CN103980292B - The crystallization method of cefixime trihydrate - Google Patents
The crystallization method of cefixime trihydrate Download PDFInfo
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- CN103980292B CN103980292B CN201310238183.6A CN201310238183A CN103980292B CN 103980292 B CN103980292 B CN 103980292B CN 201310238183 A CN201310238183 A CN 201310238183A CN 103980292 B CN103980292 B CN 103980292B
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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
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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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
- C07D501/12—Separation; Purification
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Abstract
The invention provides a kind of crystallization method of cefixime trihydrate, comprise the following steps: Cefixime Micronized is formed suspension by (1) in water, then add alkali wherein and Cefixime Micronized is dissolved completely, form alkaline solution; (2) mixed solvent of water and organic solvent is prepared, the 10-18 that the volume of described mixed solvent is Cefixime Micronized weight described in step (1) doubly, the volume ratio of water and organic solvent is 1:1, described mixed solvent is warming up to 20 DEG C-45 DEG C, and the acid with 2 % by weight-15 % by weight regulates the pH to 2-4 of described mixed solvent; (3) described alkaline solution is dropped in described mixed solvent, and in dropping process, control the pH of solution with the acid of 2 % by weight-15 % by weight be 2-4; (4) after being added dropwise to complete, cooling crystallization.The crystallization method technique of cefixime trihydrate of the present invention is simple, and consuming time short, yield is high.Products obtained therefrom good fluidity, quality is high, significantly improves the stability of product.
Description
Technical field
The application relates to pharmaceutical chemistry crystallization technique field.More specifically, the application relates to the crystallization method of cefixime trihydrate.
Background technology
Cefixime Micronized is third generation oral cephalosporin, plays germicidal action by anti-bacteria Cell wall synthesis, stablizes, has a broad antifungal spectrum to most beta lactamase.To gram-positive cocci as streptococcus pneumoniae, micrococcus scarlatinae, gram negative bacillus is as hemophilus influenza (comprise and produce enzyme strain), moraxelle catarrhalis (comprise and produce enzyme strain), intestinal bacteria, Proteus mirabilis, gonococcus (comprise and produce enzyme strain) all good anti-microbial effects of tool.
The chemical name of Cefixime Micronized is: (6R; 7R)-7 [[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxyl) imino-] ethanoyl] is amino]-3-vinyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid trihydrate, molecular formula is C
16h
15n
5o
7s
23H
2o, molecular weight is 507.50, and its structural formula is:
Current cefixime trihydrate crystallization is mainly obtained by the method for alkali-soluble acid analysis from the mixed solvent of water or water and organic solvent.But quality product is not high, especially stability is all poor, is not easy to suitability for industrialized production and storage.
Therefore, need to find a kind of method improving cefixime trihydrate quality product and stability, so that suitability for industrialized production and storage.
Summary of the invention
The invention provides a kind of crystallization method of cefixime trihydrate, comprise the following steps:
(1) Cefixime Micronized is formed suspension in water, then add alkali wherein and Cefixime Micronized is dissolved completely, form alkaline solution;
(2) mixed solvent of water and organic solvent is prepared, the 10-18 that the volume of described mixed solvent is Cefixime Micronized weight described in step (1) doubly, the volume ratio of water and organic solvent is 1:1, above-mentioned mixed solvent is warming up to 20 DEG C-45 DEG C, preferably 30 DEG C-40 DEG C, with 2 % by weight-15 % by weight, preferably the acid of 8 % by weight-15 % by weight regulates the pH to 2-4 of described mixed solvent, preferred 2.5-3.2;
(3) described alkaline solution is dropped in described mixed solvent, and with 2 % by weight-15 % by weight in dropping process, preferably the acid of 8 % by weight-15 % by weight controls the pH of solution is 2-4, preferred 2.5-3.2;
(4) after being added dropwise to complete, cooling crystallization.
The crystallization method technique of cefixime trihydrate of the present invention is simple, and consuming time short, yield is high.Products obtained therefrom good fluidity, quality product is high, and general purity is about 99.4%-99.5%.Method of the present invention significantly improves the stability of product.Under the condition of 40 DEG C of relative humidity 75%, stability experiment shows: after 6 months, and single mixing is less than 0.5%, and content is greater than 98.5%.
