CN102875576A - Synthesis of antibiotic ceftazidime, ceftazidime for injection and preparation method of ceftazidime - Google Patents
Synthesis of antibiotic ceftazidime, ceftazidime for injection and preparation method of ceftazidime Download PDFInfo
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- CN102875576A CN102875576A CN2012104291454A CN201210429145A CN102875576A CN 102875576 A CN102875576 A CN 102875576A CN 2012104291454 A CN2012104291454 A CN 2012104291454A CN 201210429145 A CN201210429145 A CN 201210429145A CN 102875576 A CN102875576 A CN 102875576A
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Abstract
The invention discloses synthesis of antibiotic ceftazidime, ceftazidime for injection and a preparation method of ceftazidime. 7-ACA is served as a raw material, silanization and iodo reaction are carried out, and pyridine, hydrochloric acid and water are added to obtain TA (7-PyCA); ceftazidime active ester is added in an organic solvent and an inorganic solvent to obtain new modified ceftazidime active ester; TA is added in new modified ceftazidime active ester, organic mixed solvent and triethylamine are added, then acid water and an acetone solution are added to obtain TC (ceftazidime dihydrochloride), and ceftazidime is obtained through the reaction. The synthesis of ceftazidime provided by the invention has the advantages that ceftazidime is high in yield, operation processes are simplified, production cost is low, ceftazidime is applicable to industrial production, obtained products can be stored for a long time, a structure is stable, and impurity content is low. Ceftazidime for injection has the advantages of being moderate in grain size, good in clarity, less in impurity content, excellent in quality, stable and the like, and is high in split charging efficiency in production, good in content uniformity, high in medicine dissolution rate in clinical application and good in dissolubility.
Description
Technical field
The invention belongs to the antibiotic medicine preparation field, relate in particular to synthetic, ceftazidime for inj of a kind of antibiotic ceftazime and preparation method thereof, belong to the antibiotic medicine preparation field.
Background technology
Ceftazime (Ceftazidime) is the third generation cephalosporin of GlaxoSmithKline PLC company wound; obtain FDA approval listing in July, 1985; the ceftazime chemistry is by name: (6R; 7R)-7-[[(2-amino-4-thiazolyl)-[(1-carboxyl-1-methyl ethoxy) imino-] ethanoyl] amino]-2-carboxyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-3-picoline inner salt pentahydrate, its structural formula is as follows:
Ceftazime has following characteristics: 1, super wide spectrum third-generation cephalosporin; 2, the anti Bacillus pyocyaneu Flugge activity is the strongest, is to treat at present the first-selected medication of charrin's disease; 3, the first-selected recommended drug of severe infections; 4, the first-selected medication of hot neutropenia cancer patient; 5, β-lactamase is had high stability, seldom have under rational Application and the generation of medicine situation, rate of side effects is low.Be used for the treatment of septicemia, lower respiratory infection, abdominal cavity and biliary tract infection, complicacy urinary tract infections and serious skin soft-tissue infection etc. due to the responsive gram negative bacilli.Central nervous system infection is particularly applicable due to immune deficiency person's infection, nosocomial infection and the gram negative bacilli that causes for the several drug resistance gram negative bacilli or the Pseudomonas aeruginosa.
The synthetic method of the ceftazime of present bibliographical information, generally be that (or GCLE is raw material take 7-ACA as raw material, the reaction scheme that 7-ACA is raw material only is discussed) here, pass through Silanization reaction, iodide reaction, react with pyridine, salify in water is situated between obtains 7-PyCA, adds the reaction of ceftazime side-chain acid and obtains the ceftazime tert-butyl ester, continuation reaction in water is situated between obtains the ceftazime dihydrochloride, and the process reaction soluble in water of ceftazime dihydrochloride is obtained ceftazime without hydrate.In this route, 7-APCA and ceftazime side-chain acid reaction yield is low, cost is high, the gained ceftazime is unstable, foreign matter content is high.
Ceftazime normally uses with the form of ceftazidime for inj sterilized powder clinically.Common ceftazidime for inj is that ceftazime and pharmaceutical excipient mix aseptic subpackaged forming, and exists grain diameter larger, mixes inhomogeneously, and content uniformity is large, causes that effective active composition ceftazime is not easy accurate quantitative analysis in the use procedure.
Summary of the invention
For addressing the above problem, the first purpose of the present invention is for providing a kind of synthetic method that is more suitable for large-scale industrial production, ceftazime that quality product is higher.
The second purpose of the present invention is to provide ceftazidime for inj, clarity is good after this ceftazidime for inj dissolving, good stability in the aqueous solution, and the packing efficient in can guaranteeing to produce is high, content uniformity is little, guarantee that again the medicine dissolution rate is fast in the clinical application, solvability is good.
The 3rd purpose of the present invention is to provide the preparation method of ceftazidime for inj, and the method packing is effective, and solvability is good, and is simple to operation.
Ceftazime synthetic method technical scheme provided by the invention comprises following processing step:
(ⅰ) take the ceftazime active ester as raw material, add organic solvent, inorganic solvent, the control temperature of reaction adds reaction solvent again, obtains improved new ceftazime active ester, and the temperature of reaction is 20 ℃ ~ 25 ℃, and optimum temps is 21 ℃ ~ 22 ℃.
