CN104644630A - Amoxicillin sodium and sulbactam sodium preparation for injection and preparation method thereof - Google Patents
Amoxicillin sodium and sulbactam sodium preparation for injection and preparation method thereof Download PDFInfo
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- CN104644630A CN104644630A CN201510040673.4A CN201510040673A CN104644630A CN 104644630 A CN104644630 A CN 104644630A CN 201510040673 A CN201510040673 A CN 201510040673A CN 104644630 A CN104644630 A CN 104644630A
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Abstract
The invention discloses an amoxicillin sodium and sulbactam sodium preparation for injection and a preparation method thereof. The amoxicillin sodium and sulbactam sodium preparation for injection is formed by uniformly mixing high purity amoxicillin sodium and high purity sulbactam sodium, wherein the weight ratio of amoxicillin sodium to sulbactam sodium is (2-4): 1. The amoxicillin sodium and sulbactam sodium preparation for injection disclosed by the invention has the advantages of being high in purity, few in impurities, high in stability, hard to irritate and the like.
Description
Technical field
The present invention relates to a kind of amoxicillin sodium for injection sulbactam sodium preparation and preparation method thereof, belong to medical art.
Background technology
Amoxicillin sodium for injection sulbactam sodium is compound preparation, and its component is Amoxicillin Sodium and the mixed uniformly sterilized powder of sulbactam sodium.
Amoxicillin Sodium, chemistry (2S by name, 5R, 6R)-3,3-dimethyl-6-[(R)-(-)-2-amino-2-(4-hydroxy phenyl) acetylamino]-7-oxo-4 thia-1-azabicyclo (3.2.0) heptane-2-sodium formate.Molecular formula: C
16h
18n
3naO
5s, molecular weight: 387.40.Amoxicillin Sodium is a kind of semi-synthetic penicillins antibiotic, is applicable to the treatment of following disease: 1. the upper respiratory tract infection such as otitis media, sinusitis, pharyngitis, tonsillitis caused by Streptococcus hemolyticus, streptococcus pneumoniae, staphylococcus or hemophilus influenza.2. the urogenital infections caused by escherichia coli, proteus mirabilis or enterococcus faecalis.3. the skin soft-tissue infection caused by Streptococcus hemolyticus, staphylococcus or escherichia coli.4. the lower respiratory infection such as Streptococcus hemolyticus, streptococcus pneumoniae, staphylococcus or hemophilus influenza induced Acute bronchitis, pneumonia.
Sulbactam sodium, chemistry (2S, 5R) by name-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid sodium-4,4-dioxide.Molecular formula: C
8h
10nNaO
5s, molecular weight: 255.23.Sulbactam sodium is by the irreversibility competitive type beta-lactamase inhibitor of synthetic.
Penicillin be in the world first be applied to clinical anti-infection drug, it is the antibiotic that the mankind find the earliest, nineteen twenty-eight London university Sheng Mali medical college (Xian Shu London's Imperial College) bacteriology teaches Fleming and finds that penicillium has bactericidal action in the lab, within 1938, extract by the team of Oxonian money grace, Florey and Basil Heatley (NormanHeatley, 1911-2004) leader.
Penicillin (Penicillin, or transliteration penicillin) refers to containing penam, the cell wall that can destroy antibacterial play a class antibiotic of bactericidal action in the idiophase of bacterial cell in molecule, is by the antibiotic extracted in penicillium.Penicillin antibiotics is the general name of the beta-lactam antibiotic to penicillin with the similar mechanism of action.Penicillin antibiotics chemical structure of general formula is as follows:
R---represent a kind of organic group
The toxicity of Penicillin antibiotics is very little, it is the maximum antibiotic of chemotherapeutic index, but the common anaphylaxis of its Penicillin antibiotics ranks first in various medicine, incidence rate reaches as high as 5% ~ 10%, the impurity (comprising related substances, residual solvent, polymer etc.) that its irritated main cause produces for penicillins production and storage transportation.
The shortcomings such as it is low that current amoxicillin sodium for injection sulbactam sodium exists purity, and impurity is many, poor stability, easy allergy.
Summary of the invention:
The object of this invention is to provide a kind of amoxicillin sodium for injection sulbactam sodium preparation and preparation method thereof, make amoxicillin sodium for injection sulbactam sodium preparation have purity high, impurity is few, good stability, is not easy the advantages such as irritated.
A kind of amoxicillin sodium for injection sulbactam sodium preparation is the invention provides for solving the problem, this amoxicillin sodium for injection sulbactam sodium preparation is formed by highly purified Amoxicillin Sodium and highly purified sulbactam sodium Homogeneous phase mixing, and the weight ratio of Amoxicillin Sodium and sulbactam sodium is 2 ~ 4:1.
The invention provides a kind of preparation method of amoxicillin sodium for injection sulbactam sodium preparation for solving the problem, comprising the following steps: (1) prepares highly purified Amoxicillin Sodium; (2) highly purified sulbactam sodium is prepared; (3) take Amoxicillin Sodium and sulbactam sodium according to the weight ratio 2 ~ 4:1 of Amoxicillin Sodium and sulbactam sodium, mix in mixed powder machine under nitrogen protection; (4) amoxicillin sodium and sulbactam sodium being mixed powder is distributed in the injection bottle of sterilization treatment, through filling nitrogen, jumping a queue, rolling lid, packaging, inspection, warehouse-in, obtained amoxicillin sodium for injection sulbactam sodium preparation; Wherein highly purified Amoxicillin Sodium is prepared according to following steps:
1. the preparation of mixed acid anhydride: in dichloromethane, adds hydroxyl Deng salt, adds N simultaneously under temperature 10-15 DEG C of rapid stirring, N-dimethyl acetylamide, when cooling to 0 DEG C, add 2,6-lutidines, continue to be cooled to-30 ~-38 DEG C, at the uniform velocity add pivaloyl chloride in 10 minutes, control mixed anhydride temperature, carry out insulation reaction, add isooctyl acid when being cooled to-50 DEG C after end, continue to be cooled to-50 DEG C for subsequent use;
2. the preparation of 6-amino-penicillanic acid saline solution: in dichloromethane, add purified water and isopropyl alcohol, stir, 6-amino-penicillanic acid is added when being cooled to 0-6 DEG C, in 20 minutes, at the uniform velocity add triethylamine, temperature controls at 0-3 DEG C, reacts 30 minutes, 6-amino-penicillanic acid dissolves completely, be cooled to-15 DEG C for subsequent use;
3. condensation reaction: 6-amino-penicillanic acid saline solution is gone to mixed acid anhydride, after having turned saline solution, carries out condensation reaction at low temperatures, and when residual quantity≤0.5% of 6-amino-penicillanic acid, reaction terminates;
4. hydrolysis: join in purified water by solution after condensation reaction, rapid stirring, at the uniform velocity add hydrochloric acid, controlled hydrolysis temperature, stirred after 10 minutes, detected aqueous pH values, stopped stirring, left standstill 10 minutes, water intaking phase.
