CN102838622A - Preparation method of stable cefuroxime sodium - Google Patents
Preparation method of stable cefuroxime sodium Download PDFInfo
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- CN102838622A CN102838622A CN 201110168229 CN201110168229A CN102838622A CN 102838622 A CN102838622 A CN 102838622A CN 201110168229 CN201110168229 CN 201110168229 CN 201110168229 A CN201110168229 A CN 201110168229A CN 102838622 A CN102838622 A CN 102838622A
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Abstract
The invention belongs to the technical field of medicine, relates to a preparation method of cephalosporin, and more specifically relates to a preparation method of a stable cefuroxime sodium. According to the invention, a process control technique and a multiscale simulation technology are utilized to conduct on-line crystallization control of cefuroxime sodium, so as to obtain a cefuroxime sodium product with stable quality and crystal form, and moderate particles. The quality and especially the stability of the product are improved greatly, and product quality achieves a same level as that of ''Xilixin'' from an original researching factory.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of preparation method of cynnematin, more specifically, relate to a kind of preparation method of stable Cefuroxime sodium.
Background technology
Cefuroxime sodium is a national essential drugs, also is that the antibacterials of China's appearance soon in 2011 are used one of 8 cephalo kinds of unrestricted use in the management at different levels catalogue.About 500 tons of domestic Cefuroxime sodium YO in 2010 is the big kind of widely used clinically cynnematin, in the hospital administration amount of money, and rank the 2nd.The cephalofruxin product is by the exploitation of Britain Glaxo company, and clinical application is extensive.Be used for treating by genus clostridium and the Bacteroides in the gram negative bacilli and the caused respiratory tract infection of Fusobacterium, urogenital infections, gonorrhoea and skin soft-tissue infection in the Peptococcus in hemophilus influenzae (comprising amp-R bacterial strain), haemophilus parainfluenzae, branhamella catarrhalis, intestinal bacteria, Klebsiella, Proteus mirabilis, lack perseverance Bacillus proteus, thunder utmost point Providence and the neisseria gonorrhoeae (comprise and producing and the bacterial strain that does not produce the mould enzyme) of gram negative aerobic bacteria, streptococcus aureus (comprise the bacterial strain that produces the mould enzyme, but do not comprise the bacterial strain of methicillin-resistant), staphylococcus epidermidis, streptococcus pneumoniae (comprising other Hemolytic streptococcus), Lu family suis (streptococcus agalactiae) and propionibacterium, gram-positive and the negative anaerobic cocci in the gram positive aerobic bacteria and Peptostreptococcus, the gram-positive bacillus.Because determined curative effect, so be widely used in resisting the multiple infection that responsive mushroom causes, this medicine has become world's situation of selling well anti-infectives, is still the outstanding person in the beta-lactam anti-infective after the patent protection expiration.In nearly 40 cynnematins that China has gone on the market, only 5 cynnematins are national essential drugs.
The chemical name of Cefuroxime sodium is that (6R, 7R)-7-[2-furyl (methoxyimino) kharophen]-3-carbamyl oxygen methyl-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-sodium formiate, molecular formula is: C
16H
15N
4NaO
8S, molecular weight is 446.36, chemical structural formula is represented with following formula I:
Although the listing of these article for many years; But this product stability is poor, and product is variable color very easily, though there is domestic preparation producer in preparation process, to adopt nitrogen protection; Make the product variable color slow down to some extent; But do not solve product inner quality instability problem, the stability of product is still very poor, and manufacturer fails fundamentally to solve the stable difficult problem of product.Existing domestic Cefuroxime sodium product and most of external product (it is to remove former " zinacef " that grinds factory) all do not reach shady and cool library storage condition effect in the phase product color meet Chinese Pharmacopoeia and European Pharmacopoeia requirement, this brings than hidden danger greatly to clinical use.So be badly in need of the product of exploitation high quality, good stability, so that satisfy clinical demand.
Summary of the invention
The present invention utilizes process control technology (PAT) and multiple dimensioned simulation (multi-scale modeling) technology; Cephalofruxin sodium is carried out online crystallization technique research; Develop quality and stable crystal form, the moderate Cefuroxime sodium product of particle; Improve the quality of products, particularly product stability makes quality product reach the former same level of factory's " zinacef " of grinding.