(ⅱ) with TA(7-PyCA) add the improved new ceftazime active ester that obtains in the step (ⅰ), then add successively organic solvent, triethylamine (as catalyzer), add again sour water, acetone soln after the reaction, filtration, washing, drying obtain TC(ceftazime dihydrochloride), the temperature of reaction is 1 ℃ ~ 10 ℃, and optimum temps is 4 ℃ ~ 5 ℃.
The compound TC(ceftazime dihydrochloride that (ⅲ) in step (ⅱ), obtains) in, regulates the pH value, add macroporous resin, carry out again wash-out, separate obtaining ceftazime.
Wherein, the TA described in the step (ⅱ) adopts following method to be prepared from:
(1), take 7-ACA as raw material, add hexamethyldisilazane, trimethylchlorosilane carries out Silanization reaction, obtains compound 1, the temperature of Silanization reaction is 20 ℃ ~ 80 ℃, optimum temps is 40 ℃ ~ 50 ℃.
(2) add Iodotrimethylsilane in the compound 1 that obtains in the step (1) and carry out iodide reaction, obtain compound 2, the temperature of iodide reaction is 10 ℃ ~ 20 ℃, and optimum temps is 12 ℃ ~ 15 ℃.
(3) pyridine is added in the compound 2 that obtains in the step (2), reaction obtains compound 3, and the temperature of reaction is 0 ℃ ~ 10 ℃, and optimum temps is 3 ℃ ~ 5 ℃.
(4) in the compound 3 that obtains in the step (3), add successively the mixed solvent of methyl alcohol, hydrochloric acid and water, salify obtains TA(7-PyCA in water is situated between), the temperature of reaction is 0 ℃ ~ 20 ℃, optimum temps is 10 ℃ ~ 15 ℃.
Organic solvent in the described processing step (ⅰ) is preferably anhydrous formic acid, anhydrous acetic acid, tartrate, citric acid, oxalic acid, Whitfield's ointment, methylsulfonic acid, triethylamine, toxilic acid, acetone, phenylformic acid, oxalic acid, methylene dichloride, N, the mixture of one or more in dinethylformamide (DMF), the tetrahydrofuran (THF), more preferably anhydrous formic acid; Add ceftazime active ester and organic solvent mass ratio be preferably 1:0.5-1:1, be preferably 1:0.7.
Inorganic solvent in the described processing step (ⅰ) is preferably one or more the mixture in sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, the carbonic acid, hydrochloric acid more preferably, add ceftazime active ester and inorganic solvent mass ratio be preferably 1:1.0-1:2.0,1:1.4 more preferably.
Reaction solvent in the described processing step (ⅰ) is preferably acetone, N, dinethylformamide (DMF), acetonitrile, tetrahydrofuran (THF), methylene dichloride, N, the mixture of one or more in N-N,N-DIMETHYLACETAMIDE (DMAC), ethylene dichloride, the chloroform, more preferably acetone.
Described organic solvent in the described processing step (ⅱ) is preferably triethylamine, Trimethylamine 99, acetone, methyl alcohol, ethanol, phenylformic acid, oxalic acid, methylene dichloride, ethylene dichloride, N, the mixture of one or more in dinethylformamide (DMF), N,N-dimethylacetamide (DMAC), acetonitrile, the tetrahydrofuran (THF).
Described organic solvent in the described processing step (ⅱ) is the mixed solvent of methylene dichloride and methyl alcohol more preferably, and the mass ratio of this mixed solvent is preferably 1:0.01 ~ 0.1, more preferably 1:0.054.
Described sour water in the described processing step (ⅱ) is preferably one or more and the mixing solutions of water, the more preferably mixing solutions of hydrochloric acid and water in sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, the carbonic acid.
The synthetic route of described ceftazime is as follows:
Advantage of the present invention: the ceftazime active ester is transformed first, be hydrolyzed to carboxyl, then directly and TA(7-PyCA) reaction obtains TC(ceftazime dihydrochloride), the synthetic ceftazime tert-butyl ester reaches synthetic route to adopt simple hydrolysis reaction to substitute in the past, with respect to yield was low in the past, the large synthetic route of reaction control difficulty, simplified operating procedure, improved the single step yield, also shorten the production cycle, effectively reduced energy consumption and material consumption, reached energy-saving and emission-reduction, reduce production costs, improve the stability of product, reduced foreign matter content, greatly promoted quality product and suitable large-scale industrial production.
The present invention also provides the preparation method of ceftazidime for inj and ceftazidime for inj.
Ceftazidime for inj contains above-mentioned ceftazime and pharmaceutical excipient, and pharmaceutical excipient is a kind of in yellow soda ash, the arginine, and weight ratio is 3 ~ 10:1.
The particle diameter of ceftazidime for inj is 38～75um.
