CN104086569A - Preparation method of cefotaxime sodium - Google Patents
Preparation method of cefotaxime sodium Download PDFInfo
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- CN104086569A CN104086569A CN201410365593.1A CN201410365593A CN104086569A CN 104086569 A CN104086569 A CN 104086569A CN 201410365593 A CN201410365593 A CN 201410365593A CN 104086569 A CN104086569 A CN 104086569A
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- cefotaxime
- acetone
- cefotaxime sodium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a preparation method of cefotaxime sodium. Ceftizoxime acid used as the initial raw material reacts with anhydrous sodium acetate to generate the cefotaxime sodium. In such process, purified water, butanol and acetone are selected as crystallizing solvents to control the mixing speed and crystallization temperature in the crystallization process, so that the finally obtained cefotaxime sodium has favorable flowability and can satisfy the subpackaging requirements in production. Various quality indexes of the obtained cefotaxime sodium conform to the requirements for medicinal standard, and thus, the cefotaxime sodium can satisfy the demands for clinical application.
Description
Technical field
The invention belongs to technical field prepared by medical technology Raw medicine, be specifically related to a kind of preparation method of microbiotic cefotaxime sodium.
Background technology
Cefotaxime sodium is clinical conventional microbiotic, powder injection, and intramuscular injection or quiet note, for the multi-infection due to sensitive organism.
Cefotaxime sodium for injection is obtained through aseptic subpackaged by cefotaxime sodium bulk drug, and the process of packing is all power operation, and loading amount can regulate according to actual needs.Because loading amount is automatically to control, therefore the mobility of mechanical packing Cefotaxime sodium raw materials medicine is had relatively high expectations, in the situation of poor fluidity, the loading amount deviation of cefotaxime sodium is larger, cause the unacceptable product quantity of packing too much, not only the cost of manufacturer increases, and has caused great waste, has brought potential safety hazard also to patient's medication simultaneously.Poor fluidity also can cause minute wiring to stop up, cancel closedown, cannot realize in enormous quantities, serialization is aseptic subpackaged, in addition, the maintenance of machine need to be carried out under aseptic condition, the cost of overhaul is very high.
The problem of cefotaxime sodium bulk drug poor fluidity seems simply, but drawback is a lot, is perplexing those skilled in the art always, cannot effectively be solved.
Summary of the invention
To be solved by this invention is the problem of cefotaxime sodium bulk drug poor fluidity, thereby overcomes the series of problems causing due to poor fluidity.
In order to realize object of the present invention, contriver provides following technical scheme.
A preparation method for cefotaxime sodium, take cefotaxime acid as starting raw material, comprises following operation steps:
A. temperature control 26-30 ℃, adds purified water and sodium acetate, anhydrous successively, stirs, and after solid all dissolves, adds cefotaxime acid, is stirred to solution clarification;
B. in step a gained settled solution, add gac, stir decolouring, use sterile film to filter, gained filtrate for later use;
C. in step c gained filtrate, add butanols, stir, temperature control 12-18 ℃, controls mixing speed 150-180 rev/min, and stream adds acetone, while having solid to separate out in solution, stops adding acetone and stops stirring standing growing the grain 30-40 minute;
D. open and stir, control mixing speed 150-180 rev/min, temperature control 12-18 ℃, continues stream and adds acetone;
E. stop to add after acetone, continue to stir, be cooled to 0-5 ℃, growing the grain 50-60 minute;
F. the feed liquid suction filtration after step e growing the grain being finished, filter cake washing with acetone, is then dried to cefotaxime sodium moisture≤3%.
The preparation method of above-mentioned cefotaxime sodium, in step a, the weight ratio of purified water and sodium acetate, anhydrous is 10:7.
The preparation method of above-mentioned cefotaxime sodium, in step a, the weight ratio of sodium acetate, anhydrous and cefotaxime acid is 6.5-7:20.