5. the crystallization of amoxicillin: add potassium phosphate buffer in crystallization kettle, under agitation slowly add aqueous phase and ammonia simultaneously, control ammonia rate of addition, temperature during control adds alkali, crystallize of lowering the temperature after adding alkali, stirs, leave standstill, filter, use water and washing with acetone respectively, vacuum drying obtains amoxicillin;
6. the preparation of amoxicillin solution: in dehydrated alcohol, add triethylamine, stir, cool to 0 DEG C, add amoxicillin, be stirred to and dissolve completely, solution is after membrane filtration is degerming, and the pipeline of amoxicillin process during mixed liquid washing and filtering with dehydrated alcohol and triethylamine, merging filtrate and washing liquid;
7. the preparation of sodium iso-octoate solution: add Sodium isooctanoate. in methyl acetate, be stirred to and dissolve completely, solution after membrane filtration is degerming, and with the pipeline of Sodium isooctanoate. process during methyl acetate washing and filtering, merging filtrate and washing liquid;
8. the crystallization of Amoxicillin Sodium: under at the uniform velocity stirring, sodium iso-octoate solution is joined in the solution of amoxicillin, crystal solution is cooled to 0-5 DEG C, add the Amoxicillin Sodium crystal seed filtered out, insulation 0-5 DEG C, stirs 30 minutes, after having crystal to separate out, drip aqueous sodium carbonate, continue stirring 2 hours, sucking filtration, filter cake methyl acetate washs, and vacuum drying obtains highly purified Amoxicillin Sodium.
Preferably, described step 1. in the weight ratio of hydroxyl Deng salt and dichloromethane be 1:4 ~ 5, N, the weight of N-dimethyl acetylamide is the weight of 40 ~ 50%, 2,6-lutidines of hydroxyl Deng salt is 2.5 ~ 3% of hydroxyl Deng salt, the mol ratio of hydroxyl Deng salt and pivaloyl chloride is 1:1 ~ 1.1, the weight of isooctyl acid is 2.4 ~ 2.8% of hydroxyl Deng salt, and mixed anhydride temperature controls at-15 DEG C ~-20 DEG C, and the insulation reaction time is 60 minutes.
Preferably, described step 2. in the weight ratio of 6-amino-penicillanic acid and dichloromethane be 1:1.5 ~ 1.8, the weight of purified water is 15 ~ 20% of 6-amino-penicillanic acid, the weight of isopropyl alcohol is 70 ~ 85% of 6-amino-penicillanic acid, and the mol ratio of 6-amino-penicillanic acid and triethylamine is 1:1.05 ~ 1.15.
Preferably, 3. the middle control splicing time is 20 ~ 28 minutes to described step, and setting-up point is-30 DEG C ~-38 DEG C, and condensation reaction time is 120 minutes.
Preferably, described step 4. middle purified water is chilled to 15 DEG C in advance, and the hydrochloric acid joining day is 10 minutes, and controlled hydrolysis temperature is 5 ~ 10 DEG C, and detecting aqueous pH values is 1.0 ~ 1.2.
Preferably, described step 5. in the pH of potassium phosphate buffer be 5.0-5.1, ammonia concn is 10-15%, controlling ammonia rate of addition makes pH remain on 5.0-5.1, and during adding alkali, temperature controls at 5-10 DEG C, and recrystallization temperature is 0-5 DEG C, mixing time is 1 hour, time of repose is 1 hour, and vacuum drying temperature is 45 DEG C, and the vacuum drying time is 3 hours.
Preferably, described step 6. in the weight ratio of amoxicillin and dehydrated alcohol be 1:2 ~ 2.3, the weight of triethylamine is 40 ~ 50% of amoxicillin, and the volume ratio mixing dehydrated alcohol and triethylamine in liquid is 15-17:1; Described step 7. in the weight ratio of methyl acetate and Sodium isooctanoate. be 3.8 ~ 4.2:1, stirring and dissolving temperature is 15-20 DEG C, and the weight of Sodium isooctanoate. is the 65-75% of amoxicillin.
Preferably, described step 8. middle Amoxicillin Sodium crystal seed is D50≤7.5 μm, D90≤18 μm, TOP≤40 μm; Amoxicillin Sodium Seed charge is the 0.1-0.5% of amoxicillin weight, and aqueous sodium carbonate concentration is 20-24%, and vacuum drying temperature is 40-45 DEG C, and vacuum drying pressure is-0.09MPa, and the vacuum drying time is 5-6 hour.
Preferably, described highly purified sulbactam sodium is prepared according to following steps:
A sulbactam and anhydrous sodium acetate are dissolved in the solution of purified water and n-butyl alcohol by (), be stirred to and dissolve completely, shift in the alembic of distillation crystallization apparatus after activated carbon decolorizing together, under the vacuum condition of-0.09MPa, 100 DEG C of water-bath distilling under reduced pressure, the n-butyl alcohol of equivalent is added according to distillate amount, when nucleus is formed, growing the grain 15 minutes, continues to be distilled to crystal solution moisture and is less than 1%, stops heating, be cooled to room temperature, sucking filtration, uses n-butyl alcohol washing leaching cake, and dry cake obtains sulbactam sodium crude product; The mol ratio of sulbactam and anhydrous sodium acetate is 1:1-1.05, and the weight of purified water is 1.5 times of sulbactam, and the weight of n-butyl alcohol is the 78-83% of sulbactam;
B sulbactam sodium crude product is dissolved in the purified water of 20 times by (), the hydrochloric acid solution adding 0.1mol/L regulates pH to be 2.0-3.0, stirs and separates out insoluble matter, filters, obtains solid after purified water washing; The mixture of the solid with ethyl acetate obtained and petroleum ether is dissolved, use DM-301 absorption with macroporous adsorbent resin, purify as eluent with the mixture of ethanol and ethyl acetate again, collect eluent, regulate pH to be 5.5-6.5 the eluent 0.1mol/L sodium carbonate liquor of gained, separate out solid, centrifuge 20 minutes, by washed with isopropyl alcohol, obtain highly purified sulbactam sodium at 50-60 DEG C of vacuum drying 4-6 hour; The weight of the mixture of ethyl acetate and petroleum ether is 16 times of sulbactam sodium crude product, the volume ratio 3:2 of ethyl acetate and petroleum ether in mixture, the volume ratio 1:5 of ethanol and ethyl acetate in eluant.