The preparation method of ceftazidime for inj comprises raw materials medicine ceftazime and with the bulk drug ceftazime with after containing yellow soda ash or arginic pharmaceutical excipient and pulverizing, carry out aseptic subpackaged according to weight ratio 3 ~ 10:1 mixing, wherein, and pharmaceutical excipient is pulverized, carry out aseptic subpackaged may further comprise the steps after mixing again:
1) crush and screen: the aseptic bulk drug ceftazime that above-mentioned steps 1-7 is synthetic and contain yellow soda ash or arginic pharmaceutical excipient is pulverized, screening, mix according to weight ratio 3 ~ 10:1, obtain the ceftazime mixture of particle diameter 38～75um;
2) aseptic subpackaged and moulding plug: within sterile workshop is packed the ceftazime mixture of particle diameter 38～75um into aseptic vial, cover aseptic plug;
3) roll lid: aluminium-plastic combined cover is pressed into step 2) aseptic plug on;
4) packing: send into label sticking machine labeling, packing through travelling belt through the qualified step 3) product of lamp inspection.
Ceftazidime for inj provided by the invention and preparation method thereof has following beneficial effect:
1. the ceftazidime for inj of the specified particle diameter that makes is pulverized, mixed to bulk drug ceftazime and the pharmaceutical excipient that is made by technical solution of the present invention, purity is high, the content of impurity is low especially, quality better more stable, clarity is better, the defectives such as regular injection is low with the existing drugs packaging efficient of ceftazime, content lack of homogeneity be can solve, production efficiency and quality product guaranteed.
2. among the present invention bulk drug ceftazime and pharmaceutical excipient are ground into particle diameter 38～75um, there is not the electrostatic adhesion phenomenon, easily packing, and so that the mixed powder good uniformity, redissolve soon, and clarity is good after redissolving, mobile better in minute process of assembling, content is even, without obvious content uniformity.
3. preparation method's technique of ceftazidime for inj of the present invention is simple, energy consumption is low, low for equipment requirements, with low cost, be suitable for large-scale industrial production and application, be with a wide range of applications.
Embodiment
Embodiment 1
Synthesizing TA(7-PyCA)
In flask, add 7-ACA 55g, hexamethyldisilane 45g, promoting agent trimethylchlorosilane 1ml, 40 ℃ ~ 50 ℃ of control temperature, insulation reaction 4 hours obtains compound 1.
In compound 1, with 50 ~ 60 minutes slow Iodotrimethylsilane 65g that drip, 12 ℃ ~ 15 ℃ of control charge temperatures, insulation reaction 2 hours obtains compound 2.
In flask, with 40 ~ 45 minutes slow pyridine 35g that drip, 3 ℃ ~ 5 ℃ of control temperature, insulation reaction 1 hour obtains compound 3.
In compound 3, with 60 minutes slow methyl alcohol 45g that drip, 10 ℃ ~ 15 ℃ of control temperature, add the mixing solutions that 100g hydrochloric acid and 100g water form, stirred 30 minutes, carried out growing the grain 30 minutes, continue to stir 2 hours, obtain compound TA(7-PyCA), mass yield is 1.30%.
The transformation of ceftazime active ester
In flask, add anhydrous formic acid 42g, hydrochloric acid 84g, with 30 minutes slow ceftazime active ester 60g that add, 21 ℃ ~ 22 ℃ of control temperature, insulation reaction 2 hours adds acetone again, reaction obtains improved new ceftazime active ester, and mass yield is 0.85%.
Synthesizing TC(ceftazime dihydrochloride)
In flask, with 13g TA(7-PyCA) the improved new ceftazime active ester of adding 20g, add successively methylene dichloride 100g, methyl alcohol 5.4g, triethylamine 19g, 4 ℃ ~ 5 ℃ of control temperature were reacted 20 hours, add appropriate hydrochloric acid and water, acetone soln after the reaction, filter, add the washing with acetone drying, obtain compound TC(ceftazime dihydrochloride), weight yield is 1.55%, and purity is 99.6%.
The preparation of ceftazime
In flask, add TC(ceftazime dihydrochloride) 50g, regulate PH2.0 ~ 6.0, add macroporous resin, carry out again wash-out, separate obtaining ceftazime, mass yield is 0.85%.
Embodiment 2
Synthesizing TA(7-PyCA)
In flask, add 7-ACA 55g, hexamethyldisilane 45g, promoting agent trimethylchlorosilane 1ml, 20 ℃ ~ 30 ℃ of control temperature, insulation reaction 4 hours obtains compound 1.
In compound 1, with 50 ~ 60 minutes slow Iodotrimethylsilane 65g that drip, 10 ℃ ~ 11 ℃ of control charge temperatures, insulation reaction 2 hours obtains compound 2.
In flask, with 40 ~ 45 minutes slow pyridine 35g that drip, 0 ℃ ~ 3 ℃ of control temperature, insulation reaction 1 hour obtains compound 3.
In compound 3, with 60 minutes slow methyl alcohol 45g that drip, 0 ℃ ~ 5 ℃ of control temperature, add the mixing solutions that 100g hydrochloric acid and 100g water form, stirred 30 minutes, carried out growing the grain 30 minutes, continue to stir 2 hours, obtain compound TA(7-PyCA), mass yield is 1.30%.
The transformation of ceftazime active ester
In flask, add anhydrous acetic acid 40g, sulfuric acid 81g, with 30 minutes slow ceftazime active ester 60g that add, 20 ℃ ~ 21 ℃ of control temperature, insulation reaction 2 hours adds tetrahydrofuran (THF) again, reaction obtains improved new ceftazime active ester, and mass yield is 0.80%.