The preparation method of above-mentioned cefotaxime sodium, in step c, in described butanols and step a, the volume ratio of purified water is 1:1.
The preparation method of above-mentioned cefotaxime sodium, in step c, the time that stream adds acetone is 1-1.5 hour.
The preparation method of above-mentioned cefotaxime sodium, in steps d, continues volume that stream adds acetone and is the 6-7 of purified water volume in step a doubly.In this step, the add-on of acetone is that the amount that the solubleness in mixed solvent and impurity that need to control are separated out according to cefotaxime sodium requires to determine.
The preparation method of above-mentioned cefotaxime sodium, in steps d, it is 2-3 hour that continuation stream adds the acetone time used.
Contriver is in research process, through constantly groping and repeatedly failure, after having summed up all experimental results, think, the cefotaxime acid of take is prepared cefotaxime sodium as starting raw material, the stirring velocity when solvent of crystallization, crystallization is the key factor that affects cefotaxime sodium mobility, therefore technical scheme provided by the present invention is being selected under the condition of suitable recrystallisation solvent and mixing speed, can access the good cefotaxime sodium bulk drug of mobility, meets the requirement of packing.
In the preparation method of cefotaxime sodium of the present invention, using the mixing solutions of purified water, butanols, acetone as recrystallisation solvent, in adding the process of acetone, control stir speed (S.S.) is 150-180 rev/min simultaneously, the slope of repose of the cefotaxime sodium determination preparing is 28-32 °, and mobility is better.
The method of the invention, define the weight ratio of sodium acetate, anhydrous and cefotaxime acid, can guarantee that cefotaxime acid reacts completely, and sodium acetate, anhydrous can be excessive not too many yet, when improving cefotaxime sodium yield, can not make the wherein amount of impurity obviously increase.
The method of the invention, defines in step c, steps d and adds the time of acetone all to limit, and the too fast or mistake adding all can cause fine crystals to increase slowly, finally causes cefotaxime sodium mobility variation.Control adding the used time of acetone, and at the uniform velocity add, the cefotaxime sodium granular size of separating out is compared with homogeneous, and mobility is better.
In the preparation process of cefotaxime sodium, the reaction solution of sodium acetate, anhydrous and cefotaxime acid can add gac and decolour, to obtain the cefotaxime sodium that look level is lower.The 0.18%-0.2% of the preferred cefotaxime acid weight of consumption of gac, both can guarantee decolorizing effect, can not lose reaction mass again, guaranteed yield.
The preparation method of cefotaxime sodium of the present invention, the rotating speed stirring during by the restriction kind of recrystallisation solvent, the ratio of recrystallisation solvent and crystallization, finally obtain the cefotaxime sodium that good fluidity is suitable for packing, and the quality of the cefotaxime sodium obtaining meets the requirement of medicinal standard.
The present invention uses butanols and acetone to carry out crystallization, and butanols can effectively dissolve pigment, reduces the look level of cefotaxime sodium; Use after acetone, compare with the butyl ester that tradition is used, when dry, the moisture of cefotaxime sodium can reach qualified in the shorter time; The weight in average yield of the method has also improved 1.5% simultaneously.By adjusting many correlative factors in preparation process, the slope of repose of embodying cefotaxime sodium mobility has been reduced to 30 ° of left and right from 45 °, and mobility significantly promotes, and can meet the requirement of client's serialization packing completely.
Embodiment
Below in conjunction with specific embodiment, content of the present invention is further described in detail.
