respectively 1.0g.
1, specification: 1.0g/ bottle
Aztreonam 1000g is (with C
13H
17N
5O
8S
2Meter)
Arginine 800g
Make 1000 bottles
Two, preparation technology
1, the processing of packaging material:
(1) after antibiotic glass bottle was used the ordinary water previous cleaning, the filterable water for injection recoil of reuse 0.2um was qualified, and aseptic compressed air dries up, and 320 ℃ of dry heat sterilizations are more than 25 minutes, and are standby;
(2) butyl rubber plug adds acid and boiled 30 minutes, is washed till neutrality with ordinary water, and the filterable water for injection recoil of reuse 0.2um is qualified, and aseptic compressed air dries up, and 120 ℃ of pressure sterilizings were dried after 2 hours, and are standby.
(3) 115 ℃ of-125 ℃ of dry heat sterilizations of aluminium-plastic cap are 2 hours.
2, sample preparation:
(1) indoorly in the sterile working accurately takes by weighing aseptic aztreonam and arginine by recipe quantity.
(2) press aztreonam (C
13H
17N
5O
8S
2) calculate the 1.0g/ bottle, arginine 0.8g/ bottle, aseptic subpackaged respectively in antibiotic glass bottle.
(3) jump a queue, roll lid.
(4) finished product packing warehouse-in and censorship.
Embodiment 6
One, prescription is formed
This product is the sterilized powder that aztreonam is made; Press aztreonam (C
13H
17N
5O
8S
2) calculate, labelled amount is respectively 2.0g.
1, specification: 2.0g/ bottle
Aztreonam 2000g is (with C
13H
17N
5O
8S
2Meter)
Arginine 1600g
Make 1000 bottles
Two, preparation technology
1, the processing of packaging material:
(1) after antibiotic glass bottle was used the ordinary water previous cleaning, the filterable water for injection recoil of reuse 0.2um was qualified, and aseptic compressed air dries up, and 320 ℃ of dry heat sterilizations are more than 25 minutes, and are standby;
(2) butyl rubber plug adds acid and boiled 30 minutes, is washed till neutrality with ordinary water, and the filterable water for injection recoil of reuse 0.2um is qualified, and aseptic compressed air dries up, and 120 ℃ of pressure sterilizings were dried after 2 hours, and are standby.
(3) 115 ℃ of-125 ℃ of dry heat sterilizations of aluminium-plastic cap are 2 hours.
2, sample preparation:
(1) indoorly in the sterile working accurately takes by weighing aseptic aztreonam and arginine by recipe quantity.
(2) press aztreonam (C
13H
17N
5O
8S
2) calculate the 2.0g/ bottle, aseptic subpackaged respectively in antibiotic glass bottle.
(3) jump a queue, roll lid.
(4) finished product packing warehouse-in and censorship.
Embodiment 7
All the other steps are all identical with embodiment 4, and different is that aseptic aztreonam and arginic weight ratio are 1: 1, i.e. specification: the 0.5g/ bottle
Aztreonam 500g is (with C
13H
17N
5O
8S
2Meter)
Arginine 500g
Make 1000 bottles
Embodiment 8
All the other steps are all identical with embodiment 5, and different is that aseptic aztreonam and arginic weight ratio are 1.5: 1, i.e. the 1.0g/ bottle
Aztreonam 1000g is (with C
13H
17N
5O
8S
2Meter)
Arginine 666g
Make 1000 bottles
Embodiment 9
All the other steps are all identical with embodiment 6, and different is that aseptic aztreonam and arginic weight ratio are 1.4: 1, i.e. specification: the 2.0g/ bottle
Aztreonam 2000g is (with C
13H
17N
5O
8S
2Meter)
Arginine 1428g
Make 1000 bottles
Test example 1
The correlated quality that this test example relates to aseptic aztreonam powder detects
One, sample and reference substance source
Test sample: test routine lot number: 031020 (according to the aseptic aztreonam powder of embodiment 1 preparation), 031027 (according to the aseptic aztreonam powder of embodiment 2 preparations), 031104 (according to the aseptic aztreonam powder of embodiment 3 preparations)
The quality contrast is the refining gained of listing aztreonam for injection extracting with the aztreonam reference substance; Assay is the American Pharmacopeia reference substance with the aztreonam reference substance.
Two, character
1. outward appearance this product three batch samples are white crystalline powder.