Obtain stablizing the low Cefuroxime sodium aseptic powder of impurity, not only need the low cefuroxime acid of the good impurity of quality, simultaneously, the crystal of Cefuroxime sodium has very big relation to the stability of product.Through relatively, we find, former " zinacef " product that grinds factory, crystal rule, size evenly, product stable fine, and domestic manufacturer's ubiquity crystal is irregular, big or small inhomogeneous, defectives such as the poor stability of product.Primary study operational condition of the present invention comprises temperature, degree of supersaturation, pH value, impurity even stirs the influence to the crystal growth behavior; Foundation meets the model (horizontal calculation model of colony's grain number and Fluid Mechanics Computation model) of industry practice; And research corresponding online measuring technology, and control techniques.The horizontal calculation model of colony's grain number of ' based on crystal shape ' that the present invention proposes has been realized the simulation to crystal shape distribution in the mold first; The online quantitative portrayal of crystal shape and the line closed loop control of crystal shape have for the first time been realized first.Primary study exists under the situation and online impurity measurement in the large-scale industry mold at low concentration impurity, simulation and multiple goal (distribution of sizes, distribution of shapes, yield etc.) optimal control.
The technical scheme that adopts is following:
In the reaction flask of jacketed, add cefuroxime acid, acetone, purified water, be stirred to complete dissolving, add gac, stir decolouring 30 minutes under the room temperature, filter; With the mixed solution washing that acetone and a small amount of purified water are formed, merging filtrate adds absolute ethyl alcohol; 0～60 ℃ of temperature control drips Sodium.alpha.-hydroxypropionate and sodium-acetate mixed sodium liquid, and Sodium.alpha.-hydroxypropionate and its mol ratio of sodium-acetate mixed sodium liquid and cefuroxime acid are 1～2: 1; After dripping end, stirring reaction 15～30min; Subsequently, in 15～45min, drip amount of acetone, be cooled to 10～30 ℃ and stir growing the grain, filter, with the mixed solution agitator treating of acetone+purified water+ethanol composition; With the proper amount of acetone washing, survey cephalofruxin sodium pH value and get final product greater than 6 again, vacuum-drying to moisture below 45 ℃ is qualified, pulverizes batch mixing, packing.
Described organic solvent can be used lower alcohol, lower ketones etc., the mixed solvent of particular methanol, ethanol, Virahol, acetone or these solvents.Solvent load is with solvent: the Cefuroxime sodium envelope-bulk to weight ratio is that 10～50: 1 (V/W) is for good.Solvent: Sodium.alpha.-hydroxypropionate or sodium-acetate envelope-bulk to weight ratio are that 5～30: 1 (V/W) is for good
Described temperature of reaction is 0 ℃～60 ℃, and more excellent TR is 20 ℃～45 ℃.Reaction times, and different, the reaction times directly influenced the yield that reacts with the kind of starting material, solvent, acid and consumption thereof, temperature of reaction.Reaction temperature is spent when hanging down, and reaction not exclusively makes product yield on the low side; Temperature of reaction is too high, the time be easy to generate side reaction, produce impurity, influence quality product and yield.
Advantage of the present invention is:
With the product that Technology of the present invention makes, product impurity is low, good stability, and yield is high,
Be a yield height, good product quality, be suitable for the stable Cefuroxime sodium preparation method of suitability for industrialized production.
Embodiment
Through following specific embodiment the present invention is described further below, but these embodiment should not be construed as the restriction to protection domain of the present invention.
Embodiment 1
In the reaction flask of jacketed, add 100 gram cefuroxime acids, 300 milliliters in acetone, 50 milliliters of purified water are stirred to complete dissolving, and add gac, stir decolouring 30 minutes under the room temperature, filter; The mixed solution of forming with acetone and a small amount of purified water washs, and merging filtrate adds absolute ethyl alcohol, and 25 ℃ of temperature controls drip Sodium.alpha.-hydroxypropionate (74 gram) and sodium-acetate (11 gram) (being dissolved in 100 milliliters of absolute ethyl alcohols), after dropping finishes, and stirring reaction 30min; Subsequently, in 15min, drip 800 milliliters acetone, be cooled to 10 ℃ and stir growing the grain, filter, with the mixed solution agitator treating of acetone+purified water+ethanol composition; With the proper amount of acetone washing, survey cephalofruxin sodium pH value and get final product greater than 6 again, vacuum-drying to moisture below 45 ℃ is qualified, obtains Cefuroxime Sodium 97 grams, purity 99.3%.
Product is placed under the condition of shady and cool storehouse (15～20 ℃), stable testing property, data are following:
Embodiment 2
In the reaction flask of jacketed, add 100 gram cefuroxime acids, 500 milliliters in acetone, 70 milliliters of purified water are stirred to complete dissolving, and add gac, stir decolouring 30 minutes under the room temperature, filter; The mixed solution of forming with acetone and a small amount of purified water washs, and merging filtrate adds absolute ethyl alcohol, and 35 ℃ of temperature controls drip Sodium.alpha.-hydroxypropionate (86 gram) and sodium-acetate (9 gram) (being dissolved in 100 milliliters of absolute ethyl alcohols), after dropping finishes, and stirring reaction 30min; Subsequently, in 45min, drip 1000 milliliters acetone, be cooled to 10 ℃ and stir growing the grain, filter, with the mixed solution agitator treating of acetone+purified water+ethanol composition; With the proper amount of acetone washing, survey cephalofruxin sodium pH6.5 again, vacuum-drying to moisture below 45 ℃ is qualified, obtains Cefuroxime Sodium 98 grams, purity 99.5%.