Accompanying drawing explanation
Fig. 1 is the TGA weightlessness figure of product in embodiment 3.
Fig. 2 is embodiment 3 product crystal morphology under 100 times of polarization microscopes.
Fig. 3 is the X-ray powder diffraction pattern of embodiment 3 product.
Embodiment
The invention provides a kind of crystallization method of cefixime trihydrate, comprise the following steps:
(1) Cefixime Micronized is formed suspension in water, then add alkali wherein and Cefixime Micronized is dissolved completely, form alkaline solution;
(2) mixed solvent of water and organic solvent is prepared, the 10-18 that the volume of described mixed solvent is Cefixime Micronized weight described in step (1) doubly, the volume ratio of water and organic solvent is 1:1, described mixed solvent is warming up to 20 DEG C-45 DEG C, preferably 30 DEG C-40 DEG C, with 2 % by weight-15 % by weight, preferably the acid of 8 % by weight-15 % by weight regulates the pH to 2-4 of described mixed solvent, preferred 2.5-3.2;
(3) described alkaline solution is dropped in described mixed solvent, and with 2 % by weight-15 % by weight in dropping process, preferably the acid of 8 % by weight-15 % by weight controls the pH of solution is 2-4, preferred 2.5-3.2;
(4) after being added dropwise to complete, cooling crystallization.
In some embodiments, in step (1), the mass ratio of Cefixime Micronized and water is 1:3-1:10, preferred 1:6.6-1:10.
In some embodiments, the alkali in step (1) can be ammoniacal liquor, sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium methylate, potassium hydroxide, salt of wormwood, saleratus, triethylamine, sodium acetate, potassium acetate, Sodium Ethylhexanoate, diisopropyl ethyl amine, Tributylamine, trolamine or dimethyl benzyl amine.In some preferred embodiments, the alkali in step (1) is sodium bicarbonate or sodium carbonate.
In some embodiments, the organic solvent in step (2) is polar aprotic solvent, polar aprotic solvent or both any mixed solvents.In some preferred embodiments, polar aprotic solvent includes but not limited to methyl alcohol, ethanol or Virahol; Polar aprotic solvent includes but not limited to acetone, butanone, tetrahydrofuran (THF), acetonitrile, DMF or DMSO.In some more preferred, the organic solvent in step (2) is ethanol, Virahol and acetone.
In some embodiments, the acid in step (2) and step (3) can be hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, Hydrogen bromide, formic acid or acetic acid.In some preferred embodiments, the acid in step (2) and step (3) is hydrochloric acid.
In some embodiments, in step (3), alkaline solution and acid are synchronously dropped in the mixed solvent of water that step (2) prepares and organic solvent, and the pH controlling solution in dropping process is 2-4, preferred 2.5-3.2.In some preferred embodiments, in dropping process, the pH fluctuation of solution is controlled within 0.2.
In step (3), do not have specific requirement to the rate of addition of alkaline solution or acid, obviously fluctuate be advisable not cause pH, pH should fluctuate in comparatively close limit, is generally advisable within 0.2.
In some embodiments, in step (4), after being added dropwise to complete, the volume ratio of organic solvent and water used is 1:1.5-1:3.5.Water used is the summation of the water in water in water in step (1) and step (2) in mixed solvent and step (2) and the middle acid of step (3).
In some embodiments, in step (4), after being added dropwise to complete, also comprise growing the grain step, growing the grain temperature is 20 DEG C-45 DEG C, preferably 30 DEG C-40 DEG C; Rearing crystal time is 0.5-3 hour, is preferably 0.5-2 hour.
In some embodiments, in step (4), after being added dropwise to complete, before growing the grain step, the step adding crystal seed is also comprised.In some preferred embodiments, the add-on of crystal seed is the 1%-30% of Cefixime Micronized weight, preferred 5%-15%.
In some embodiments, in step (4), be cooled to 0 DEG C-15 DEG C, preferably 0 DEG C-10 DEG C; The crystallization time is 1-10 hour, preferred 3-8 hour.