2. drawing moist test, to get this product an amount of, accurately claims surely, puts that moisture absorption has reached in the saturated flat type weighing botle in the closed environment of relative humidity 92.5%, and place under above-mentioned condition, in the different time sampling, measures the wet amount (%) of drawing of test sample.The results are shown in Table 1.
Table 1 aztreonam draws moist result of the test (%)
Aztreonam was placed 48 hours in relative humidity 92.5% environment, drew wet amount and was lower than 5%, and appearance character becomes pink.
Three, differentiate
1. infrared spectrum differentiates that the infrared Absorption collection of illustrative plates of this product is consistent with the infrared Absorption collection of illustrative plates of reference substance.2.HPLC differentiate that the retention time of test sample main peak is consistent with the retention time of reference substance main peak, the results are shown in Table 2 in the chromatogram that writes down under the assay item.
Table 2 aztreonam HPLC identification result
| Lot number | ??031020 | ??031027 | ??031104 | Reference substance |
| Retention time (min) | ??9.88 | ??9.73 | ??9.74 | ??9.80 |
Four, check the inspection of this product having been carried out projects such as the clarity of acidity, solution and color, moisture, residue on ignition, heavy metal, aseptic, bacterial endotoxin, organic solvent residual, related substance.
1. acidity is got this product and reference substance with reference to the JP14 standard, adds water respectively and makes the solution that contains 5mg among every 1ml, measures (two appendix VI of Chinese Pharmacopoeia version in 2005 H) pH value in accordance with the law, the results are shown in Table 3.
Table 3 aztreonam acidity assaying result
| Lot number | ??031020 | ??031027 | ??031104 | Reference substance |
| Acidity (pH value) | ??2.6 | ??2.4 | ??2.3 | ??2.5 |
As seen the pH value of this product solution is between 2.2～2.8.
2. the clarity of solution and color are got this product and each 0.5g of reference substance, add arginine solution (23.4 → 1000) (promptly taking by weighing 23.4g arginine solid is dissolved in water to 1000ml) 5ml dissolving respectively after, the results are shown in Table 4.
The clarity of table 4 aztreonam solution and colour of solution result
| Lot number | ??031020 | ??031027 | ??031104 | Reference substance |
| The clarity of solution | Clarification | Clarification | Clarification | Clarification |
| The color of solution | Less than yellow No. 2 | Less than yellow No. 2 | Less than yellow No. 2 | Less than yellow No. 2 |
As seen the color of this product is all less than yellow No. 2.
3. moisture is got this product, measures according to aquametry (two appendix VIII of Chinese Pharmacopoeia version in 2005 M), the results are shown in Table 5.
Table 5 aztreonam moisture check result
| Lot number | ??031020 | ??031027 | ??031104 | Reference substance |
| Moisture (%) | ??0.7 | ??0.8 | ??0.7 | ??0.9 |
As seen, the moisture of this product is all smaller or equal to 0.8%, and water content is low, helps the aseptic aztreonam among the present invention and the storage of aztreonam composition.
4. residue on ignition is got this product 1.0g, checks (two appendix VIII of Chinese Pharmacopoeia version in 2005 N) to the results are shown in Table 6 in accordance with the law.
Table 6 aztreonam residue on ignition check result
| Lot number | ??031020 | ??031027 | ??031104 |
| Residue on ignition (%) | ??0.05 | ??0.03 | ??0.04 |
As seen, the residue on ignition of three batch samples is all less than 0.1%.
5. the aseptic this product of getting, add through the arginine solution (23.4 → 1000) (promptly taking by weighing 23.4g arginine solid is dissolved in water to 1000ml) of sterilization and make the solution that contains aztreonam 0.1g among every 1ml, join again in 100ml 0.9% aseptic sodium chloride solution, after the membrane-filter procedure processing, check (two appendix XI of Chinese Pharmacopoeia version in 2005 H) in accordance with the law.The results are shown in Table 7.
Table 7 aztreonam sterility test result
| Lot number | ??031020 | ??031027 | ??031104 |
| Aseptic | Up to specification | Up to specification | Up to specification |
The test sample bacterial endotoxin is checked
Get this product, measure according to bacterial endotoxins test (two appendix XI of Chinese Pharmacopoeia version in 2005 E).The results are shown in Table 8.
