CN103554137A - Preparation method of cefdinir micropowder - Google Patents
Preparation method of cefdinir micropowder Download PDFInfo
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- CN103554137A CN103554137A CN201310533203.2A CN201310533203A CN103554137A CN 103554137 A CN103554137 A CN 103554137A CN 201310533203 A CN201310533203 A CN 201310533203A CN 103554137 A CN103554137 A CN 103554137A
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- cefdinir
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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
Abstract
The invention relates to a preparation method of cefdinir micropowder. The method comprises the following steps: adding cefdinir phosphate into cold water, adjusting the pH value to 6.8-7.1 by use of alkali liquor, adding active carbon, sodium hydrosulfite and EDTA (Ethylene Diamine Tetraacetic Acid), stirring, filtering and washing; mixing a filtrate and a washing liquid, and adding ethanol while stirring, wherein the addition of ethanol is 1/10 of weight of the cold water; adjusting the pH value to 4.1 by use of an acid, growing the grain for 15-25 minutes, continuously adjusting the pH value to 2.5-2.7 by use of an acid, stirring and growing the grain for 0.5-2 hours, cooling to 15-25 DEG C, stirring and growing the grain for 0.5-2 hours, cooling to 0-5 DEG C, and stirring and growing the grain for 0.5-2 hours; filtering and drying to obtain the cefdinir micropowder.
Description
Technical field:
The present invention relates to a kind of preparation of drug powder, particularly a kind of preparation method of Cefdinir micro mist
Background technology
Cefdinir (cefdinir) structural formula is as follows:
Cefdinir (belong to the 3rd generation cephalo, by Japanese Fujisawa Pharmaceutical is former, grind, within 1991, in Japan, go on the market first, be mainly used in caused infection of bacterial strain such as the Staphylococcus of Cefdinir sensitivity, streptococcus, streptococcus pneumoniae, peptostreptococcus, propionibacterium, gonococcus, moraxelle catarrhalis, escherichia coli, klebsiella spp, Proteus mirabilis, Pu Luweidengsi Pseudomonas, hemophilus influenzaes.
Cefdinir can be oral, so Cefdinir exists oral solid formulation, as, tablet, capsule, dispersible tablet etc.Cefdinir oral solid preparation, dissolution rate is the quality index of these preparations, therefore improve the major subjects that dissolution rate is researchist, the method of existing raising dissolution rate is a lot, wherein Cefdinir solid material is pulverized and is obtained the conventional technique means that micro mist is solution dissolution rate problem with pulverizer.The high temperature that micronization process produces can destroy the stability of the former powder of ground Buddhist nun, makes the Cefdinir preparation stability variation making.Therefore adopt chemical means to solve micronization problem and put on schedule.
Prior art provides the preparation method of multiple Cefdinir, as following Chinese patent:
Patent 1 title: a kind of Cefdinir compound and method for making thereof
Application number: 200910014980.X
Patent 2 titles: stable amorphous cefdinir
Application number: 200580018300.1
Patent 3 titles: three semihydrates, dehydrate and the hydrate forms of Cefdinir
Application number: 200580008739.6
Patent 4 titles: the preparation method of Cefdinir crystal form B
Application number: 201210567334.8
Specific Cefdinir solid is provided, has been beneficial to the raising of dissolution rate, but do not described the micronization problem of these solid products.
Following Chinese patent:
Patent 5 titles: a kind of preparation method of Cefdinir
Application number: 201310230139.0
Patent 6 titles: a kind of preparation method of Cefdinir
Application number: 201210140550.4
Patent 7 titles: Cefdinir ternary complex and for the preparation of the method for Cefdinir
Application number: 201210088460.5
Patent 8 titles: a kind of preparation method of Cefdinir
Application number: 201110035269.X
Patent 9 titles: a kind of preparation method of Cefdinir
Application number: 201110429321.X
Patent 10 titles: the preparation method of Cefdinir
Application number: 201010114252.9
Patent 11 titles: a kind of preparation method of Cefdinir
Application number: 201010549871.0
Patent 12 titles: a kind of novel preparation method of Cefdinir
Application number: 201010111221.8
Patent 13 titles: the preparation method of Cefdinir
Application number: 200910099380.8
Patent 14 titles: Cefdinir
Application number: 200710191614.2
The preparation of Cefdinir is all provided, has comprised that crystallization obtains the process of solid from product, but also do not described the micronization problem of these solid products.
