CN103554137B - Preparation method of cefdinir micropowder - Google Patents
Preparation method of cefdinir micropowder Download PDFInfo
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- CN103554137B CN103554137B CN201310533203.2A CN201310533203A CN103554137B CN 103554137 B CN103554137 B CN 103554137B CN 201310533203 A CN201310533203 A CN 201310533203A CN 103554137 B CN103554137 B CN 103554137B
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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
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Cephalosporin Compounds (AREA)
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 micropowder
Background technology
Cefdinir (cefdinir) structural formula is as follows:
Cefdinir (genus the 3rd generation cephalo, grind by Japanese Fujisawa Pharmaceutical is former, within 1991, first in Japan's listing, be mainly used in the infection caused by bacterial strain such as the Staphylococcus to Cefdinir sensitivity, streptococcus, streptococcus pneumoniae, peptostreptococcus, propionibacterium, gonococcus, moraxelle catarrhalis, escherichia coli, klebsiella spp, Proteus mirabilis, Pu Luweidengsi Pseudomonas, hemophilus influenzae.
Cefdinir can be oral, and therefore Cefdinir exists oral solid formulation, e.g., and tablet, capsule, dispersible tablet etc.Cefdinir oral solid preparation, dissolution rate is the quality index of these preparations, therefore the major subjects that dissolution rate is researchist is improved, the method of existing raising dissolution rate is a lot, and wherein being pulverized by Cefdinir solid material pulverizer and obtaining micro mist is solve the conventional technique means of of dissolution rate problem.The high temperature that micronization process produces can destroy the stability of the former powder of ground Buddhist nun, and the Cefdinir preparation stability obtained is deteriorated.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 title: stable amorphous cefdinir
Application number: 200580018300.1
Patent 3 title: three semihydrates of Cefdinir, dehydrate and hydrate forms
Application number: 200580008739.6
Patent 4 title: the preparation method of Cefdinir crystal form B
Application number: 201210567334.8
Provide specific Cefdinir solid, be beneficial to the raising of dissolution rate, but do not describe the micronization problem of these solid products.
Following Chinese patent:
Patent 5 title: a kind of preparation method of Cefdinir
Application number: 201310230139.0
Patent 6 title: a kind of preparation method of Cefdinir
Application number: 201210140550.4
Patent 7 title: Cefdinir ternary complex and the method for the preparation of Cefdinir thereof
Application number: 201210088460.5
Patent 8 title: a kind of preparation method of Cefdinir
Application number: 201110035269.X
Patent 9 title: a kind of preparation method of Cefdinir
Application number: 201110429321.X
Patent 10 title: the preparation method of Cefdinir
Application number: 201010114252.9
Patent 11 title: a kind of preparation method of Cefdinir
Application number: 201010549871.0
Patent 12 title: a kind of novel preparation method of Cefdinir
Application number: 201010111221.8
Patent 13 title: the preparation method of Cefdinir
Application number: 200910099380.8
Patent 14 title: Cefdinir
Application number: 200710191614.2
All provide the preparation of Cefdinir, comprise the process that crystallization from product obtains solid, but also do not describe 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, granularity its speed of stripping from preparation less of effective ingredient is faster, absorbing and more easily absorbing also sooner.Market needs micronized Cefdinir, be therefore necessary to improve prior art, find the technology of the micronized Cefdinir of a kind of more superior acquisition.
Summary of the invention
The invention provides a kind of preparation method of cefdinir micropowder, described method, step is as follows:
Step 1, Cefdinir phosphoric acid salt is added in cold water, is 6.8-7.1 by lye pH adjustment value, adds gac, vat powder, EDTA, stir, filter,
Step 2, filtrate add ethanol under stirring, and add-on is 1/10 of cold water weight, is 4.1 with sour adjust pH, growing the grain 15-25 minute, and continuing sour adjust pH is 2.5-2.7, stir growing the grain 0.5-2h.
Step 3, be cooled to 15-25 DEG C, stir growing the grain 0.5-2h, be cooled to 0-5 DEG C, stir growing the grain 0.5-2h.Filter, dry, to obtain final product.
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, adds 24kg Cefdinir phosphoric acid salt, less than 10 DEG C under agitation condition, stir 0.5h.Adjust pH to be 6.8-7.1 with 10% sodium hydroxide solution, be warming up to 25 DEG C, under agitation condition, add 2.4kg gac, 0.36kg vat powder, 0.36kg EDTA, stir 35min.Filter, with 30kg deionized water wash filter cake, merging filtrate.Filtrate goes in sterilisable chamber crystallizer (600L), 25 DEG C, and stirring velocity 300 revs/min adds 20kg ethanol as dispersion agent in filtrate, adjusts pH=4.1, growing the grain 20 minutes with 5N hydrochloric acid, continues to adjust pH=2.5-2.7 with 5N hydrochloric acid, stirs growing the grain 1h.Be cooled to 20 DEG C, stir growing the grain 1h, be cooled to 0-5 DEG C and stir growing the grain 1h.Filter, filter complete, divide 3 washing leaching cakes with 30kg5 DEG C of cold distilled water, dry 1h, 35 DEG C of vacuum-dryings.