Table 8 aztreonam bacterial endotoxin check result
| Lot number | ??031020 | ??031027 | ??031104 |
| Bacterial endotoxin | Less than 0.17EU/mg | Less than 0.17EU/mg | Less than 0.17EU/mg |
6. organic residual solvent inspection this product is used ethanol in subtractive process, considers from the clinical application safety angle, and this product used organic solvent in building-up process is studied aspect the pharmacy quality control.According to Determination of Residual Organic Solvents algoscopy (two appendix VIII of Chinese Pharmacopoeia version in 2005 P), adopt gas chromatography (two appendix VE of Chinese Pharmacopoeia version in 2005) to carrying out the content limit inspection by residual ethanol in this product.
6.1 chromatographic condition
Chromatograph GC-9790, Wenling, Zhejiang Fu Li Analytical Instrument Co., Ltd
Chromatographic column 2M * 3mm rustless steel chromatograph post
Column packing GDX-102, the 60-80 order
Detector FID Anastar chromatographic work station
Column temperature: 100 ℃;
Vapourizing temperature: 150 ℃;
Detector temperature: 150 ℃;
Carrier gas N
2, 30ml/min 0.1MPa
H
2，30ml/min?0.1MPa
Air 400ml/min 0.03MPa
Sample size 1 μ l amplifier sensitivity and decay 10
4* 1/4
6.2 the preparation ethanol limit that reaches contrast solution of determining of limit is decided to be 0.5%.
The preparation of ethanol contrast solution takes by weighing ethanol 50mg, puts in the 100ml measuring bottle, adds the dimethyl sulfoxine dissolving and is diluted to scale, shakes up, promptly.
Dimethyl sulfoxine is got in the blank solution preparation, promptly.
6.4 the test sample organic solvent residual is checked
This product 1.0g is got in the preparation of need testing solution, and accurate the title decides, and puts in the 10ml measuring bottle, adds the dimethyl sulfoxine dissolving and is diluted to scale, shakes up, as need testing solution.
Get need testing solution 1 μ l, inject gas chromatograph, record chromatogram, testing result such as table 9.
The organic residual check result of table 9 aztreonam
| Lot number | ??031020 | ??031027 | ??031104 |
| Testing result | Up to specification | Up to specification | Up to specification |
The ethanol residual quantity is all up to specification in the need testing solution.Simultaneously other organic solvents that relate in the aztreonam preparation process are detected, all up to specification.
7, the mensuration of sample related substance
This product and reference substance an amount of (being equivalent to aztreonam 25mg) are got in the preparation of need testing solution, and accurate the title decides, and puts in the 25ml measuring bottle, add mobile phase and make dissolving in right amount and be diluted to scale, shake up, as need testing solution.
The preparation precision of contrast solution pipettes need testing solution 1ml, puts in the 100ml measuring bottle, adds mobile phase and is diluted to scale, shakes up, in contrast solution.
Get contrast solution 20 μ l and inject chromatograph of liquid, regulate detection sensitivity, the peak height that makes the main constituent chromatographic peak is 10%～20% of a full scale; Get each 20 μ l of need testing solution and contrast solution again and inject chromatograph of liquid, the record chromatogram is to 2 times of main constituent peak retention time.In the need testing solution chromatogram as the isomer peak with impurity peaks is arranged, measure respectively isomer peak and other each impurity peak area and, compare with contrast solution main peak area, the results are shown in Table 10.
Table 10 aztreonam related substance check result
| Lot number | ??031020 | ??031027 | ??031104 | Reference substance |
| Related substance (%) | ??1.44 | ??1.46 | ??1.49 | ??1.55 |
| Transisomer (%) | ??0.37 | ??0.38 | ??0.36 | ??0.48 |
As seen from the above table, this product 3 batch sample related substances are all less than 3.0%, and isomer is all less than 1.0%.
Five, assay is according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2005 D)
It is an amount of that instrument and chromatographic condition are got this product with the related substance inspection, accurately claims surely, adds mobile phase dissolving and dilution and make the solution that contains aztreonam 0.2mg among every 1ml, shakes up, as need testing solution; It is an amount of that other gets the aztreonam reference substance, and accurate the title decides, and adds mobile phase dissolving and dilution and make the solution that contains 0.2mg among every 1ml, shakes up, in contrast product solution.Get each 20 μ l of above-mentioned two kinds of solution, inject chromatograph of liquid, the record chromatogram is measured peak area, calculates content with external standard method.Its result is shown in 11.
Table 11 aztreonam assay result
| Lot number | ??031020 | ??031027 | ??031104 |
| Content (% is in anhydride) | ??95.0 | ??93.5 | ??94.2 |
Press anhydride and calculate, three batch samples contain aztreonam all more than 93%.