Synthesizing TC(ceftazime dihydrochloride)
In flask, with 13g TA(7-PyCA) add the improved new ceftazime active ester of 20g, add successively DMF (DMF) 90g, ethanol 6g, triethylamine 19g, 1 ℃ ~ 4 ℃ of control temperature, reacted 20 hours, and added an amount of sulfuric acid and water, acetone soln after the reaction, filter, add washing with acetone dry, obtain compound TC(ceftazime dihydrochloride), weight yield is 1.50%, purity is 98.6%.
The preparation of ceftazime
In flask, add TC(ceftazime dihydrochloride) 50g, regulate PH2.0 ~ 6.0, add macroporous resin, carry out again wash-out, separate obtaining ceftazime, mass yield is 0.84%.
Embodiment 3
Synthesizing TA(7-PyCA)
In flask, add 7-ACA 55g, hexamethyldisilane 45g, promoting agent trimethylchlorosilane 1ml, control temperature 60 C ~ 80 ℃, insulation reaction 4 hours obtains compound 1.
In compound 1, with 50 ~ 60 minutes slow Iodotrimethylsilane 65g that drip, 15 ℃ ~ 20 ℃ of control charge temperatures,, insulation reaction 2 hours obtains compound 2.
In flask, with 40 ~ 45 minutes slow pyridine 35g that drip, 8 ℃ ~ 10 ℃ of control temperature, insulation reaction 1 hour obtains compound 3.
In compound 3, with 60 minutes slow methyl alcohol 45g that drip, 15 ℃ ~ 20 ℃ of control temperature, add the mixing solutions that 100g hydrochloric acid and 100g water form, stirred 30 minutes, carried out growing the grain 30 minutes, continue to stir 2 hours, obtain compound TA(7-PyCA), mass yield is 1.29%.
The transformation of ceftazime active ester
In flask, add methylene dichloride 50g, tetrahydrofuran (THF) 75g, with 30 minutes slow ceftazime active ester 60g that add, 24 ℃ ~ 25 ℃ of control temperature, insulation reaction 2 hours adds ethylene dichloride again, and reaction obtains improved ceftazime active ester.
Synthesizing TC(ceftazime dihydrochloride)
In flask, with 13g TA(7-PyCA) the improved ceftazime active ester of adding 20g, add successively ethylene dichloride 110g, acetonitrile 4g, triethylamine 19g, 8 ℃ ~ 10 ℃ of control temperature were reacted 20 hours, add an amount of nitric acid and water, acetone soln after the reaction, filter, add the washing with acetone drying, obtain compound TC(ceftazime dihydrochloride), weight yield is 1.47%, and purity is 98.9%.
The preparation of ceftazime
In flask, add TC(ceftazime dihydrochloride) 50g, regulate PH2.0 ~ 6.0, add macroporous resin, carry out again wash-out, separate obtaining ceftazime, mass yield is 0.85%.
Example of formulations 1
1) crushes and screens: mix after the aseptic bulk drug ceftazime that will synthesize and pharmaceutical excipient yellow soda ash are pulverized respectively, sieved, obtain the ceftazime mixture of particle diameter 38 ~ 75um, weight ratio 9:1;
2) aseptic subpackaged and moulding plug: within sterile workshop was packed the ceftazime mixture of particle diameter 38 ~ 75um into aseptic vial, every bottled amount was that 2.0g(is with C
22H
22N
6O
7S
2Meter), cover aseptic plug;
3) roll lid: aluminium-plastic combined cover is pressed into step 2) aseptic plug on;
4) packing: send into label sticking machine labeling, packing through travelling belt through the qualified step 3) product of lamp inspection.
Example of formulations 2
1) crushes and screens: mix after the aseptic bulk drug ceftazime that will synthesize and pharmaceutical excipient arginine are pulverized respectively, sieved, obtain the ceftazime mixture of particle diameter 38 ~ 75um, weight ratio 3:1;
2) aseptic subpackaged and moulding plug: within sterile workshop was packed the ceftazime mixture of particle diameter 38 ~ 75um into aseptic vial, every bottled amount was that 0.5g(is with C
22H
22N
6O
7S
2Meter), cover aseptic plug;
3) roll lid: aluminium-plastic combined cover is pressed into step 2) aseptic plug on;
4) packing: send into label sticking machine labeling, packing through travelling belt through the qualified step 3) product of lamp inspection.
Example of formulations 3
1) crushes and screens: mix after the aseptic bulk drug ceftazime that will synthesize and pharmaceutical excipient yellow soda ash are pulverized respectively, sieved, obtain the ceftazime mixture of particle diameter 38 ~ 75um, weight ratio 10:1;
2) aseptic subpackaged and moulding plug: within sterile workshop was packed the ceftazime mixture of particle diameter 38 ~ 75um into aseptic vial, every bottled amount was that 1.5g(is with C
22H
22N
6O
7S
2Meter), cover aseptic plug;
3) roll lid: aluminium-plastic combined cover is pressed into step 2) aseptic plug on;
4) packing: send into label sticking machine labeling, packing through travelling belt through the qualified step 3) product of lamp inspection.