Embodiment 3
In the reaction flask of jacketed, add 100 gram cefuroxime acids, 400 milliliters in acetone, 40 milliliters of purified water are stirred to complete dissolving, and add gac, stir decolouring 30 minutes under the room temperature, filter; The mixed solution of forming with acetone and a small amount of purified water washs, and merging filtrate adds absolute ethyl alcohol, and 15 ℃ of temperature controls drip Sodium.alpha.-hydroxypropionate (70 gram) and sodium-acetate (22 gram) (being dissolved in 100 milliliters of absolute ethyl alcohols), after dropping finishes, and stirring reaction 30min; Subsequently, in 15min, drip 1200 milliliters acetone, be cooled to 10 ℃ and stir growing the grain, filter, with the mixed solution agitator treating of acetone+purified water+ethanol composition; With the proper amount of acetone washing, it is qualified to survey cephalofruxin sodium pH value vacuum-drying to moisture below 6.9,45 ℃ again, obtains Cefuroxime Sodium 97 grams, purity 99.4%.
Claims (4)
1. the preparation method of a stable Cefuroxime sodium, this method comprises: in reaction flask, add cefuroxime acid, acetone, purified water, be stirred to complete dissolving, add gac, stir decolouring 30 minutes under the room temperature, filter; With the mixed solution washing that acetone and a small amount of purified water are formed, merging filtrate adds absolute ethyl alcohol; 0～60 ℃ of temperature control drips Sodium.alpha.-hydroxypropionate and sodium-acetate mixed sodium liquid, and Sodium.alpha.-hydroxypropionate and its mol ratio of sodium-acetate mixed sodium liquid and cefuroxime acid are 1～2: 1; After dripping end, stirring reaction 15～30min; Subsequently, in 15～45min, drip amount of acetone, be cooled to 10～30 ℃ and stir growing the grain, filter, with the mixed solution agitator treating of acetone+purified water+ethanol composition; With the proper amount of acetone washing, survey cephalofruxin sodium pH value and get final product greater than 6 again, vacuum-drying to moisture below 45 ℃ is qualified, pulverizes batch mixing, packing.
2. the preparation method of a stable Cefuroxime sodium, this method comprises: in reaction flask, add 100 gram cefuroxime acids, 300 milliliters in acetone, 50 milliliters of purified water are stirred to complete dissolving, and add gac, stir decolouring 30 minutes under the room temperature, filter; The mixed solution of forming with acetone and a small amount of purified water washs, and merging filtrate adds absolute ethyl alcohol, and 25 ℃ of temperature controls drip Sodium.alpha.-hydroxypropionate (74 gram) and sodium-acetate (11 gram) (being dissolved in 100 milliliters of absolute ethyl alcohols), after dropping finishes, and stirring reaction 30min; Subsequently, in 15min, drip 800 milliliters acetone, be cooled to 10 ℃ and stir growing the grain, filter, with the mixed solution agitator treating of acetone+purified water+ethanol composition; With the proper amount of acetone washing, survey cephalofruxin sodium pH value and get final product greater than 6 again, vacuum-drying to moisture below 45 ℃ is qualified, obtains Cefuroxime Sodium 97 grams, purity 99.3%.
3. the preparation method of a stable Cefuroxime sodium, this method comprises: in reaction flask, add 100 gram cefuroxime acids, 500 milliliters in acetone, 70 milliliters of purified water are stirred to complete dissolving, and add gac, stir decolouring 30 minutes under the room temperature, filter; The mixed solution of forming with acetone and a small amount of purified water washs, and merging filtrate adds absolute ethyl alcohol, and 35 ℃ of temperature controls drip Sodium.alpha.-hydroxypropionate (86 gram) and sodium-acetate (9 gram) (being dissolved in 100 milliliters of absolute ethyl alcohols), after dropping finishes, and stirring reaction 30min; Subsequently, in 45min, drip 1000 milliliters acetone, be cooled to 10 ℃ and stir growing the grain, filter, with the mixed solution agitator treating of acetone+purified water+ethanol composition; With the proper amount of acetone washing, survey cephalofruxin sodium pH6.5 again, vacuum-drying to moisture below 45 ℃ is qualified, obtains Cefuroxime Sodium 98 grams, purity 99.5%.