Effective effect of the present invention is:
(1) improve the reaction temperature of mixed acid anhydride, Reaction time shorten, can reduce by-product, improves reaction yield.
(2) shorten the time that 6-APA saline solution goes to mixed acid anhydride, can by-product be reduced, improve reaction yield.
(3) improve setting-up point, shorten condensation reaction time, can by-product be reduced, improve reaction yield.
(4) controlled hydrolysis temperature is 5 ~ 10 DEG C, rapid stirring, and controlling the hydrochloric acid joining day is 10 minutes, hydrolytic process can be made not have crystallize, improve the quality of products and yield.
(5) amoxicillin crystallization is carry out in the potassium phosphate buffer of 5.0-5.1 at pH, and control ammonia rate of addition and make pH remain on 5.0-5.1, it is high that the amoxicillin that crystallization can be made to obtain has purity, the advantages such as impurity is few, good stability.
(6) the Amoxicillin Sodium crystal seed filtered out is added when amoxicillin sodium crystal, these crystal seed D50≤7.5 μm, D90≤18 μm, TOP≤40 μm, it is high that the Amoxicillin Sodium that crystallization can be made to obtain has purity, and impurity is few, good stability, is not easy the advantages such as irritated.
(7) adopt water-bath azeotropic distilling under reduced pressure crystallization processes and DM-301 purification with macroreticular resin technique, highly purified sulbactam sodium can be obtained.
(8) amoxicillin sodium for injection sulbactam sodium preparation stabilization, long-time preservation also can not rubescent variable color.
Detailed description of the invention
Below in conjunction with specific embodiment, embodiment of the present invention are described in detail.Should be appreciated that enforcement of the present invention is not limited to the following examples, any pro forma accommodation make the present invention and/or change all will fall into protection scope of the present invention.
Embodiment 1
A kind of amoxicillin sodium for injection sulbactam sodium preparation, formed by highly purified Amoxicillin Sodium and highly purified sulbactam sodium Homogeneous phase mixing, the weight ratio of Amoxicillin Sodium and sulbactam sodium is 2:1.
Prepared by these amoxicillin sodium for injection sulbactam sodium preparation following steps:
(1) highly purified Amoxicillin Sodium is prepared; Prepared by the following method of this highly purified Amoxicillin Sodium:
1. the preparation of mixed acid anhydride: add dichloromethane 906ml, adds 300 grams of D-pHPG dane potassium salts (hydroxyl Deng salt), adds 130mlN simultaneously under rapid stirring, N-dimethyl acetylamide (DMA), keep temperature 10-15 DEG C, cooling, when temperature drops to 0 DEG C, add 2,6-lutidines 7.5 grams, continues to be cooled to-30 DEG C, at the uniform velocity adds 119 cut valeric chlorides in 10 minutes, temperature controls at-15 DEG C, insulation reaction 60 minutes.Add isooctyl acid 7.2 grams when being cooled to-50 DEG C, continue to be cooled to-50 DEG C for subsequent use.
2. the preparation of 6-amino-penicillanic acid (6-APA) saline solution: in dichloromethane 226ml, add 30ml purified water and 178ml isopropyl alcohol, stir, add 200 grams of 6-APA when being cooled to 0-6 DEG C, in 20 minutes, at the uniform velocity add triethylamine 98.3 grams, temperature controls at 0-3 DEG C, react 30 minutes, sampling is observed 6-APA and is dissolved situation, surveys pH value, 6-APA dissolves completely, be cooled to-15 DEG C for subsequent use.
3. condensation reaction: 6-APA saline solution is gone to mixed acid anhydride, controlling the splicing time is 20 minutes, has turned saline solution ,-30 DEG C of insulation reaction 120 minutes, when residual quantity≤0.5% of 6-APA, reaction end.
4. hydrolysis: joined by solution after reaction and be chilled in the 2400ml purified water of 15 DEG C in advance, rapid stirring, at the uniform velocity added hydrochloric acid in 10 minutes, and keep temperature control at 5-10 DEG C, stir after 10 minutes, detection aqueous pH values is 1.0-1.2, stop stirring, leave standstill 10 minutes, water intaking phase.
5. the crystallization of amoxicillin: add the potassium phosphate buffer 200ml that pH is 5.0-5.1 in crystallization kettle, under agitation slowly add the ammonia of aqueous phase and concentration 10% simultaneously, controlling ammonia rate of addition makes pH remain on 5.0-5.1, during adding alkali, temperature controls at 10 DEG C, and this add-subtract time is about 120 minutes.Be cooled to 5 DEG C after adding alkali, stir 1 hour, leave standstill 1 hour, filter, use water and washing with acetone respectively, vacuum drying discharging after 3 hours at 45 DEG C, obtains 354 grams, amoxicillin.
6. the preparation of amoxicillin solution: in 253ml dehydrated alcohol, adds 55ml triethylamine, stirs, and cools to 0 DEG C, adds 100 grams, amoxicillin, is stirred to and dissolves completely.Solution is after membrane filtration is degerming, and pipeline, merging filtrate and the washing liquid of amoxicillin process during mixed liquid washing and filtering with 120ml dehydrated alcohol and 8ml triethylamine.
7. the preparation of sodium iso-octoate solution: add 65 grams of Sodium isooctanoate. in 268ml methyl acetate, is stirred to and dissolves completely at temperature 15-20 DEG C.Solution after membrane filtration is degerming, and by pipeline, merging filtrate and the washing liquid of Sodium isooctanoate. process during 90ml methyl acetate washing and filtering.