Test example 2
This test example relates to synthetic method to the purity of aseptic aztreonam and the influence of yield
One, synthetic method is to the influence of aztreonam purity and yield
(1) in the synthesis step of aztreonam, adopt among the embodiment 1 among the present invention TAEM is dropped in the triethylamine mixed solution of MSA, wherein rate of addition is that the TAEM that per minute drips is 1/240 of a total amount, and resulting aztreonam crude product is a sample 1; All the other are identical with embodiment 1, and wherein rate of addition is that the TAEM that per minute drips is 1/120 of a total amount, and resulting aztreonam crude product is a sample 2; All the other are identical with embodiment 1, and wherein rate of addition is that the TAEM that per minute drips is 1/360 of a total amount, and resulting aztreonam crude product is a sample 3; And the reference substance employing directly mixes TAEM, MSA and these three kinds of materials of triethylamine, and all the other are identical with embodiment 1, and resulting aztreonam crude product is a reference substance 1.Comparative result is as shown in table 12:
Table 12 rate of addition is to the influence of the yield of aztreonam crude product
| Sequence number | Sample 1 | Sample 2 | Sample 3 | Reference substance |
| Rate of addition | Per minute drips 1/240 of total amount | Per minute drips 1/120 of total amount | Per minute drips 1/360 of total amount | Reactant is directly mixed |
| Aztreonam crude product weight | ??2.23 | ??2.15 | ??2.24 | ??2.05 |
| Yield | ??83.5％ | ??80.5％ | ??83.8％ | ??76.7％ |
As can be seen from the above table, adopt the method that drips to add TAEM, make the yield of aztreonam crude product be greatly improved.
(2) preparation process of the refining and aseptic aztreonam of aztreonam is to the yield of aseptic aztreonam and the influence of purity.
In the subtractive process of aztreonam, among the embodiment 1, adopt the HP-20 resin column that aztreonam is made with extra care among the present invention, resulting aztreonam elaboration is a sample 4; All the other are identical with embodiment 1, and different is that the speed that stirs when the dissolving aztreonam is 150 rev/mins, and resulting aztreonam elaboration is a sample 5; All the other are identical with embodiment 1, and different is that the speed that stirs when the dissolving aztreonam is 190 rev/mins, and resulting aztreonam elaboration is a sample 6; All the other are identical with embodiment 1, adopting the method for carrying out recrystallization with ethanol of prior art to make with extra care in the subtractive process of different is aztreonam (is added to the aztreonam crude product in the dehydrated alcohol, be heated to 55 ℃, after stirring made its dissolving, mixing speed was 180 rev/mins, stopped heating, stirred 3 hours, be chilled to 0 ℃, filter, drying obtains the aztreonam elaboration) resulting aztreonam elaboration is reference substance 2.
Table 13 process for purification is to the influence of aztreonam elaboration yield and aseptic aztreonam yield and purity
| Sequence number | Sample 4 | Sample 5 | Sample 6 | Reference substance 2 |
| Mixing speed | 180 rev/mins | 150 rev/mins | 190 rev/mins | 180 rev/mins |
| Aztreonam elaboration weight | ??2.11 | ??2.05 | ??1.99 | ??1.98 |
| The elaboration yield | ??94.6％ | ??91.9％ | ??89.2 | ??88.8％ |
| Sequence number | Sample 4 | Sample 5 | Sample 6 | Reference substance 2 |
| The weight of aseptic aztreonam | ??1.85 | ??1.78 | ??1.81 | ??1.68 |
| The yield of aseptic aztreonam | ??92.0％ | ??91.3％ | ??91.0％ | ??84.8％ |
| The purity of aseptic aztreonam | ??95.5％ | ??93.8％ | ??94.7％ | ??89.9％ |
As can be seen from the above table, all the method than prior art is all high to utilize the yield of the prepared aseptic aztreonam that goes out of method of the present invention and purity.
Test example 3
What this test example related to is aztreonam composition of the present invention (aztreonam for injection powder) influence factor's investigation.
1, sample preparation: the method according to embodiment 4 is prepared respectively
2, setting-out: sample is placed room temperature (25 ℃) respectively, under high temperature (60 ℃), high temperature (40 ℃), relative humidity 75%, relative humidity 92.5% and six kinds of conditions of illumination 4500Lx.