Embodiment 1
26 ℃ of temperature controls, in 500mL purified water, add sodium acetate, anhydrous 350g, stir molten clear after, add cefotaxime acid 1000g, be stirred to solution clarification, add 2g activated carbon decolorizing 10min, then use sterile film to filter, in filtrate, add butanols 500mL, stir 5min, control and stir 150 revs/min, 12 ℃ of temperature controls, stream adds acetone, observe the variation of solution, while having solid to separate out in finding solution, stop adding acetone, stop stirring, 1h when stream adds acetone and shares, standing growing the grain 30min, subsequently, open and stir, control 150 revs/min of mixing speed, 12 ℃ of temperature controls, in 2 hours, continue stream and add acetone 3L, after acetone adds, feed liquid is cooled to 0 ℃, growing the grain 50 minutes, feed liquid is carried out to suction filtration, filter cake washing with acetone three times, put into baking box, temperature control 63-65 ℃, be dried to moisture≤3%, obtain cefotaxime sodium 1010g, weight yield is 101%.
Embodiment 2
30 ℃ of temperature controls, in 4.64L purified water, add sodium acetate, anhydrous 3.25kg, stir molten clear after, add cefotaxime acid 10kg, be stirred to solution clarification, add 18g activated carbon decolorizing 10min, then use sterile film to filter, in filtrate, add butanols 4.64L, stir 5min, control and stir 180 revs/min, 18 ℃ of temperature controls, stream adds acetone, observe the variation of solution, while having solid to separate out in finding solution, stop adding acetone, stop stirring, 1.5h when stream adds acetone and shares, standing growing the grain 40min, subsequently, open and stir, control 180 revs/min of mixing speed, 18 ℃ of temperature controls, in 3 hours, continue stream and add acetone 32.48L, after acetone adds, feed liquid is cooled to 5 ℃, growing the grain 60 minutes, feed liquid is carried out to suction filtration, filter cake washing with acetone three times, put into baking box, temperature control 63-65 ℃, be dried to moisture≤3%, obtain cefotaxime sodium 10.2kg, weight yield is 102%.
Contriver detects the product preparing according to method described in embodiment 1 and embodiment 2, and result is as shown in table 1.
Table 1
| Detect sample | Content | Look level | Acidity | Cefotaxime polymkeric substance | Residual solvent |
| Embodiment 1 | 95.6％ | 2# | 5.6 | 0.04％ | Acetone 0.028%; Butanols does not detect |
| Embodiment 2 | 94.8％ | 2# | 5.5 | 0.04％ | Acetone 0.029%; Butanols does not detect |
Contriver has also carried out accelerated test to the product preparing according to method described in embodiment 1 and embodiment 2, and result is as shown in table 2.
Accelerated test condition: 40 ± 2 ℃ of temperature-, relative humidity 75 ± 5%, condition under place 6 months, respectively 0,1,2,3, sampling the last day in June detects.
Table 2 cefotaxime sodium accelerated test data
Contriver detects the product preparing according to method described in embodiment 1 and embodiment 2 with FT-104B Repose angle gauge, and result is as shown in table 3.
Table 3
| Detect sample | Slope of repose |
| Embodiment 1 | 28° |
| Embodiment 2 | 32° |
Claims (7)
1. a preparation method for cefotaxime sodium, take cefotaxime acid as starting raw material, it is characterized in that, comprises following operation steps:
A. temperature control 26-30 ℃, adds purified water and sodium acetate, anhydrous successively, stirs, and after solid all dissolves, adds cefotaxime acid, is stirred to solution clarification;
B. in step a gained settled solution, add gac, stir decolouring, use sterile film to filter, gained filtrate for later use;
C. in step c gained filtrate, add butanols, stir, temperature control 12-18 ℃, controls mixing speed 150-180 rev/min, and stream adds acetone, while having solid to separate out in solution, stops adding acetone and stops stirring standing growing the grain 30-40 minute;
D. open and stir, control mixing speed 150-180 rev/min, temperature control 12-18 ℃, continues stream and adds acetone;
E. stop to add after acetone, continue to stir, be cooled to 0-5 ℃, growing the grain 50-60 minute;
F. the feed liquid suction filtration after step e growing the grain being finished, filter cake washing with acetone, is then dried to cefotaxime sodium moisture≤3%.