8. the crystallization of Amoxicillin Sodium: under at the uniform velocity stirring, sodium iso-octoate solution is joined in the solution of amoxicillin, crystal solution is cooled to 0-5 DEG C, add Amoxicillin Sodium crystal seed (these crystal seed D50≤7.5 μm filtered out, D90≤18 μm, TOP≤40 μm, ) 0.1 gram, insulation 0-5 DEG C, stir 30 minutes, a large amount of crystal is now had to separate out, drip the aqueous sodium carbonate 9ml of 20%, continue stirring 2 hours, sucking filtration, filter cake 250ml methyl acetate is (degerming after filtration, and be pre-chilled to 0-5 DEG C) point 3 washings, wet feed in vacuum drying oven in 40 DEG C, dry 6 hours of-0.09MPa, obtain highly purified 84.2 grams, white crystals type Amoxicillin Sodium powder, purity is 99.8%.
(2) highly purified sulbactam sodium is prepared;
A 100 grams of sulbactams and 35.2 grams of anhydrous sodium acetates are dissolved in the solution of 150ml purified water and 96ml n-butyl alcohol by (), be stirred to and dissolve completely, shift together in the alembic of distillation crystallization apparatus after activated carbon decolorizing.Under the vacuum condition of-0.09MPa, 100 DEG C of water-bath distilling under reduced pressure, add the n-butyl alcohol of equivalent according to distillate amount, when nucleus is formed, growing the grain 15 minutes, continues to be distilled to crystal solution moisture and is less than 1%, stops heating, be cooled to room temperature, sucking filtration, uses n-butyl alcohol washing leaching cake, and dry cake can obtain sulbactam sodium crude product 107 grams, yield 97.8%, purity 92.4%.
B 100 grams of sulbactam sodium crude products are dissolved in 2000ml purified water by (), the hydrochloric acid solution adding 0.1mol/L regulates pH to be 2.0, stirs and separates out insoluble matter, filters, obtains solid after purified water washing.The mixture 2000ml of the solid with ethyl acetate obtained and petroleum ether (volume ratio 3:2) is dissolved, add the pillar being filled with DM-301 macroporous adsorbent resin to pass through, purify as eluent with ethanol and ethyl acetate (volume ratio 1:5) mixture 700ml again, collect eluent.Regulate pH to be 5.5 the eluent 0.1mol/L sodium carbonate liquor of gained, separate out solid, centrifuge 20 minutes, uses 500ml washed with isopropyl alcohol, and 50 DEG C of vacuum dryings 6 hours, obtain highly finished product 93.7 grams, and it is 99.8% that yield 93.7%, HPLC detects purity.
(3) take Amoxicillin Sodium and sulbactam sodium according to the weight ratio 2:1 of Amoxicillin Sodium and sulbactam sodium, mix in mixed powder machine under nitrogen protection;
(4) amoxicillin sodium and sulbactam sodium being mixed powder is distributed in the injection bottle of sterilization treatment, through filling nitrogen, jumping a queue, rolling lid, packaging, inspection, warehouse-in, obtained amoxicillin sodium for injection sulbactam sodium preparation.
Embodiment 2
A kind of amoxicillin sodium for injection sulbactam sodium preparation, formed by highly purified Amoxicillin Sodium and highly purified sulbactam sodium Homogeneous phase mixing, the weight ratio of Amoxicillin Sodium and sulbactam sodium is 3:1.
Prepared by these amoxicillin sodium for injection sulbactam sodium preparation following steps:
(1) highly purified Amoxicillin Sodium is prepared; Prepared by the following method of this highly purified Amoxicillin Sodium:
1. the preparation of mixed acid anhydride: add dichloromethane 1000ml, adds 300 grams of D-pHPG dane potassium salts (hydroxyl Deng salt), adds 150mlN simultaneously under rapid stirring, N-dimethyl acetylamide (DMA), keep temperature 10-15 DEG C, cooling, when temperature drops to 0 DEG C, add 2,6-lutidines 8.2 grams, continues to be cooled to-34 DEG C, at the uniform velocity adds 125 cut valeric chlorides in 10 minutes, temperature controls at-18 DEG C, insulation reaction 60 minutes.Add isooctyl acid 7.7 grams when being cooled to-50 DEG C, continue to be cooled to-50 DEG C for subsequent use.
2. the preparation of 6-amino-penicillanic acid (6-APA) saline solution: in dichloromethane 250ml, add 35ml purified water and 200ml isopropyl alcohol, stir, add 200 grams of 6-APA when being cooled to 0-6 DEG C, in 20 minutes, at the uniform velocity add triethylamine 104 grams, temperature controls at 0-3 DEG C, react 30 minutes, sampling is observed 6-APA and is dissolved situation, surveys pH value, 6-APA dissolves completely, be cooled to-15 DEG C for subsequent use.
3. condensation reaction: 6-APA saline solution is gone to mixed acid anhydride, controlling the splicing time is 24 minutes, has turned saline solution ,-34 DEG C of insulation reaction 120 minutes, when residual quantity≤0.5% of 6-APA, reaction end.
4. hydrolysis: joined by solution after reaction and be chilled in the 2400ml purified water of 15 DEG C in advance, rapid stirring, at the uniform velocity added hydrochloric acid in 10 minutes, and keep temperature control at 5-10 DEG C, stir after 10 minutes, detection aqueous pH values is 1.0-1.2, stop stirring, leave standstill 10 minutes, water intaking phase.
5. the crystallization of amoxicillin: add the potassium phosphate buffer 250ml that pH is 5.0-5.1 in crystallization kettle, under agitation slowly add the ammonia of aqueous phase and concentration 12% simultaneously, controlling ammonia rate of addition makes pH remain on 5.0-5.1, during adding alkali, temperature controls at 8 DEG C, and this add-subtract time is about 120 minutes.Be cooled to 2 DEG C after adding alkali, stir 1 hour, leave standstill 1 hour, filter, use water and washing with acetone respectively, vacuum drying discharging after 3 hours at 45 DEG C, obtains 355 grams, amoxicillin.