In some embodiments, by the filtration of the crystal of precipitation in step (4), drying.Filter cake after filtration can with the water washing of appropriate 0-10 DEG C.Drying can adopt forced air drying or vacuum-drying, and drying temperature can be room temperature to 40 DEG C.
Below in conjunction with embodiment, the invention will be further described, and in embodiment, Cefixime Micronized raw material is according to embodiment in patent CN200810120071.X 3 method preparation synthesis.Gained Cefixime Micronized crude product is carried out to the stability experiment of 40 DEG C of-75%RH: after 6 months, it is 1.35% that maximum list is mixed, content 92.92%.In following embodiment, acid concentration used is weight percentage concentration.
embodiment 1
Cefixime trihydrate crystal seed is prepared according to following step:
(1) alkali is molten: Cefixime Micronized crude product 35g, and add water 350mL, and ice-water bath is down to about 3 DEG C, adds sodium bicarbonate 12.0g in batches, stirs clearly molten, stand-by.
(2) acid out: add water and each 175ml of acetone in four-hole boiling flask, be warming up to 35 DEG C, online pH meter monitoring pH value, adjusts about pH=2.72 with 10% hydrochloric acid of about 2ml; Slowly drip the alkaline solution of preparation in step (1) wherein, and adjust pH between 2.70-2.90 with 10% hydrochloric acid simultaneously, terminal pH is 2.82, consumes 10% hydrochloric acid and is about 60ml.
(3) crystallization: after being added dropwise to complete, cooling crystallization, the cooling used time is about 9h, and terminal temperature is about 5 DEG C.
(4) filtration drying: filter, a small amount of water washing of filter cake, 35 DEG C of vacuum-drying 5h, obtain cefixime trihydrate crystal 29.7g, yield 84.8%, HPLC purity 99.48%.
The cefixime trihydrate obtained to embodiment 1 carries out the stability experiment of 40 DEG C of-75%RH: after 6 months, it is 0.45% that maximum list is mixed, content 98.78%.
embodiment 2
Cefixime trihydrate is prepared according to following step:
(1) alkali is molten: Cefixime Micronized crude product 35g, and add water 280mL, and ice-water bath is down to about 5 DEG C, adds sodium carbonate 7.0g in batches, stirs clearly molten, stand-by.
(2) acid out: add water and each 230ml of acetone in four-hole boiling flask, be warming up to 40 DEG C, online pH meter monitoring pH value, adjusts about pH=2.50 with 4% hydrochloric acid of about 4ml; Slowly drip the alkaline solution of preparation in step (1) wherein, and adjust pH between 2.50-2.70 with 4% hydrochloric acid simultaneously, terminal pH is 2.53, consumes 4% hydrochloric acid and is about 150ml.
(3) growing the grain and crystallization: after being added dropwise to complete, adds embodiment 1 gained crystal seed 1.8g, is incubated 40 DEG C of growing the grain 0.5h; Cooling crystallization 8 hours, terminal temperature is about 8 DEG C.
(4) filtration drying: filter, a small amount of water washing of filter cake, 35 DEG C of vacuum-drying 6h, obtain cefixime trihydrate crystal 35.0g, it is 99.42% that HPLC detects purity, yield 95.1%.
The cefixime trihydrate obtained to embodiment 2 carries out the stability experiment of 40 DEG C of-75%RH: after 6 months, it is 0.38% that maximum list is mixed, content 98.98%.
embodiment 3
Cefixime trihydrate is prepared according to following step:
(1) alkali is molten: Cefixime Micronized crude product 35g, and add water 300ml, and ice-water bath is down to about 5 DEG C, adds sodium bicarbonate 11.5g in batches, stirs clearly molten, stand-by.
(2) acid out: add water and each 240ml of acetone in four-hole boiling flask, be warming up to 30 DEG C, online pH meter monitoring pH value, adjusts about pH=2.50 with 7.5% hydrochloric acid of about 3ml; Slowly drip the alkaline solution of preparation in step (1) wherein, and adjust pH between 2.52-2.70 with 7.5% hydrochloric acid simultaneously, terminal pH is 2.69, consumes 7.5% hydrochloric acid and is about 80ml.