2. the preparation method of a kind of cefotaxime sodium according to claim 1, is characterized in that, in step a, the weight ratio of purified water and sodium acetate, anhydrous is 10:7.
3. the preparation method of a kind of cefotaxime sodium according to claim 1, is characterized in that, in step a, the weight ratio of sodium acetate, anhydrous and cefotaxime acid is 6.5-7:20.
4. the preparation method of a kind of cefotaxime sodium according to claim 1, is characterized in that, in step c, in described butanols and step a, the volume ratio of purified water is 1:1.
5. the preparation method of a kind of cefotaxime sodium according to claim 1, is characterized in that, in step c, the time that stream adds acetone is 1-1.5 hour.
6. the preparation method of a kind of cefotaxime sodium according to claim 1, is characterized in that, in steps d, continues volume that stream adds acetone and be the 6-7 of purified water volume in step a doubly.
7. the preparation method of a kind of cefotaxime sodium according to claim 1, is characterized in that, in steps d, it is 2-3 hour that continuation stream adds the acetone time used.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892636A (en) * | 2015-05-21 | 2015-09-09 | 天津大学 | Method for preparing cefotaxime sodium crystal |
| CN105884800A (en) * | 2015-10-28 | 2016-08-24 | 石药集团中诺药业（石家庄）有限公司 | Novel cefotaxime sodium compound |
| CN107049958A (en) * | 2017-04-26 | 2017-08-18 | 四川制药制剂有限公司 | The preparation technology of cefotaxime sodium for injection powder-injection |
| CN109081847A (en) * | 2017-06-14 | 2018-12-25 | 郝志艳 | A kind of 1/2 water cefotaxime sodium compound |
| CN109096305A (en) * | 2017-06-20 | 2018-12-28 | 刘兆娟 | A kind of 1/4 water cefotaxime sodium compound |
| CN113666947A (en) * | 2021-07-23 | 2021-11-19 | 无锡海伦生物科技有限公司 | Preparation method of cefotaxime sodium |
| CN114028336A (en) * | 2021-10-20 | 2022-02-11 | 华北制药河北华民药业有限责任公司 | Preparation method of cefotaxime sodium for injection |
| CN114874237A (en) * | 2022-04-21 | 2022-08-09 | 华北制药河北华民药业有限责任公司 | Refining method of cefotaxime sodium |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892636A (en) * | 2015-05-21 | 2015-09-09 | 天津大学 | Method for preparing cefotaxime sodium crystal |
| CN105884800A (en) * | 2015-10-28 | 2016-08-24 | 石药集团中诺药业（石家庄）有限公司 | Novel cefotaxime sodium compound |
| CN107049958A (en) * | 2017-04-26 | 2017-08-18 | 四川制药制剂有限公司 | The preparation technology of cefotaxime sodium for injection powder-injection |
| CN109081847A (en) * | 2017-06-14 | 2018-12-25 | 郝志艳 | A kind of 1/2 water cefotaxime sodium compound |
| CN109096305A (en) * | 2017-06-20 | 2018-12-28 | 刘兆娟 | A kind of 1/4 water cefotaxime sodium compound |
| CN113666947A (en) * | 2021-07-23 | 2021-11-19 | 无锡海伦生物科技有限公司 | Preparation method of cefotaxime sodium |
| CN114028336A (en) * | 2021-10-20 | 2022-02-11 | 华北制药河北华民药业有限责任公司 | Preparation method of cefotaxime sodium for injection |
| CN114874237A (en) * | 2022-04-21 | 2022-08-09 | 华北制药河北华民药业有限责任公司 | Refining method of cefotaxime sodium |
| WO2023202567A1 (en) * | 2022-04-21 | 2023-10-26 | 华北制药河北华民药业有限责任公司 | Method for refining cefotaxime sodium |
| CN114874237B (en) * | 2022-04-21 | 2024-01-19 | 华北制药河北华民药业有限责任公司 | Refining method of cefotaxime sodium |
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