6. the preparation of amoxicillin solution: in 270ml dehydrated alcohol, adds 62ml triethylamine, stirs, and cools to 0 DEG C, adds 100 grams, amoxicillin, is stirred to and dissolves completely.Solution is after membrane filtration is degerming, and pipeline, merging filtrate and the washing liquid of amoxicillin process during mixed liquid washing and filtering with 130ml dehydrated alcohol and 8ml triethylamine.
7. the preparation of sodium iso-octoate solution: add 69.5 grams of Sodium isooctanoate. in 300ml methyl acetate, is stirred to and dissolves completely at temperature 15-20 DEG C.Solution after membrane filtration is degerming, and by pipeline, merging filtrate and the washing liquid of Sodium isooctanoate. process during 100ml methyl acetate washing and filtering.
8. the crystallization of Amoxicillin Sodium: under at the uniform velocity stirring, sodium iso-octoate solution is joined in the solution of amoxicillin, crystal solution is cooled to 0-5 DEG C, add Amoxicillin Sodium crystal seed (these crystal seed D50≤7.5 μm filtered out, D90≤18 μm, TOP≤40 μm, ) 0.3 gram, insulation 0-5 DEG C, stir 30 minutes, a large amount of crystal is now had to separate out, drip the aqueous sodium carbonate 8ml of 22%, continue stirring 2 hours, sucking filtration, filter cake 250ml methyl acetate is (degerming after filtration, and be pre-chilled to 0-5 DEG C) point 3 washings, wet feed in vacuum drying oven in 42 DEG C, dry 5.5 hours of-0.09MPa, obtain highly purified 84.7 grams, white crystals type Amoxicillin Sodium powder, purity is 99.9%.
(2) highly purified sulbactam sodium is prepared;
A 100 grams of sulbactams and 36 grams of anhydrous sodium acetates are dissolved in the solution of 150ml purified water and 100ml n-butyl alcohol by (), be stirred to and dissolve completely, shift together in the alembic of distillation crystallization apparatus after activated carbon decolorizing.Under the vacuum condition of-0.09MPa, 100 DEG C of water-bath distilling under reduced pressure, add the n-butyl alcohol of equivalent according to distillate amount, when nucleus is formed, growing the grain 15 minutes, continues to be distilled to crystal solution moisture and is less than 1%, stops heating, be cooled to room temperature, sucking filtration, uses n-butyl alcohol washing leaching cake, and dry cake can obtain sulbactam sodium crude product 107 grams, yield 98.2%, purity 92.5%.
B 100 grams of sulbactam sodium crude products are dissolved in 2000ml purified water by (), the hydrochloric acid solution adding 0.1mol/L regulates pH to be 2.5, stirs and separates out insoluble matter, filters, obtains solid after purified water washing.The mixture 2000ml of the solid with ethyl acetate obtained and petroleum ether (volume ratio 3:2) is dissolved, add the pillar being filled with DM-301 macroporous adsorbent resin to pass through, purify as eluent with ethanol and ethyl acetate (volume ratio 1:5) mixture 700ml again, collect eluent.Regulate pH to be 6.0 the eluent 0.1mol/L sodium carbonate liquor of gained, separate out solid, centrifuge 20 minutes, uses 500ml washed with isopropyl alcohol, and 55 DEG C of vacuum dryings 5 hours, obtain highly finished product 93.8 grams, and it is 99.8% that yield 93.8%, HPLC detects purity.
(3) take Amoxicillin Sodium and sulbactam sodium according to the weight ratio 3:1 of Amoxicillin Sodium and sulbactam sodium, mix in mixed powder machine under nitrogen protection;
(4) amoxicillin sodium and sulbactam sodium being mixed powder is distributed in the injection bottle of sterilization treatment, through filling nitrogen, jumping a queue, rolling lid, packaging, inspection, warehouse-in, obtained amoxicillin sodium for injection sulbactam sodium preparation.
Embodiment 3
A kind of amoxicillin sodium for injection sulbactam sodium preparation, formed by highly purified Amoxicillin Sodium and highly purified sulbactam sodium Homogeneous phase mixing, the weight ratio of Amoxicillin Sodium and sulbactam sodium is 4:1.
Prepared by these amoxicillin sodium for injection sulbactam sodium preparation following steps:
(1) highly purified Amoxicillin Sodium is prepared; Prepared by the following method of this highly purified Amoxicillin Sodium:
1. the preparation of mixed acid anhydride: add dichloromethane 1132ml, adds 300 grams of D-pHPG dane potassium salts (hydroxyl Deng salt), adds 160mlN simultaneously under rapid stirring, N-dimethyl acetylamide (DMA), keep temperature 10-15 DEG C, cooling, when temperature drops to 0 DEG C, add 2,6-lutidines 9.0 grams, continues to be cooled to-38 DEG C, at the uniform velocity adds 131 cut valeric chlorides in 10 minutes, temperature controls at-20 DEG C, insulation reaction 60 minutes.Add isooctyl acid 8.4 grams when being cooled to-50 DEG C, continue to be cooled to-50 DEG C for subsequent use.
2. the preparation of 6-amino-penicillanic acid (6-APA) saline solution: in dichloromethane 272ml, add 40ml purified water and 216ml isopropyl alcohol, stir, add 200 grams of 6-APA when being cooled to 0-6 DEG C, in 20 minutes, at the uniform velocity add triethylamine 108 grams, temperature controls at 0-3 DEG C, react 30 minutes, sampling is observed 6-APA and is dissolved situation, surveys pH value, 6-APA dissolves completely, be cooled to-15 DEG C for subsequent use.
3. condensation reaction: 6-APA saline solution is gone to mixed acid anhydride, controlling the splicing time is 28 minutes, has turned saline solution ,-38 DEG C of insulation reaction 120 minutes, when residual quantity≤0.5% of 6-APA, reaction end.
4. hydrolysis: joined by solution after reaction and be chilled in the 2400ml purified water of 15 DEG C in advance, rapid stirring, at the uniform velocity added hydrochloric acid in 10 minutes, and keep temperature control at 5-10 DEG C, stir after 10 minutes, detection aqueous pH values is 1.0-1.2, stop stirring, leave standstill 10 minutes, water intaking phase.