Example of formulations 4
1) crushes and screens: mix after the aseptic bulk drug ceftazime that will synthesize and pharmaceutical excipient arginine are pulverized respectively, sieved, obtain the ceftazime mixture of particle diameter 38 ~ 75um, weight ratio 4:1;
2) aseptic subpackaged and moulding plug: within sterile workshop was packed the ceftazime mixture of particle diameter 38 ~ 75um into aseptic vial, every bottled amount was that 1.0g(is with C
22H
22N
6O
7S
2Meter), cover aseptic plug;
3) roll lid: aluminium-plastic combined cover is pressed into step 2) aseptic plug on;
4) packing: send into label sticking machine labeling, packing through travelling belt through the qualified step 3) product of lamp inspection.
Effect embodiment
In order to understand better beneficial effect of the present invention, the below will illustrate essence of the present invention with various tests, but content of the present invention is not limited to this.
One main research
1, test item and detection method
Proterties: be white or off-white color crystalline powder.
Potential of hydrogen: add water and make the solution that contains 0.1g among every 1ml, the pH value should be 5.0 ~ 7.5.
Clarity of solution and color: get 5 bottles, add respectively water by labelled amount and make the solution that contains 0.1g among every 1ml, solution should be clarified colourless; As aobvious muddy, also compare with No. 1 turbidity standard, all must not be denseer; Such as colour developing, compare with yellow or No. 6 standard color solutions of yellow-green colour, all must not be darker.
Related substance: add mobile phase A dissolving and be diluted to by labelled amount and the solution that does not approximately contain ceftazime 1mg among the 1ml, as need testing solution; Precision measures 1ml, puts in the 100ml measuring bottle, and (7:93) is diluted to scale with mobile phase A-Mobile phase B, shakes up, in contrast solution.Be weighting agent with octadecylsilane chemically bonded silica; Mobile phase A is acetonitrile, and Mobile phase B is phosphate buffer soln (get primary ammonium phosphate 22.6g and add the aqueous solution and be diluted to 1000ml, regulating the pH value with 10% phosphoric acid solution is 3.9), and according to the form below carries out linear gradient elution.35 degrees centigrade of column temperatures detect wavelength 255nm.Get ceftazime reference substance 60mg, put in the 50ml measuring bottle, add 0.1mol/L hydrochloric acid soln 5ml dissolving, be diluted with water to scale, shake up.In boiling water, placed 20 minutes, take out, let cool, as system suitability solution, get 20ul injection liquid chromatography, the record color atlas.Number of theoretical plate calculates by the ceftazime peak and is not less than 3000, and the resolution at ceftazime and its front adjacent assorted peak should be not less than 1.5. and get contrast solution 20ul injection liquid chromatography, regulates detection sensitivity, makes the peak height of principal constituent chromatographic peak be about 25% of full range.Precision measures need testing solution and a contrast solution 20ul, difference injection liquid chromatography, the record color atlas, in the need testing solution color atlas if any impurity peaks, single impurity peak area must not be greater than 0.5 times (0.5%) of contrast solution main peak area, each impurity peak area and must not be greater than 2 times (2.0%) of contrast solution main peak area, any impurity peaks less than 0.05 times of contrast solution main peak area can be ignored in the need testing solution color atlas.
Pyridine: by labelled amount be dissolved in water and quantitatively dilution make and contain ceftazime 6mg among every 1ml, as need testing solution.Be weighting agent with octadecylsilane chemically bonded silica, (get primary ammonium phosphate 57.515g with acetonitrile-0.25mol/L ammonium dihydrogen phosphate, with water dissolution and be diluted to 2000ml)-to regulate pH value to 7.0 with ammonia solution be moving phase to water (300:100:600), flow velocity is 1.0ml/min, detects wavelength 254nm.Number of theoretical plate should be not less than 3000. and get reference substance solution 20ul injection liquid chromatography, calculates for several times sample introduction result, and its relative standard deviation must not cross 3.0%.Precision takes by weighing approximately 1g of pyridine, puts in the 100ml measuring bottle, is dissolved in water and is diluted to scale, shakes up, and precision measures 10ml, puts in the 100ml measuring bottle, and thin up shakes up to scale, in 15 degrees centigrade of lower storages.Precision measures 2ml before use, puts in the 200ml measuring bottle, is diluted to scale with pH7.0 phosphate buffered saline buffer (take by weighing five water SODIUM PHOSPHATE, MONOBASIC 5.68g, potassium primary phosphate 3.63g is dissolved in water and be diluted to 1000ml), shakes up, in contrast product solution.Precision measures 20ul need testing solution injection liquid chromatography, and the record color atlas goes reference substance solution in addition, measures with method, goes out the content of pyridine in the trial-product with calculated by peak area by external standard method, must not cross 0.12%.