Through Cefdinir dry powder prepared by the inventive method, have micro mist character, its median size is between 20-30um,
And the former powder median size of ground Buddhist nun prepared by existing technique is at about 100um, the former powder of ground Buddhist nun that the inventive method obtains does not need micronization, inherently micro mist, can be directly used in the preparation of preparation.Below by way of experimental data, beneficial effect of the present invention is described:
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, adds 24kg Cefdinir phosphoric acid salt, less than 10 DEG C under agitation condition, stir 0.5h.Adjust pH to be 6.8-7.1 with 10% sodium hydroxide solution, under agitation condition, add 2.4kg gac, 0.36kg vat powder, 0.36kgEDTA, stirring at room temperature reaction 35min.Filter, with 30kg deionized water wash filter cake, merging filtrate.Filtrate goes in sterilisable chamber crystallizer (600L), adjusts pH=5.0, be warming up to 30-35 DEG C with 5N hydrochloric acid, adjusts crystallization with 5N hydrochloric acid, stirs 20min, continues to adjust pH=2.5-2.7 with 5N hydrochloric acid, stirs growing the grain 2h.Be cooled to 0-5 DEG C and stir growing the grain 1h.Filter, filter complete, divide 3 washing leaching cakes with 30kg5 DEG C of cold distilled water, dry 1h, 35 DEG C of vacuum-dryings.
Granularity data contrasts:
The inventive method is through screening acquisition, and screening process is as follows:
First carry out repeated experiment to prior art, find the Cefdinir dry powder that following Chinese patent method obtains, granularity is as follows:
On the basis of existing technology, the present invention prepares the Cefdinir dry powder reaching effect of the present invention by the method adding dispersion agent and alternating temperature growing the grain.
The screening of experiment 2, dispersion agent:
When other conditions are constant, it is as follows to add different dispersion agent products obtained therefrom granularities:
By comparing, when ethanol is dispersion agent, granularity is minimum, therefore selects ethanol to be dispersion agent.And be the dissolution phase water yield 1/10 in add-on, granularity is close to 30um, and now uniform particles, mobility is better, is easy to suction filtration, meets demand of industrial production.And after increasing ethanol consumption, undersized, the raw material viscosity obtained is comparatively large, suction filtration difficulty, does not meet demand of industrial production.Therefore finally determine with the ethanol of the dissolution phase water yield 1/10 for dispersion agent.
Experiment 3, alternating temperature growing the grain conditional filtering
When other conditions are constant, change alternating temperature growing the grain condition products obtained therefrom granularity as follows:
Embodiment:
Further illustrate the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1
Crystallization method: add 170kg distilled water in dissolving vessel, adds 24kg Cefdinir phosphoric acid salt, less than 10 DEG C under agitation condition, stir 0.5h.Adjust pH to be 6.8-7.1 with 10% sodium hydroxide solution, be warming up to 25 DEG C, under agitation condition, add 2.4kg gac, 0.36kg vat powder, 0.36kg EDTA, stir 35min.Filter, with 30kg deionized water wash filter cake, merging filtrate.Filtrate goes in sterilisable chamber crystallizer (600L), 25 DEG C, and stirring velocity 300 revs/min adds 20kg ethanol as dispersion agent in filtrate, adjusts pH=4.1, growing the grain 20 minutes with 5N hydrochloric acid, continues to adjust pH=2.5-2.7 with 5N hydrochloric acid, stirs growing the grain 1h.Be cooled to 20 DEG C, stir growing the grain 1h, be cooled to 0-5 DEG C and stir growing the grain 1h.Filter, filter complete, divide 3 washing leaching cakes with 30kg5 DEG C of cold distilled water, dry 1h, 35 DEG C of vacuum-dryings.
Attached: particle size detection method:
Get the sample disc that appropriate amount of sample is placed in Malvern MS2000 particle size analyzer dry method sampler, click " the enabling SOP " in measurement window, select the SOP set, run the numbering of SOP prompting input sample according to instrument, then instrument can be tested automatically, terminates until measure.
Claims (1)
1. a preparation method for cefdinir micropowder, described method, step is as follows:
170kg cold distilled water is added in dissolving vessel, 24kg Cefdinir phosphoric acid salt is added under agitation condition, less than 10 DEG C, stir 0.5h, pH is adjusted to be 6.8-7.1 with 10% sodium hydroxide solution, be warming up to 25 DEG C, 2.4kg gac is added under agitation condition, 0.36kg vat powder, 0.36kgEDTA, stir 35min, filter, with 30kg deionized water wash filter cake, merging filtrate, filtrate goes in sterilisable chamber 600L crystallizer, 25 DEG C, stirring velocity 300 revs/min, 20kg ethanol is added as dispersion agent in filtrate, pH=4.1 is adjusted with 5N hydrochloric acid, 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 DEG C, stir growing the grain 1h, be cooled to 0-5 DEG C and stir growing the grain 1h, filter, filter complete, 3 washing leaching cakes are divided with 30kg 5 DEG C of cold distilled waters, dry 1h, 35 DEG C of vacuum-dryings.
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| 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 CN103554137A (en) | 2014-02-05 |
| CN103554137B true CN103554137B (en) | 2015-07-15 |
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| CN108892677B (en) * | 2018-06-22 | 2021-04-27 | 苏州盛达药业有限公司 | Particle size control method of cefdinir |
| CN108653214B (en) * | 2018-06-28 | 2020-11-06 | 苏州盛达药业有限公司 | Cefdinir granules and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| ITMI20071628A1 (en) * | 2007-08-06 | 2007-11-05 | Acs Dobfar Spa | SYNTHESIS OF 3-ALCHENYLCEPHALOSPORINES AND NEW INTERMEDIATE USEFUL RELATED |
| CN101830946B (en) * | 2010-05-05 | 2012-12-19 | 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 |
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Granted publication date: 20150715 Termination date: 20191031 |