(3) growing the grain and crystallization: after being added dropwise to complete, adds embodiment 1 gained crystal seed 3.5g, is incubated 30 DEG C of growing the grain 0.5h; Cooling crystallization 7 hours, terminal temperature is about 6 DEG C.
(4) filtration drying: filter, a small amount of water washing of filter cake, 35 DEG C of vacuum-drying 8h, obtain cefixime trihydrate crystal 36.5g, it is 99.50% that HPLC detects purity, yield 94.8%.
The cefixime trihydrate obtained to embodiment 3 carries out the stability experiment of 40 DEG C of-75%RH: after 6 months, it is 0.39% that maximum list is mixed, content 98.95%.
Other stability experiment that the cefixime trihydrate obtained to embodiment 3 carries out:
Fig. 1 is the TGA weightlessness figure of product in embodiment 3.
Fig. 2 is this product crystal morphology under 200 times of polarization microscopes.
Fig. 3 is this product X-ray powder diffraction pattern, and the X-ray powder diffraction represented with 2 θ angles has characteristic peak at 6.0,7.7,9.2,15.3,15.6,19.7,19.8,20.8,21.2,22.9,23.7,27.6 ± 0.2 places.
embodiment 4
Cefixime trihydrate is prepared according to following step:
(1) alkali is molten: Cefixime Micronized crude product 35g, and add water 235mL, and ice-water bath is down to about 5 DEG C, adds sodium methylate 7.2g in batches, stirs clearly molten, stand-by.
(2) acid out: add water and each 200ml of methyl alcohol in four-hole boiling flask, be warming up to 20 DEG C, online pH meter monitoring pH value, adjusts about pH=2.60 with 10% hydrochloric acid of about 2ml; Slowly drip the alkaline solution of preparation in step (1) wherein, and adjust pH between 2.70-2.85 with 10% hydrochloric acid simultaneously, terminal pH is 2.82, consumes 10% hydrochloric acid and is about 60ml.
(3) growing the grain and crystallization: after being added dropwise to complete, adds embodiment 1 gained crystal seed 10.0g, is incubated 20 DEG C of growing the grain 0.5h; Cooling crystallization 2 hours, terminal temperature is about 3 DEG C.
(4) filtration drying: filter, a small amount of water washing of filter cake, 35 DEG C of vacuum-drying 8h, obtain cefixime trihydrate crystal 40.5g, it is 99.45% that HPLC detects purity, yield 90.0%.
The cefixime trihydrate obtained to embodiment 4 carries out the stability experiment of 40 DEG C of-75%RH: after 6 months, it is 0.48% that maximum list is mixed, content 98.52%.
embodiment 5
Cefixime trihydrate is prepared according to following step:
(1) alkali is molten: Cefixime Micronized crude product 35g, and add water 350mL, adds potassium hydroxide 7.0g in batches, stirs clearly molten, stand-by.
(2) acid out: add water and each 315ml of acetone in four-hole boiling flask, be warming up to 45 DEG C, online pH meter monitoring pH value, adjusts about pH=2.62 with 15% hydrochloric acid of about 1.5ml; Slowly drip the alkaline solution of preparation in step (1) wherein, and adjust pH between 3.01-3.20 with 15% hydrochloric acid simultaneously, terminal pH is 3.05, consumes 15% hydrochloric acid and is about 40ml.
(3) growing the grain and crystallization: after being added dropwise to complete, adds embodiment 1 gained crystal seed 3.5g, is incubated 45 DEG C of growing the grain 1h; Cooling crystallization 6 hours, terminal temperature is about 3 DEG C.
(4) filtration drying: filter, a small amount of water washing of filter cake, 35 DEG C of vacuum-drying 8h, obtain cefixime trihydrate crystal 36.7g, it is 99.41% that HPLC detects purity, yield 95.3%.
The cefixime trihydrate obtained to embodiment 5 carries out the stability experiment of 40 DEG C of-75%RH: after 6 months, it is 0.46% that maximum list is mixed, content 98.78%.
embodiment 6
Cefixime trihydrate is prepared according to following step:
(1) alkali is molten: Cefixime Micronized crude product 35g, and add water 230mL, adds salt of wormwood 7.0g in batches, stirs clearly molten, stand-by.