The ceftazime polymkeric substance: by labelled amount be dissolved in water and quantitatively the dilution make the solution that contains ceftazime 20mg among every 1ml, be need testing solution.Be weighting agent with sephadex G-40, the glass column internal diameter is 1.0 ~ 1.4cm, column length 45cm, and take the 0.1mol/L phosphate buffered saline buffer of the pH7.0 that contains 3.5% ammonium sulfate as mobile phase A, take water as Mobile phase B, flow velocity is 0.8ml/min, detects wavelength 254nm.Measure 1.5mg/ml blue dextran 2000 solution 100 ~ 200ul, the injection liquid chromatography, respectively with mobile phase A, B measures, the record color atlas.Be not less than 500 by blue dextran 2000 peak theory of computation plate number averages, tailing factor all should be less than 2.0.The retention time ratio at blue dextran 2000 peaks should be between 0.93 ~ 1.07 in two kinds of flow phase system.Take by weighing ceftazime approximately 0.2g and yellow soda ash 20mg, put in the 10ml measuring bottle, with the dissolving of blue dextran 2000 solution of 1.5mg/ml and be diluted to scale, shake up.Get 100 ~ 200ul injection liquid chromatography, measure with mobile phase A, the record color atlas.Paddy between the peak height of high polymer and monomer and the high polymer is high, and precision measures contrast solution 100 ~ 200ul than being moving phase greater than the other Mobile phase B of 1.5., continuous sample introduction 5 times, and the relative standard deviation of peak area should be not more than 5.0%.Get the ceftazime reference substance an amount of, accurately weighed, be dissolved in water and quantitatively make the solution that approximately contains ceftazime 0.1mg among every 1ml.Get the trial-product precision and measure 100 ~ 200ul injection liquid chromatography, measure with mobile phase A, the record color atlas.Precision measures contrast solution 100 ~ 200ul injection liquid chromatography in addition, measures the record color atlas take Mobile phase B as moving phase., contain the ceftazime polymkeric substance and must not cross 1.0% of ceftazime amount in ceftazime with calculated by peak area by external standard method.
Weight loss on drying: to constant weight, less loss weight must not be crossed 13.5%(yellow soda ash at 60 degrees centigrade of drying under reduced pressure), less loss weight must not be crossed the 12.5%(arginine).
Uniformity of dosage units: with the every bottle of ceftazime cubage that records under the assay item, should be up to specification.
Assay: be weighting agent with octadecylsilane chemically bonded silica, take acetonitrile-pH7.0 phosphate buffered saline buffer-water (40:200:1760) as moving phase, flow velocity is 1.5ml/min, detects wavelength 254nm.Get reference substance solution 20ul injection liquid chromatography, the record color atlas, the resolution of ceftazime peak and adjacent impurity peaks should meet the requirements.Get 10 bottles, by labelled amount be dissolved in water respectively and quantitatively the dilution make the solution that approximately contains ceftazime 1mg among every 1ml, precision measures 15ml, put in the 100ml measuring bottle, be diluted with water to scale, shake up, precision measures 20ul, the injection liquid chromatography, the record color atlas, other removes the ceftazime reference substance, makes the solution that approximately contains ceftazime 0.15mg among every 1ml, measure with method, calculate and obtain 10 bottles average content by external standard method.In addition to take by weighing this product content an amount of for precision, is dissolved in water and quantitatively is diluted to the solution that approximately contains ceftazime 0.15mg among every 1ml, measures with method, by the calculated by peak area of external standard method.
2. test of long duration
Get example of formulations 1 of the present invention, 2 production method is produced a batch sample that obtains respectively, contains yellow soda ash and each a collection of comparing of arginic ceftazidime for inj with commercially available respectively.Under the commercially available back condition, in the climatic chamber of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10%, place, respectively at 0 day, March, June, September, December, 18 months, 24 months sampling, investigate its proterties, potential of hydrogen, clarity of solution and color, related substance, pyridine, polymkeric substance, weight loss on drying, uniformity of dosage units, content etc.The results are shown in following table.
Above-mentioned long-term test results shows, placed 24 months in the climatic chamber of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10%, ceftazidime for inj proterties, potential of hydrogen, clarity are compared without considerable change with 0 month with color, moisture, polymkeric substance, related substances and assay result.And commercially availablely contain respectively yellow soda ash and arginic ceftazidime for inj was placed 24 months in the climatic chamber of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10%, potential of hydrogen, color, moisture, polymkeric substance, related substance and content all have than considerable change, and as seen the ceftazidime for inj quality with method preparation of the present invention is more excellent more stable.
Claims (11)
1. the synthetic method of an antibiotic ceftazime is characterized in that the method comprises following processing step:
(ⅰ) take the ceftazime active ester as raw material, add organic solvent, inorganic solvent, the control temperature of reaction adds reaction solvent again, obtains improved new ceftazime active ester, and the temperature of reaction is 20 ℃ ~ 25 ℃;
(ⅱ) TA is added in the improved new ceftazime active ester that obtains in the step (ⅰ), then add successively organic solvent, triethylamine adds sour water, acetone soln again after the reaction, filtration, washing, drying obtain the ceftazime dihydrochloride, and the temperature of reaction is 1 ℃ ~ 10 ℃;
In the compound ceftazime dihydrochloride that (ⅲ) in step (ⅱ), obtains, regulate the pH value, add macroporous resin, carry out again wash-out, separate obtaining ceftazime.