3, investigate the result: investigate every index in sampling in the 5th day, 10 days, and be contrast, the results are shown in down with 0 day result:
Table 14 factors influencing (specification 1)
| Condition | Time (my god) | Acid-base value | The clarity of solution | Moisture (%) | Transisomer | Related substance (%) | Content (%) |
| ??-- | ??0 | ??6.0 | Clarify colourless | ??0.7 | ??0.37 | ??1.44 | ??95.58％ |
| 25 ℃ of room temperatures | ??5 | ??6.0 | Clarify colourless | ??0.7 | ??0.37 | ??1.44 | ??95.58％ |
| ??10 | ??6.0 | Clarify colourless | ??0.7 | ??0.37 | ??1.47 | ??95.56％ | |
| 40 ℃ of high temperature | ??5 | ??6.0 | Clarify colourless | ??0.7 | ??0.37 | ??1.45 | ??95.57％ |
| ??10 | ??6.1 | Clarify colourless | ??0.6 | ??0.37 | ??1.48 | ??95.55％ | |
| 60 ℃ of high temperature | ??5 | ??6.1 | Clarify colourless | ??0.6 | ??0.37 | ??1.47 | ??95.56 |
| ??10 | ??6.1 | Clarify colourless | ??0.6 | ??0.38 | ??1.52 | ??94.81％ | |
| Relative humidity 75% | ??5 | ??6.0 | Clarify colourless | ??0.8 | ??0.37 | ??1.44 | ??95.58％ |
| ??10 | ??5.9 | Clarify colourless | ??0.8 | ??0.37 | ??1.45 | ??95.57％ |
| Condition | Time (my god) | Acid-base value | The clarity of solution | Moisture (%) | Transisomer | Related substance (%) | Content (%) |
| Relative humidity 92.5% | ??5 | ??5.9 | Clarify colourless | ??0.8 | ??0.37 | ??1.44 | ??95.58％ |
| ??10 | ??5.9 | Clarify colourless | ??0.9 | ??0.39 | ??1.45 | ??95.57％ | |
| Illumination 4500Lx | ??5 | ??6.0 | Clarify colourless | ??0.7 | ??0.38 | ??1.44 | ??95.58％ |
| ??10 | ??6.0 | Clarify colourless | ??0.8 | ??0.39 | ??1.48 | ??95.55％ |
Therefore this product every index under 25 ℃ of conditions of room temperature does not have significant change; Placed 5 days, 10 days under the condition of relative humidity 75%, relative humidity 92.5% and illumination 4500Lx, except that related substance slightly raise, all the other every indexs did not have significant change; Under 40 ℃ of high temperature, 60 ℃ of conditions, related substance raises very fast, so determine the holding conditions of this product is: airtight, and in preservation below 25 ℃.
Respectively the product of other embodiment is tested accordingly, its result is as above-mentioned experimental result.
Claims (10)
1. an aztreonam composition is characterized in that, comprises aseptic aztreonam and arginine in the described compositions, and aseptic aztreonam and arginic weight ratio are 1: 1～1.5: 1; Aseptic aztreonam and arginic weight ratio are 1.25: 1 in the preferred described compositions; Described aseptic aztreonam weight is in C13H17N5O8S2.
2. aztreonam composition according to claim 1 is characterized in that, described aseptic aztreonam is prepared by following method:
(1) aztreonam is synthetic;
Earlier with triethylamine and dimethyl sulfoxide mix homogeneously, obtain the triethylamine mixed solution, MSA is added in the above-mentioned mixed solution again, obtain the MSA mixed solution, under stirring condition, TAEM is dropped in the above-mentioned MSA mixed solution, dropwise the back and continue reaction 5-10 hour, TLC check reaction finishes, and obtains reactant liquor;
Reactant liquor is cooled off, add entry and concentrated hydrochloric acid successively, 0 ℃ of-5 ℃ of stirring, centrifugalize, washing obtains the aztreonam crude product after the drying;
(2) aztreonam is refining
The aztreonam crude product is made with extra care, obtained the aztreonam elaboration;
(3) preparation of aseptic aztreonam
Aztreonam elaboration at step (2) gained carries out aseptic process, obtains aseptic aztreonam.
3. aztreonam composition according to claim 2, it is characterized in that, in the described step (1), when dropping to TAEM in the MSA mixed solution, described dropping is at the uniform velocity dripping, and the speed of dropping is that the TAEM amount that per minute drips is 1/360～1/120 of TAEM total amount.