(2) acid out: add water and each 190ml of Virahol in four-hole boiling flask, be warming up to 20 DEG C, online pH meter monitoring pH value, adjusts about pH=2.72 with 8% citric acid of about 2.5ml; Slowly drip the alkaline solution of preparation in step (1) wherein, and adjust pH between 2.85-3.05 with 8% citric acid simultaneously, terminal pH is 2.89, consumes 8% citric acid and is about 75ml.
(3) growing the grain and crystallization: after being added dropwise to complete, adds embodiment 1 gained crystal seed 0.35g, is incubated 20 DEG C of growing the grain 1h; Cooling crystallization 3 hours, terminal temperature is about 4 DEG C.
(4) filtration drying: filter, a small amount of water washing of filter cake, 35 DEG C of vacuum-drying 8h, obtain cefixime trihydrate crystal 32.1g, it is 99.41% that HPLC detects purity, yield 90.8%.
The cefixime trihydrate obtained to embodiment 6 carries out the stability experiment of 40 DEG C of-75%RH: after 6 months, it is 0.46% that maximum list is mixed, content 98.78%.
embodiment 7
Cefixime trihydrate is prepared according to following step:
(1) alkali is molten: Cefixime Micronized crude product 35g, and add water 220mL, adds sodium carbonate 7.0g in batches, stirs clearly molten, stand-by.
(2) acid out: add water and each 200ml of ethanol in four-hole boiling flask, be warming up to 20 DEG C, online pH meter monitoring pH value, adjusts about pH=2.92 with 4% sulfuric acid of about 1.0ml; Slowly drip the alkaline solution of preparation in step (1) wherein, and adjust pH between 2.85-3.05 with 4% sulfuric acid simultaneously, terminal pH is 2.91, consumes 4% sulfuric acid and is about 75ml.
(3) growing the grain and crystallization: after being added dropwise to complete, adds embodiment 1 gained crystal seed 1.0g, is incubated 25 DEG C of growing the grain 1h; Cooling crystallization 4 hours, terminal temperature is about 5 DEG C.
(4) filtration drying: filter, a small amount of water washing of filter cake, 35 DEG C of vacuum-drying 8h, obtain cefixime trihydrate crystal 32.8g, it is 99.42% that HPLC detects purity, yield 91.0%.
The cefixime trihydrate obtained to embodiment 6 carries out the stability experiment of 40 DEG C of-75%RH: after 6 months, it is 0.47% that maximum list is mixed, content 98.68%.
embodiment 8
Repeat embodiment 1 and embodiment 2 method in document CN201110429323.9 and prepare products obtained therefrom, carry out the stability experiment 6 months of temperature 40 DEG C, relative humidity 75% with the embodiment of the present invention 2 and embodiment 3 products obtained therefrom, concrete data are as follows:
Stability data contrasts
Above-mentioned experimental data shows, the product of the present invention stability data of 6 months is obviously better than document CN201110429323.9 product.
The above; be only the specific embodiment of the present invention; but protection scope of the present invention is not limited thereto; any those of ordinary skill in the art are in the technical scope disclosed by the present invention; the change can expected without creative work or replacement, all should be encompassed within protection scope of the present invention.Therefore, the protection domain that protection scope of the present invention should limit with claims is as the criterion.
Claims (24)
1. a crystallization method for cefixime trihydrate, is characterized in that, comprises the following steps:
(1) Cefixime Micronized is formed suspension in water, then add alkali wherein and Cefixime Micronized is dissolved completely, form alkaline solution;
(2) mixed solvent of water and organic solvent is prepared, the 10-18 that the volume of described mixed solvent is Cefixime Micronized weight described in step (1) doubly, the volume ratio of water and organic solvent is 1:1, above-mentioned mixed solvent is warming up to 20 DEG C-45 DEG C, and the acid with 2 % by weight-15 % by weight regulates the pH to 2-4 of described mixed solvent;
(3) described alkaline solution is dropped in described mixed solvent, and in dropping process, control the pH of solution with the acid of 2 % by weight-15 % by weight be 2-4;
(4) after being added dropwise to complete, cooling crystallization.