2. the synthetic method of a kind of antibiotic ceftazime according to claim 1 is characterized in that the TA described in the step (ⅱ) adopts following method to be prepared from:
(1) take 7-ACA as raw material, adding hexamethyldisilazane, trimethylchlorosilane carry out Silanization reaction, obtain compound 1, and the temperature of Silanization reaction is 20 ℃ ~ 80 ℃;
(2) add Iodotrimethylsilane in the compound 1 that obtains in the step (1) and carry out iodide reaction, obtain compound 2, the temperature of iodide reaction is 10 ℃ ~ 20 ℃;
(3) pyridine is added in the compound 2 that obtains in the step (2), reaction obtains compound 3, and the temperature of reaction is 0 ℃ ~ 10 ℃;
(4) in the compound 3 that obtains in the step (3), add successively methyl alcohol, hydrochloric acid and water, salify obtains TA(7-PyCA in water is situated between), the temperature of reaction is 0 ℃ ~ 20 ℃.
3. the synthetic method of a kind of antibiotic ceftazime according to claim 1, it is characterized in that organic solvent in the described processing step (ⅰ) is one or more the mixture in anhydrous formic acid, anhydrous acetic acid, tartrate, citric acid, oxalic acid, Whitfield's ointment, methylsulfonic acid, triethylamine, toxilic acid, acetone, phenylformic acid, oxalic acid, methylene dichloride, DMF, the tetrahydrofuran (THF); Add ceftazime active ester and organic solvent mass ratio be 1:0.5-1:1.
4. the synthetic method of a kind of antibiotic ceftazime according to claim 1, it is characterized in that inorganic solvent in the described processing step (ⅰ) is one or more the mixture in sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, the carbonic acid, add ceftazime active ester and inorganic solvent mass ratio be 1:1.0-1:2.0.
5. the synthetic method of a kind of antibiotic ceftazime according to claim 1, it is characterized in that reaction solvent comprises acetone, N in the described processing step (ⅰ), the mixture of one or more in dinethylformamide, acetonitrile, tetrahydrofuran (THF), methylene dichloride, N,N-dimethylacetamide, ethylene dichloride, the chloroform.
6. the synthetic method of a kind of antibiotic ceftazime according to claim 1, it is characterized in that the described organic solvent in the described processing step (ⅱ) is triethylamine, Trimethylamine 99, acetone, methyl alcohol, ethanol, phenylformic acid, oxalic acid, methylene dichloride, ethylene dichloride, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetonitrile, the tetrahydrofuran (THF).
7. according to claim 1 or the synthetic method of 6 described a kind of antibiotic ceftazimes, it is characterized in that the described organic solvent in the described processing step (ⅱ) is the mixed solvent of methylene dichloride and methyl alcohol, the mass ratio of this mixed solvent is 1:0.01 ~ 0.1.
8. the synthetic method of a kind of antibiotic ceftazime according to claim 1 is characterized in that the sour water described in the described processing step (ⅱ) is one or more and the mixing solutions of water in sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, the carbonic acid.
9. ceftazidime for inj, its feature is being to contain 1 described ceftazime and the pharmaceutical excipient of having the right, and pharmaceutical excipient is a kind of in yellow soda ash, the arginine, and the weight ratio of ceftazime and pharmaceutical excipient is 3 ~ 10:1.
10. ceftazidime for inj according to claim 9 is characterized in that, the particle diameter of described ceftazidime for inj is 38 ~ 75um.
11. one kind prepares ceftazidime for inj method claimed in claim 9, it is characterized in that, and under aseptic condition, the operation following steps::
1) crushes and screens: ceftazime and pharmaceutical excipient are pulverized, sieved, obtain the ceftazime mixture of particle diameter 38～75um;
2) aseptic subpackaged and moulding plug: within sterile workshop is packed the ceftazime mixture of particle diameter 38～75um into aseptic vial, cover aseptic plug;
3) roll lid: aluminium-plastic combined cover is pressed into step 2) aseptic plug on;
4) packing: send into label sticking machine labeling, packing through travelling belt through the qualified step 3) product of lamp inspection.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103110643A (en) * | 2013-03-08 | 2013-05-22 | 海南卫康制药(潜山)有限公司 | Powder injection of drug composition of ceftazidime for injection |
| CN104761570A (en) * | 2015-04-27 | 2015-07-08 | 四川制药制剂有限公司 | Preparation technology for ceftazidime for injection |
| CN104860964A (en) * | 2015-04-27 | 2015-08-26 | 四川制药制剂有限公司 | Product zero load avoiding injection ceftazidime preparation method |