5. the crystallization of amoxicillin: add the potassium phosphate buffer 300ml that pH is 5.0-5.1 in crystallization kettle, under agitation slowly add the ammonia of aqueous phase and concentration 15% simultaneously, controlling ammonia rate of addition makes pH remain on 5.0-5.1, during adding alkali, temperature controls at 5 DEG C, and this add-subtract time is about 120 minutes.Be cooled to 0 DEG C after adding alkali, stir 1 hour, leave standstill 1 hour, filter, use water and washing with acetone respectively, vacuum drying discharging after 3 hours at 45 DEG C, obtains 356 grams, amoxicillin.
6. the preparation of amoxicillin solution: in 292ml dehydrated alcohol, adds 68ml triethylamine, stirs, and cools to 0 DEG C, adds 100 grams, amoxicillin, is stirred to and dissolves completely.Solution is after membrane filtration is degerming, and pipeline, merging filtrate and the washing liquid of amoxicillin process during mixed liquid washing and filtering with 136ml dehydrated alcohol and 8ml triethylamine.
7. the preparation of sodium iso-octoate solution: add 75 grams of Sodium isooctanoate. in 342ml methyl acetate, is stirred to and dissolves completely at temperature 15-20 DEG C.Solution after membrane filtration is degerming, and by pipeline, merging filtrate and the washing liquid of Sodium isooctanoate. process during 110ml methyl acetate washing and filtering.
8. the crystallization of Amoxicillin Sodium: under at the uniform velocity stirring, sodium iso-octoate solution is joined in the solution of amoxicillin, crystal solution is cooled to 0-5 DEG C, add Amoxicillin Sodium crystal seed (these crystal seed D50≤7.5 μm filtered out, D90≤18 μm, TOP≤40 μm, ) 0.5 gram, insulation 0-5 DEG C, stir 30 minutes, a large amount of crystal is now had to separate out, drip the aqueous sodium carbonate 8ml of 24%, continue stirring 2 hours, sucking filtration, filter cake 250ml methyl acetate is (degerming after filtration, and be pre-chilled to 0-5 DEG C) point 3 washings, wet feed in vacuum drying oven in 45 DEG C, dry 5 hours of-0.09MPa, obtain highly purified 85.1 grams, white crystals type Amoxicillin Sodium powder, purity is 99.8%.
(2) highly purified sulbactam sodium is prepared;
A 100 grams of sulbactams and 36.9 grams of anhydrous sodium acetates are dissolved in the solution of 150ml purified water and 102ml n-butyl alcohol by (), be stirred to and dissolve completely, shift together in the alembic of distillation crystallization apparatus after activated carbon decolorizing.Under the vacuum condition of-0.09MPa, 100 DEG C of water-bath distilling under reduced pressure, add the n-butyl alcohol of equivalent according to distillate amount, when nucleus is formed, growing the grain 15 minutes, continues to be distilled to crystal solution moisture and is less than 1%, stops heating, be cooled to room temperature, sucking filtration, uses n-butyl alcohol washing leaching cake, and dry cake can obtain sulbactam sodium crude product 108 grams, yield 98.9%, purity 92.5%.
B 100 grams of sulbactam sodium crude products are dissolved in 2000ml purified water by (), the hydrochloric acid solution adding 0.1mol/L regulates pH to be 3.0, stirs and separates out insoluble matter, filters, obtains solid after purified water washing.The mixture 2000ml of the solid with ethyl acetate obtained and petroleum ether (volume ratio 3:2) is dissolved, add the pillar being filled with DM-301 macroporous adsorbent resin to pass through, purify as eluent with ethanol and ethyl acetate (volume ratio 1:5) mixture 700ml again, collect eluent.Regulate pH to be 6.5 the eluent 0.1mol/L sodium citrate solution of gained, separate out solid, centrifuge 20 minutes, uses 500ml washed with isopropyl alcohol, and 60 DEG C of vacuum dryings 4 hours, obtain highly finished product 93.9 grams, and it is 99.8% that yield 93.9%, HPLC detects purity.
(3) take Amoxicillin Sodium and sulbactam sodium according to the weight ratio 4:1 of Amoxicillin Sodium and sulbactam sodium, mix in mixed powder machine under nitrogen protection;
(4) amoxicillin sodium and sulbactam sodium being mixed powder is distributed in the injection bottle of sterilization treatment, through filling nitrogen, jumping a queue, rolling lid, packaging, inspection, warehouse-in, obtained amoxicillin sodium for injection sulbactam sodium preparation.
Hot test
Amoxicillin sodium for injection sulbactam sodium formulation samples prepared by random Example 1-3 and commercially available each 1 batch of the amoxicillin sodium for injection sulbactam sodium of reference examples, sample opening is placed in clean container, place 10 days at 60 DEG C of temperature, in the 0th day, the 5th day and sampling in the 10th day, detect by stability high spot reviews project, result of the test is in table 1.
Table 1
Result shows: this product is in hot test, and outward appearance, pH value, related substance etc. are without significant change, and therefore this product is highly stable, and its stability is much higher than commercially available amoxicillin sodium for injection sulbactam sodium.
Accelerated test
Amoxicillin sodium for injection sulbactam sodium formulation samples prepared by random Example 1-3 and commercially available each 1 batch of the amoxicillin sodium for injection sulbactam sodium of reference examples, be placed in 40 DEG C and 75% humidity light protected environment, respectively at placement after the 1st, 2,3,6 months sampling investigate, with within 0 month, investigate data and compare, result of the test is in table 2.
Table 2
Result shows: this product is in accelerated test, and outward appearance, pH value, related substance, content etc. are without significant change, and therefore this product is highly stable, and its stability is much higher than commercially available amoxicillin sodium for injection sulbactam sodium.
Claims (10)
1. an amoxicillin sodium for injection sulbactam sodium preparation, it is characterized in that: described amoxicillin sodium for injection sulbactam sodium preparation is formed by highly purified Amoxicillin Sodium and highly purified sulbactam sodium Homogeneous phase mixing, the weight ratio of Amoxicillin Sodium and sulbactam sodium is 2 ~ 4:1.