Micronization is generally that pressed powder is ground into fine grain process from coarse particles, and in general, less its speed of stripping from preparation of the granularity of effective ingredient is faster, also just faster absorbing and more easily absorbing.On market, need micronized Cefdinir, be therefore necessary prior art to improve, find a kind of technology of the more superior micronized Cefdinir of acquisition.
Summary of the invention
The invention provides a kind of preparation method of Cefdinir micro mist, described method, step is as follows:
Step 1, Cefdinir phosphoric acid salt being added in cold water, is 6.8-7.1 by lye pH adjustment value, adds gac, vat powder, EDTA, stirs, filter,
Step 2, filtrate add ethanol under stirring, and add-on is 1/10 of cold water weight, with sour adjust pH, is 4.1, growing the grain 15-25 minute, and continuing sour adjust pH is 2.5-2.7, stirs growing the grain 0.5-2h.
Step 3, be cooled to 15-25 ℃, stir growing the grain 0.5-2h, be cooled to 0-5 ℃, stir growing the grain 0.5-2h.Filter, dry, obtain.
Wherein alkali lye described in step 1 is sodium hydroxide solution.
Wherein described in step 2, acid is hydrochloric acid.
The most preferred preparation method of the present invention is as follows:
Crystallization method: add 170kg distilled water in dissolving vessel, add 24kg Cefdinir phosphoric acid salt under agitation condition, below 10 ℃, stir 0.5h.With 10% sodium hydroxide solution, adjusting pH is 6.8-7.1, is warming up to 25 ℃, adds 2.4kg gac, 0.36kg vat powder, 0.36kg EDTA under agitation condition, stirs 35min.Filter, with 30kg deionized water wash filter cake, merging filtrate.Filtrate goes in sterilisable chamber crystallizer (600L), and 25 ℃, 300 revs/min of stirring velocitys add 20kg ethanol as dispersion agent in filtrate, with 5N hydrochloric acid, adjusts pH=4.1, and growing the grain 20 minutes continues to adjust pH=2.5-2.7 with 5N hydrochloric acid, stirs growing the grain 1h.Be cooled to 20 ℃, stir growing the grain 1h, be cooled to 0-5 ℃ and stir growing the grain 1h.Filter, filter completely, with 30kg5 ℃ of cold distilled water, divide washing leaching cake 3 times, drying 1h, 35 ℃ of vacuum-dryings.
The Cefdinir dry powder of preparing through the inventive method, has micro mist character, and its median size is between 20-30um,
And the prepared former powder median size of ground Buddhist nun of existing technique is in 100um left and right, the former powder of ground Buddhist nun that the inventive method makes does not need micronization, itself is exactly micro mist, can be directly used in the preparation of preparation.Below data declaration beneficial effect of the present invention by experiment:
The granularity data contrast of experiment 1, existing method and the inventive method products obtained therefrom:
Existing crystallization method: add 170kg distilled water in dissolving vessel, add 24kg Cefdinir phosphoric acid salt under agitation condition, below 10 ℃, stir 0.5h.With 10% sodium hydroxide solution, adjusting pH is 6.8-7.1, adds 2.4kg gac, 0.36kg vat powder, 0.36kgEDTA under agitation condition, stirring at room reaction 35min.Filter, with 30kg deionized water wash filter cake, merging filtrate.Filtrate goes in sterilisable chamber crystallizer (600L), with 5N hydrochloric acid, adjusts pH=5.0, is warming up to 30-35 ℃, with 5N hydrochloric acid, adjusts crystallization, stirs 20min, continues to adjust pH=2.5-2.7 with 5N hydrochloric acid, stirs growing the grain 2h.Be cooled to 0-5 ℃ and stir growing the grain 1h.Filter, filter completely, with 30kg5 ℃ of cold distilled water, divide washing leaching cake 3 times, drying 1h, 35 ℃ of vacuum-dryings.