| CN104892638A (en) * | 2015-05-28 | 2015-09-09 | 齐鲁安替制药有限公司 | Method for preparing ceftazidime by one-pot process |
| CN106317080A (en) * | 2016-08-17 | 2017-01-11 | 陕西顿斯制药有限公司 | Ceftazidime compound prepared by adopting coupling crystallization technology and preparation thereof |
| CN107266473A (en) * | 2017-07-14 | 2017-10-20 | 苏州中联化学制药有限公司 | A kind of synthetic method of cefotaxime |
| CN107922435A (en) * | 2015-09-08 | 2018-04-17 | 桑多斯股份公司 | The method for preparing cephalo Luozha by 7 amino-cephalo-alkanoic acids (7 ACA) |
| CN109900812A (en) * | 2017-12-07 | 2019-06-18 | 北京济美堂医药研究有限公司 | Cefixime and its detection method in relation to substance |
| CN110396104A (en) * | 2018-07-26 | 2019-11-01 | 赛法洛抗生素有限公司 | The new indication of Tai Siting cefotaxime pharmaceutical preparation treatment gynecological infection |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4329453A (en) * | 1979-10-02 | 1982-05-11 | Glaxo Group Limited | Cephalosporin antibiotic |
| US4769450A (en) * | 1984-03-09 | 1988-09-06 | Glaxo Group Limited | Process for recovering ceftazidime |
| CN1043717A (en) * | 1988-12-29 | 1990-07-11 | 田边制药株式会社 | Cephalosporin compound |
| WO2007086013A1 (en) * | 2006-01-25 | 2007-08-02 | Jegannathan Srinivas | Formulation comprising of ceftazidime, tazobactam and linezolid |
| JP2007238491A (en) * | 2006-03-08 | 2007-09-20 | Nipro Corp | Medical preparation |
| CN101607966A (en) * | 2008-06-19 | 2009-12-23 | 上海新先锋药业有限公司 | The preparation method of ceftazidime pentahydrate |
| CN101810623B (en) * | 2009-11-19 | 2011-06-08 | 罗诚 | Ceftazidime medicinal composition for injection and preparation method thereof |
| CN102286003A (en) * | 2011-08-05 | 2011-12-21 | 哈药集团制药总厂 | Synthesis method of ceftazidime |
-
2012
- 2012-10-31 CN CN2012104291454A patent/CN102875576A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4329453A (en) * | 1979-10-02 | 1982-05-11 | Glaxo Group Limited | Cephalosporin antibiotic |
| US4769450A (en) * | 1984-03-09 | 1988-09-06 | Glaxo Group Limited | Process for recovering ceftazidime |
| CN1043717A (en) * | 1988-12-29 | 1990-07-11 | 田边制药株式会社 | Cephalosporin compound |
| WO2007086013A1 (en) * | 2006-01-25 | 2007-08-02 | Jegannathan Srinivas | Formulation comprising of ceftazidime, tazobactam and linezolid |
| JP2007238491A (en) * | 2006-03-08 | 2007-09-20 | Nipro Corp | Medical preparation |
| CN101607966A (en) * | 2008-06-19 | 2009-12-23 | 上海新先锋药业有限公司 | The preparation method of ceftazidime pentahydrate |
| CN101810623B (en) * | 2009-11-19 | 2011-06-08 | 罗诚 | Ceftazidime medicinal composition for injection and preparation method thereof |
| CN102286003A (en) * | 2011-08-05 | 2011-12-21 | 哈药集团制药总厂 | Synthesis method of ceftazidime |
Non-Patent Citations (2)
| Title |
|---|
| 王冬慧，等: "头孢他啶侧链活性硫酯合成的研究", 《化工时刊》 * |
| 郑玉林: "头孢他啶的合成工艺改进", 《中国药物化学杂志》 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103110643A (en) * | 2013-03-08 | 2013-05-22 | 海南卫康制药(潜山)有限公司 | Powder injection of drug composition of ceftazidime for injection |
| CN104761570A (en) * | 2015-04-27 | 2015-07-08 | 四川制药制剂有限公司 | Preparation technology for ceftazidime for injection |
| CN104860964A (en) * | 2015-04-27 | 2015-08-26 | 四川制药制剂有限公司 | Product zero load avoiding injection ceftazidime preparation method |
| CN104892638A (en) * | 2015-05-28 | 2015-09-09 | 齐鲁安替制药有限公司 | Method for preparing ceftazidime by one-pot process |
| CN107922435A (en) * | 2015-09-08 | 2018-04-17 | 桑多斯股份公司 | The method for preparing cephalo Luozha by 7 amino-cephalo-alkanoic acids (7 ACA) |
| CN107922435B (en) * | 2015-09-08 | 2022-05-17 | 桑多斯股份公司 | Method for preparing ceftaroline from 7-aminocephalosporanic acid (7-ACA) |
| CN106317080A (en) * | 2016-08-17 | 2017-01-11 | 陕西顿斯制药有限公司 | Ceftazidime compound prepared by adopting coupling crystallization technology and preparation thereof |
| CN107266473A (en) * | 2017-07-14 | 2017-10-20 | 苏州中联化学制药有限公司 | A kind of synthetic method of cefotaxime |
| CN109900812A (en) * | 2017-12-07 | 2019-06-18 | 北京济美堂医药研究有限公司 | Cefixime and its detection method in relation to substance |
| CN110396104A (en) * | 2018-07-26 | 2019-11-01 | 赛法洛抗生素有限公司 | The new indication of Tai Siting cefotaxime pharmaceutical preparation treatment gynecological infection |
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Address after: 215415, Jiangsu, Suzhou province Taicang Regal Economic Development Zone Applicant after: Sinopharm (Suzhou) Pharmaceutical Co., Ltd. Applicant after: Zhijun Pharmaceutical Co., Ltd., Shenzhen Address before: 215415, Jiangsu, Suzhou province Taicang Regal Economic Development Zone Applicant before: Suzhou Zhijun Wanqing Pharmaceutical Co., Ltd. Applicant before: Zhijun Pharmaceutical Co., Ltd., Shenzhen |
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