2. a preparation method for amoxicillin sodium for injection sulbactam sodium preparation, is characterized in that: comprise the following steps: (1) prepares highly purified Amoxicillin Sodium; (2) highly purified sulbactam sodium is prepared; (3) take Amoxicillin Sodium and sulbactam sodium according to the weight ratio 2 ~ 4:1 of Amoxicillin Sodium and sulbactam sodium, mix in mixed powder machine under nitrogen protection; (4) amoxicillin sodium and sulbactam sodium being mixed powder is distributed in the injection bottle of sterilization treatment, through filling nitrogen, jumping a queue, rolling lid, packaging, inspection, warehouse-in, obtained amoxicillin sodium for injection sulbactam sodium preparation; Wherein highly purified Amoxicillin Sodium is prepared according to following steps:
1. the preparation of mixed acid anhydride: in dichloromethane, adds hydroxyl Deng salt, adds N simultaneously under temperature 10-15 DEG C of rapid stirring, N-dimethyl acetylamide, when cooling to 0 DEG C, add 2,6-lutidines, continue to be cooled to-30 ~-38 DEG C, at the uniform velocity add pivaloyl chloride in 10 minutes, control mixed anhydride temperature, carry out insulation reaction, add isooctyl acid when being cooled to-50 DEG C after end, continue to be cooled to-50 DEG C for subsequent use;
2. the preparation of 6-amino-penicillanic acid saline solution: in dichloromethane, add purified water and isopropyl alcohol, stir, 6-amino-penicillanic acid is added when being cooled to 0-6 DEG C, in 20 minutes, at the uniform velocity add triethylamine, temperature controls at 0-3 DEG C, reacts 30 minutes, 6-amino-penicillanic acid dissolves completely, be cooled to-15 DEG C for subsequent use;
3. condensation reaction: 6-amino-penicillanic acid saline solution is gone to mixed acid anhydride, after having turned saline solution, carries out condensation reaction at low temperatures, and when residual quantity≤0.5% of 6-amino-penicillanic acid, reaction terminates;
4. hydrolysis: join in purified water by solution after condensation reaction, rapid stirring, at the uniform velocity add hydrochloric acid, controlled hydrolysis temperature, stirred after 10 minutes, detected aqueous pH values, stopped stirring, left standstill 10 minutes, water intaking phase.
5. the crystallization of amoxicillin: add potassium phosphate buffer in crystallization kettle, under agitation slowly add aqueous phase and ammonia simultaneously, control ammonia rate of addition, temperature during control adds alkali, crystallize of lowering the temperature after adding alkali, stirs, leave standstill, filter, use water and washing with acetone respectively, vacuum drying obtains amoxicillin;
6. the preparation of amoxicillin solution: in dehydrated alcohol, add triethylamine, stir, cool to 0 DEG C, add amoxicillin, be stirred to and dissolve completely, solution is after membrane filtration is degerming, and the pipeline of amoxicillin process during mixed liquid washing and filtering with dehydrated alcohol and triethylamine, merging filtrate and washing liquid;
7. the preparation of sodium iso-octoate solution: add Sodium isooctanoate. in methyl acetate, be stirred to and dissolve completely, solution after membrane filtration is degerming, and with the pipeline of Sodium isooctanoate. process during methyl acetate washing and filtering, merging filtrate and washing liquid;
8. the crystallization of Amoxicillin Sodium: under at the uniform velocity stirring, sodium iso-octoate solution is joined in the solution of amoxicillin, crystal solution is cooled to 0-5 DEG C, add the Amoxicillin Sodium crystal seed filtered out, insulation 0-5 DEG C, stirs 30 minutes, after having crystal to separate out, drip aqueous sodium carbonate, continue stirring 2 hours, sucking filtration, filter cake methyl acetate washs, and vacuum drying obtains highly purified Amoxicillin Sodium.
3. the preparation method of amoxicillin sodium for injection sulbactam sodium preparation according to claim 2, it is characterized in that: described step 1. in the weight ratio of hydroxyl Deng salt and dichloromethane be 1:4 ~ 5, N, the weight of N-dimethyl acetylamide is 40 ~ 50% of hydroxyl Deng salt, 2, the weight of 6-lutidines is 2.5 ~ 3% of hydroxyl Deng salt, the mol ratio of hydroxyl Deng salt and pivaloyl chloride is 1:1 ~ 1.1, the weight of isooctyl acid is 2.4 ~ 2.8% of hydroxyl Deng salt, mixed anhydride temperature controls at-15 DEG C ~-20 DEG C, and the insulation reaction time is 60 minutes.
4. the preparation method of amoxicillin sodium for injection sulbactam sodium preparation according to claim 2, it is characterized in that: described step 2. in the weight ratio of 6-amino-penicillanic acid and dichloromethane be 1:1.5 ~ 1.8, the weight of purified water is 15 ~ 20% of 6-amino-penicillanic acid, the weight of isopropyl alcohol is 70 ~ 85% of 6-amino-penicillanic acid, and the mol ratio of 6-amino-penicillanic acid and triethylamine is 1:1.05 ~ 1.15.
5. the preparation method of amoxicillin sodium for injection sulbactam sodium preparation according to claim 2, is characterized in that: 3. the middle control splicing time is 20 ~ 28 minutes to described step, and setting-up point is-30 DEG C ~-38 DEG C, and condensation reaction time is 120 minutes.
6. the preparation method of amoxicillin sodium for injection sulbactam sodium preparation according to claim 2, it is characterized in that: described step 4. middle purified water is chilled to 15 DEG C in advance, the hydrochloric acid joining day is 10 minutes, and controlled hydrolysis temperature is 5 ~ 10 DEG C, and detecting aqueous pH values is 1.0 ~ 1.2.
7. the preparation method of amoxicillin sodium for injection sulbactam sodium preparation according to claim 2, it is characterized in that: described step 5. in the pH of potassium phosphate buffer be 5.0-5.1, ammonia concn is 10-15%, controlling ammonia rate of addition makes pH remain on 5.0-5.1, and during adding alkali, temperature controls at 5-10 DEG C, and recrystallization temperature is 0-5 DEG C, mixing time is 1 hour, time of repose is 1 hour, and vacuum drying temperature is 45 DEG C, and the vacuum drying time is 3 hours.