Granularity data contrast:
The inventive method obtains through screening, and screening process is as follows:
First prior art is carried out to repeated experiment, find the resulting Cefdinir dry powder of following Chinese patent method, granularity is as follows:
On the basis of existing technology, the present invention reaches the Cefdinir dry powder of effect of the present invention by adding the method for dispersion agent and alternating temperature growing the grain to prepare.
The screening of experiment 2, dispersion agent:
In the situation that other conditions are constant, add different dispersion agent products obtained therefrom granularities as follows:
By comparing, when ethanol is dispersion agent, granularity is minimum, therefore select ethanol, is dispersion agent.And be the dissolution phase water yield 1/10 in add-on, granularity approaches 30um, uniform particles now, and mobility is better, is easy to suction filtration, meets demand of industrial production.And increase after ethanol consumption, undersized, the raw material viscosity obtaining is larger, and suction filtration difficulty does not meet demand of industrial production.Therefore final definite ethanol of take the dissolution phase water yield 1/10 is dispersion agent.
Experiment 3, alternating temperature growing the grain conditional filtering
In the situation that other conditions are constant, change alternating temperature growing the grain condition products obtained therefrom granularity as follows:
Embodiment:
Further illustrate by the following examples the present invention, but not as limitation of the present invention.
Embodiment 1
Crystallization method: add 170kg distilled water in dissolving vessel, add 24kg Cefdinir phosphoric acid salt under agitation condition, below 10 ℃, stir 0.5h.With 10% sodium hydroxide solution, adjusting pH is 6.8-7.1, is warming up to 25 ℃, adds 2.4kg gac, 0.36kg vat powder, 0.36kg EDTA under agitation condition, stirs 35min.Filter, with 30kg deionized water wash filter cake, merging filtrate.Filtrate goes in sterilisable chamber crystallizer (600L), and 25 ℃, 300 revs/min of stirring velocitys add 20kg ethanol as dispersion agent in filtrate, with 5N hydrochloric acid, adjusts pH=4.1, and growing the grain 20 minutes continues to adjust pH=2.5-2.7 with 5N hydrochloric acid, stirs growing the grain 1h.Be cooled to 20 ℃, stir growing the grain 1h, be cooled to 0-5 ℃ and stir growing the grain 1h.Filter, filter completely, with 30kg5 ℃ of cold distilled water, divide washing leaching cake 3 times, drying 1h, 35 ℃ of vacuum-dryings.
Attached: particle size detection method:
Get appropriate sample and be placed in the sample disc of Ma Erwen MS2000 particle size analyzer dry method sampler, click " enabling SOP " in measurement window, the SOP that selection has set, according to the numbering of instrument operation SOP prompting input sample, then instrument can be tested automatically, until measure, finishes.
Claims (5)
1. a preparation method for Cefdinir micro mist, described method, step is as follows:
1) Cefdinir phosphoric acid salt being added in cold water, is 6.8-7.1 by lye pH adjustment value, adds gac, vat powder, EDTA, stirs, and filters washing;
2) filtrate and washings mix, and under stirring, add ethanol, and amount of alcohol added is 1/10 of cold water weight, with sour adjust pH, is 4.1, growing the grain 15-25 minute, and continuing sour adjust pH is 2.5-2.7, stirs growing the grain 0.5-2h;
3) be cooled to 15-25 ℃, stir growing the grain 0.5-2h, be cooled to 0-5 ℃, stir growing the grain 0.5-2h.Filter, dry, obtain.
2. preparation method as claimed in claim 1, wherein alkali lye described in step 1 is sodium hydroxide solution.