4. aztreonam composition according to claim 2 is characterized in that, described step (2) specifically comprises:
The aztreonam crude product is added in the reactor, adds dehydrated alcohol, be cooled to 0 ℃-5 ℃, add triethylamine again, after the stirring and dissolving, preferred its speed of described stirring is 150-180 rev/min, obtain the aztreonam crude product solution, the aztreonam crude product solution is crossed the HP-20 resin column at ambient temperature, and the gained solution temperature rises to room temperature, uses the hydrochloric acid adjust pH to 1.5-2.5, and then slowly be cooled to 0 ℃-5 ℃, behind the crystallize, washing is drying to obtain the aztreonam elaboration.
5. aztreonam composition according to claim 4 is characterized in that, described slow cooling is that per minute descends 1 ℃-3 ℃, and preferred described slow cooling is that per minute descends 1 ℃-2 ℃.
6. aztreonam composition according to claim 2 is characterized in that, described step (3) specifically comprises:
In the aztreonam elaboration of step (2) gained, add dehydrated alcohol, cooling, add triethylamine again, treat aztreonam dissolving after, add active carbon and handle, carry out sucking filtration through 0.22 μ m filter membrane then, the filtrate that obtains is transferred in the aseptic reactor, regulates pH value to 1.5-2.5 with hydrochloric acid, cooling, in the time of 0 ℃-5 ℃, under stirring condition, separate out crystal, will promptly obtain described aseptic aztreonam after crystal washing, the drying.
7. aztreonam composition according to claim 6 is characterized in that, the consumption of described triethylamine is the 20-30% of aztreonam elaboration weight, and the consumption of preferred described triethylamine is the 22-24% of aztreonam elaboration weight; The addition of dehydrated alcohol is 3-6 a times of aztreonam elaboration weight; The addition of preferred dehydrated alcohol is 5 times of aztreonam elaboration weight.
8. aztreonam composition according to claim 6 is characterized in that, the consumption of described active carbon is the 1-2% of aztreonam elaboration weight, and the consumption of preferred described active carbon is 1.5% of an aztreonam elaboration weight.
9. an aztreonam sterile powder injection is characterized in that, described sterile powder injection comprises any described aztreonam composition of claim 1-8.
10. a method for preparing the described aztreonam sterile powder injection of claim 9 is characterized in that, described method comprises: indoor in the sterile working, take by weighing aseptic aztreonam according to recipe quantity, and aseptic subpackaged in antibiotic glass bottle, and jump a queue, roll lid promptly.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102119924A (en) * | 2011-01-24 | 2011-07-13 | 山东鲁抗立科药物化学有限公司 | Monodisperse nano aztreonam liposome preparation and preparation method thereof |
| CN102119924B (en) * | 2011-01-24 | 2012-09-05 | 山东鲁抗立科药物化学有限公司 | Monodisperse nano aztreonam liposome preparation and preparation method thereof |
| CN102218059A (en) * | 2011-04-07 | 2011-10-19 | 罗诚 | Aztreonam-compound-containing composition |
| CN102218059B (en) * | 2011-04-07 | 2012-07-25 | 罗诚 | Aztreonam-compound-containing composition |
| CN102552151A (en) * | 2011-12-16 | 2012-07-11 | 苏州二叶制药有限公司 | Preparation technology of aztreonam for injection |
| CN104071363A (en) * | 2014-07-04 | 2014-10-01 | 海南通用康力制药有限公司 | Arginine aspirin powder injection split filling process and automatic split filing system thereof |
| CN105017241A (en) * | 2015-06-24 | 2015-11-04 | 山东罗欣药业集团股份有限公司 | Aztreonam compound and preparation thereof |
| CN105017241B (en) * | 2015-06-24 | 2018-03-06 | 山东罗欣药业集团股份有限公司 | A kind of aztreonam compound and its preparation |
| CN105055406A (en) * | 2015-08-10 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Antibacterial drug aztreonam composition |
| CN105646475A (en) * | 2016-03-04 | 2016-06-08 | 中山福运生物科技有限公司 | Method for producing beta-aztreonam sterile powder |
| CN113876722A (en) * | 2021-11-04 | 2022-01-04 | 海南皇隆制药股份有限公司 | Aztreonam for injection and preparation method thereof |
| CN113876722B (en) * | 2021-11-04 | 2022-12-02 | 海南皇隆制药股份有限公司 | Aztreonam for injection and preparation method thereof |
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| CN101695489B (en) | 2011-11-02 |
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