8. the preparation method of amoxicillin sodium for injection sulbactam sodium preparation according to claim 2, it is characterized in that: described step 6. in the weight ratio of amoxicillin and dehydrated alcohol be 1:2 ~ 2.3, the weight of triethylamine is 40 ~ 50% of amoxicillin, and in mixed liquid, the volume ratio of dehydrated alcohol and triethylamine is 15-17:1; Described step 7. in the weight ratio of methyl acetate and Sodium isooctanoate. be 3.8 ~ 4.2:1, stirring and dissolving temperature is 15-20 DEG C, and the weight of Sodium isooctanoate. is the 65-75% of amoxicillin.
9. the preparation method of amoxicillin sodium for injection sulbactam sodium preparation according to claim 2, is characterized in that: described step 8. middle Amoxicillin Sodium crystal seed is D50≤7.5 μm, D90≤18 μm, TOP≤40 μm; Amoxicillin Sodium Seed charge is the 0.1-0.5% of amoxicillin weight, and aqueous sodium carbonate concentration is 20-24%, and vacuum drying temperature is 40-45 DEG C, and vacuum drying pressure is-0.09MPa, and the vacuum drying time is 5-6 hour.
10. the preparation method of amoxicillin sodium for injection sulbactam sodium preparation according to claim 2, is characterized in that: described highly purified sulbactam sodium is prepared according to following steps:
A sulbactam and anhydrous sodium acetate are dissolved in the solution of purified water and n-butyl alcohol by (), be stirred to and dissolve completely, shift in the alembic of distillation crystallization apparatus after activated carbon decolorizing together, under the vacuum condition of-0.09MPa, 100 DEG C of water-bath distilling under reduced pressure, the n-butyl alcohol of equivalent is added according to distillate amount, when nucleus is formed, growing the grain 15 minutes, continues to be distilled to crystal solution moisture and is less than 1%, stops heating, be cooled to room temperature, sucking filtration, uses n-butyl alcohol washing leaching cake, and dry cake obtains sulbactam sodium crude product; The mol ratio of sulbactam and anhydrous sodium acetate is 1:1-1.05, and the weight of purified water is 1.5 times of sulbactam, and the weight of n-butyl alcohol is the 78-83% of sulbactam;
B sulbactam sodium crude product is dissolved in the purified water of 20 times by (), the hydrochloric acid solution adding 0.1mol/L regulates pH to be 2.0-3.0, stirs and separates out insoluble matter, filters, obtains solid after purified water washing; The mixture of the solid with ethyl acetate obtained and petroleum ether is dissolved, use DM-301 absorption with macroporous adsorbent resin, purify as eluent with the mixture of ethanol and ethyl acetate again, collect eluent, regulate pH to be 5.5-6.5 the eluent 0.1mol/L sodium carbonate liquor of gained, separate out solid, centrifuge 20 minutes, by washed with isopropyl alcohol, obtain highly purified sulbactam sodium at 50-60 DEG C of vacuum drying 4-6 hour; The weight of the mixture of ethyl acetate and petroleum ether is 16 times of sulbactam sodium crude product, the volume ratio 3:2 of ethyl acetate and petroleum ether in mixture, the volume ratio 1:5 of ethanol and ethyl acetate in eluant.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104876946A (en) * | 2015-04-30 | 2015-09-02 | 王雪雁 | Sulbactam compound for treating infectious diseases, and preparation method therefor |
| CN104910180A (en) * | 2015-05-28 | 2015-09-16 | 浙江长典医药有限公司 | Children amoxicillin sodium compound entity and drug preparation thereof |
| CN104958253A (en) * | 2015-05-28 | 2015-10-07 | 浙江长典医药有限公司 | Child type amoxicillin sulbactam sodium and low-sodium carrier medicine composition |
| CN105343067A (en) * | 2015-10-29 | 2016-02-24 | 华北制药股份有限公司 | Amoxicillin sodium potassium clavulanate preparation for injection and preparation method of preparation |
| CN106946908A (en) * | 2017-04-25 | 2017-07-14 | 四川制药制剂有限公司 | A kind of production technology of amoxicillin sodium for injection sulbactam |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103301123A (en) * | 2013-06-17 | 2013-09-18 | 四川制药制剂有限公司 | Preparation method for controlling pH (Potential of Hydrogen) of amoxicillin sodium/sulbactam sodium |
| CN103432121A (en) * | 2013-06-17 | 2013-12-11 | 四川制药制剂有限公司 | Preparation method of amoxicillim sodium and sulbactam sodium for injection |
-
2015
- 2015-01-27 CN CN201510040673.4A patent/CN104644630A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103301123A (en) * | 2013-06-17 | 2013-09-18 | 四川制药制剂有限公司 | Preparation method for controlling pH (Potential of Hydrogen) of amoxicillin sodium/sulbactam sodium |
| CN103432121A (en) * | 2013-06-17 | 2013-12-11 | 四川制药制剂有限公司 | Preparation method of amoxicillim sodium and sulbactam sodium for injection |
Non-Patent Citations (4)
| Title |
|---|
| 姜浩伟: "舒巴坦钠结晶工艺的改进", 《中国药业》 * |
| 杜丙松，等: "溶媒结晶法制备阿莫西林钠工艺改进", 《中国抗生素杂志》 * |
| 王丹，等: "注射用阿莫西林钠舒巴坦钠（4:1）与（2:1）药效学比较", 《中国药师》 * |
| 王鹏辉，等: "阿莫西林的反应机理及反应进程的监测", 《河北化工》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104876946A (en) * | 2015-04-30 | 2015-09-02 | 王雪雁 | Sulbactam compound for treating infectious diseases, and preparation method therefor |
| CN104910180A (en) * | 2015-05-28 | 2015-09-16 | 浙江长典医药有限公司 | Children amoxicillin sodium compound entity and drug preparation thereof |
| CN104958253A (en) * | 2015-05-28 | 2015-10-07 | 浙江长典医药有限公司 | Child type amoxicillin sulbactam sodium and low-sodium carrier medicine composition |
| CN105343067A (en) * | 2015-10-29 | 2016-02-24 | 华北制药股份有限公司 | Amoxicillin sodium potassium clavulanate preparation for injection and preparation method of preparation |
| CN106946908A (en) * | 2017-04-25 | 2017-07-14 | 四川制药制剂有限公司 | A kind of production technology of amoxicillin sodium for injection sulbactam |
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