2. crystallization method according to claim 1, is characterized in that, in described step (2), described mixed solvent is warming up to 30 DEG C-40 DEG C.
3. crystallization method according to claim 1, is characterized in that, in described step (2), the acid with 8 % by weight-15 % by weight regulates the pH to 2.5-3.2 of described mixed solvent.
4. crystallization method according to claim 1, is characterized in that, in described step (3), the pH that the acid with 8 % by weight-15 % by weight controls solution is 2.5-3.2.
5. crystallization method according to claim 1, is characterized in that, in described step (1), the mass ratio of described Cefixime Micronized and water is 1:3-1:10.
6. crystallization method according to claim 5, is characterized in that, in described step (1), the mass ratio of described Cefixime Micronized and water is 1:6.6-1:10.
7. crystallization method according to any one of claim 1 to 6, it is characterized in that, in described step (1), described alkali is ammoniacal liquor, sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium methylate, potassium hydroxide, salt of wormwood, saleratus, triethylamine, sodium acetate, potassium acetate, Sodium Ethylhexanoate, diisopropyl ethyl amine, Tributylamine, trolamine or dimethyl benzyl amine.
8. crystallization method according to claim 7, is characterized in that, in described step (1), described alkali is sodium bicarbonate or sodium carbonate.
9. crystallization method according to claim 1, is characterized in that, in described step (2), described organic solvent is polar aprotic solvent, polar aprotic solvent or both any mixed solvents.
10. crystallization method according to claim 9, is characterized in that, described polar aprotic solvent is methyl alcohol, ethanol or Virahol; Described polar aprotic solvent is acetone, butanone, tetrahydrofuran (THF), acetonitrile, DMF or DMSO.
11. crystallization method according to claim 1, is characterized in that, the described acid in described step (2) and step (3) is hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, Hydrogen bromide, formic acid or acetic acid.
12. crystallization method according to claim 11, is characterized in that, the described acid in described step (2) and step (3) is hydrochloric acid.
13. crystallization method according to claim 1, is characterized in that, in described step (3), synchronously drop in described mixed solvent by described alkaline solution and described acid, the pH controlling solution in dropping process is 2-4.
14. crystallization method according to claim 13, is characterized in that, in described step (3), synchronously drop in described mixed solvent by described alkaline solution and described acid, the pH controlling solution in dropping process is 2.5-3.2.
15. crystallization method according to claim 1, is characterized in that, in described step (3), control the pH fluctuation of solution in dropping process within 0.2.
16. crystallization method according to claim 1, it is characterized in that, in described step (4), after being added dropwise to complete, the volume ratio of described organic solvent and water used is 1:1.5 to 1:3.5, and water used is the summation of the water in acid described in the water in mixed solvent described in the water in step (1) and step (2) and step (2) and step (3).
17. crystallization method according to claim 1, is characterized in that, in described step (4), after being added dropwise to complete, also comprise growing the grain step, and growing the grain temperature is 20 DEG C-45 DEG C; Rearing crystal time is 0.5-3 hour; Described cooling is 0 DEG C-15 DEG C; The described crystallization time is 1-10 hour.
18. crystallization method according to claim 17, is characterized in that, in described step (4), described growing the grain temperature is 30 DEG C-40 DEG C.
19. crystallization method according to claim 17, is characterized in that, in described step (4), described rearing crystal time is 0.5-2 hour.
20. crystallization method according to claim 17, is characterized in that, in described step (4), described cooling is 0 DEG C-10 DEG C.
21. crystallization method according to claim 17, is characterized in that, in described step (4), the described crystallization time is 3-8 hour.
22. crystallization method according to any one of claim 17-21, is characterized in that, in described step (4), after being added dropwise to complete, before growing the grain step, also comprise the step adding crystal seed.
23. crystallization method according to claim 22, is characterized in that, in described step (4), the add-on of described crystal seed is the 1%-30% of Cefixime Micronized weight.
24. crystallization method according to claim 22, is characterized in that, in described step (4), the add-on of described crystal seed is the 5%-15% of Cefixime Micronized weight.
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| US6800755B2 (en) * | 2002-10-24 | 2004-10-05 | Orchid Chemicals And Pharmaceuticals Limited | Process for the preparation of cefixime |
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