4. the preparation method of a stable Cefuroxime sodium, this method comprises: in reaction flask, add 100 gram cefuroxime acids, 400 milliliters in acetone, 40 milliliters of purified water are stirred to complete dissolving, and add gac, stir decolouring 30 minutes under the room temperature, filter; The mixed solution of forming with acetone and a small amount of purified water washs, and merging filtrate adds absolute ethyl alcohol, and 15 ℃ of temperature controls drip Sodium.alpha.-hydroxypropionate (70 gram) and sodium-acetate (22 gram) (being dissolved in 100 milliliters of absolute ethyl alcohols), after dropping finishes, and stirring reaction 30min; Subsequently, in 15min, drip 1200 milliliters acetone, be cooled to 10 ℃ and stir growing the grain, filter, with the mixed solution agitator treating of acetone+purified water+ethanol composition; With the proper amount of acetone washing, it is qualified to survey cephalofruxin sodium pH value vacuum-drying to moisture below 6.9,45 ℃ again, obtains Cefuroxime Sodium 97 grams, purity 99.4%.
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| CN 201110168229 CN102838622A (en) | 2011-06-21 | 2011-06-21 | Preparation method of stable cefuroxime sodium |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044452A (en) * | 2013-01-10 | 2013-04-17 | 潘行远 | Preparation method of low-moisture and high-stability sterile cefuroxime sodium |
| CN103102357A (en) * | 2013-02-21 | 2013-05-15 | 广东立国制药有限公司 | Synthesis method of cefuroxime sodium |
| CN103819490A (en) * | 2014-03-20 | 2014-05-28 | 悦康药业集团有限公司 | Cefuroxime sodium compound |
| CN104530084A (en) * | 2014-12-23 | 2015-04-22 | 天津大学 | Novel crystal form of cefuroxime sodium and preparation method of cefuroxime sodium crystal |
| CN104771372A (en) * | 2015-03-10 | 2015-07-15 | 华北制药河北华民药业有限责任公司 | Cefuroxime sodium powder preparation for injection |
| CN104910187A (en) * | 2015-05-28 | 2015-09-16 | 浙江长典医药有限公司 | Children cefuroxime sodium compound entity and preparation thereof |
| CN106279209A (en) * | 2016-08-24 | 2017-01-04 | 南昌立健药业有限公司 | A kind of preparation technology of cefuroxime sodium for injection |
| CN110437258A (en) * | 2019-08-12 | 2019-11-12 | 上海龙翔生物医药开发有限公司 | The preparation method and applications of Cefuroxime Sodium |
| CN110483553A (en) * | 2019-08-12 | 2019-11-22 | 上海龙翔生物医药开发有限公司 | A kind of stable Cefuroxime Sodium and preparation method thereof |
-
2011
- 2011-06-21 CN CN 201110168229 patent/CN102838622A/en active Pending
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044452A (en) * | 2013-01-10 | 2013-04-17 | 潘行远 | Preparation method of low-moisture and high-stability sterile cefuroxime sodium |
| CN103102357A (en) * | 2013-02-21 | 2013-05-15 | 广东立国制药有限公司 | Synthesis method of cefuroxime sodium |
| CN103102357B (en) * | 2013-02-21 | 2016-01-13 | 广东立国制药有限公司 | A kind of synthetic method of Cefuroxime sodium |
| CN103819490A (en) * | 2014-03-20 | 2014-05-28 | 悦康药业集团有限公司 | Cefuroxime sodium compound |
| CN103819490B (en) * | 2014-03-20 | 2016-03-30 | 悦康药业集团有限公司 | A kind of cephalofruxin sodium compound |
| CN104530084A (en) * | 2014-12-23 | 2015-04-22 | 天津大学 | Novel crystal form of cefuroxime sodium and preparation method of cefuroxime sodium crystal |
| CN104771372A (en) * | 2015-03-10 | 2015-07-15 | 华北制药河北华民药业有限责任公司 | Cefuroxime sodium powder preparation for injection |
| CN104910187A (en) * | 2015-05-28 | 2015-09-16 | 浙江长典医药有限公司 | Children cefuroxime sodium compound entity and preparation thereof |
| CN106279209A (en) * | 2016-08-24 | 2017-01-04 | 南昌立健药业有限公司 | A kind of preparation technology of cefuroxime sodium for injection |
| CN110437258A (en) * | 2019-08-12 | 2019-11-12 | 上海龙翔生物医药开发有限公司 | The preparation method and applications of Cefuroxime Sodium |
| CN110483553A (en) * | 2019-08-12 | 2019-11-22 | 上海龙翔生物医药开发有限公司 | A kind of stable Cefuroxime Sodium and preparation method thereof |
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Application publication date: 20121226 |