3. preparation method as claimed in claim 1, wherein described in step 2, acid is hydrochloric acid.
4. preparation method as claimed in claim 1, comprises the following steps:
In dissolving vessel, add 170kg cold distilled water, under agitation condition, add 24kg Cefdinir phosphoric acid salt, below 10 ℃, stir 0.5h.With 10% sodium hydroxide solution, adjusting pH is 6.8-7.1, is warming up to 25 ℃, adds 2.4kg gac, 0.36kg vat powder, 0.36kgEDTA under agitation condition, stir 35min, filter, with 30kg deionized water wash filter cake, merging filtrate, filtrate goes in sterilisable chamber crystallizer (600L), 25 ℃, 300 revs/min of stirring velocitys, in filtrate, add 20kg ethanol as dispersion agent, with 5N hydrochloric acid, adjust pH=4.1, growing the grain 20 minutes, continue to adjust pH=2.5-2.7 with 5N hydrochloric acid, stir growing the grain 1h.Be cooled to 20 ℃, stir growing the grain 1h, be cooled to 0-5 ℃ and stir growing the grain 1h, filter, filter completely, with 30kg5 ℃ of cold distilled water, divide washing leaching cake 3 times, drying 1h, 35 ℃ of vacuum-dryings.
5. a Cefdinir dry powder, has micro mist character, and its median size is between 20-30um.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201310533203.2A CN103554137B (en) | 2013-10-31 | 2013-10-31 | Preparation method of cefdinir micropowder |
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| CN201310533203.2A CN103554137B (en) | 2013-10-31 | 2013-10-31 | Preparation method of cefdinir micropowder |
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| CN103554137A true CN103554137A (en) | 2014-02-05 |
| CN103554137B CN103554137B (en) | 2015-07-15 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108653214A (en) * | 2018-06-28 | 2018-10-16 | 苏州中联化学制药有限公司 | A kind of cefdinir granules and preparation method thereof |
| CN108892677A (en) * | 2018-06-22 | 2018-11-27 | 苏州中联化学制药有限公司 | A kind of granularity control method of Cefdinir |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2030975A1 (en) * | 2007-08-06 | 2009-03-04 | ACS DOBFAR S.p.A. | CEFDINIR synthesis process |
| CN101830946A (en) * | 2010-05-05 | 2010-09-15 | 南阳普康药业有限公司 | Method for synthesizing clindamycin phosphate |
| CN102516261A (en) * | 2011-12-20 | 2012-06-27 | 浙江国邦药业有限公司 | Preparation method of cefdinir |
| CN103319503A (en) * | 2013-06-09 | 2013-09-25 | 四川方向药业有限责任公司 | Preparation method of cefdinir |
-
2013
- 2013-10-31 CN CN201310533203.2A patent/CN103554137B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2030975A1 (en) * | 2007-08-06 | 2009-03-04 | ACS DOBFAR S.p.A. | CEFDINIR synthesis process |
| CN101830946A (en) * | 2010-05-05 | 2010-09-15 | 南阳普康药业有限公司 | Method for synthesizing clindamycin phosphate |
| CN102516261A (en) * | 2011-12-20 | 2012-06-27 | 浙江国邦药业有限公司 | Preparation method of cefdinir |
| CN103319503A (en) * | 2013-06-09 | 2013-09-25 | 四川方向药业有限责任公司 | Preparation method of cefdinir |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108892677A (en) * | 2018-06-22 | 2018-11-27 | 苏州中联化学制药有限公司 | A kind of granularity control method of Cefdinir |
| CN108892677B (en) * | 2018-06-22 | 2021-04-27 | 苏州盛达药业有限公司 | Particle size control method of cefdinir |
| CN108653214A (en) * | 2018-06-28 | 2018-10-16 | 苏州中联化学制药有限公司 | A kind of cefdinir granules and preparation method thereof |
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| CN103554137B (en) | 2015-07-15 |
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