CN100352826C - Process for preparing high purity scutellarin raw materials - Google Patents
Process for preparing high purity scutellarin raw materials Download PDFInfo
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- CN100352826C CN100352826C CNB2005100107230A CN200510010723A CN100352826C CN 100352826 C CN100352826 C CN 100352826C CN B2005100107230 A CNB2005100107230 A CN B2005100107230A CN 200510010723 A CN200510010723 A CN 200510010723A CN 100352826 C CN100352826 C CN 100352826C
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Abstract
The present invention relates to a process for preparing raw material medicine in the pharmaceutical industry, particularly to a process for preparing the raw material medicine with high purity. The process for preparing the raw material medicine of the high-purity breviscapine of the present invention is composed of the following steps that breviscapine is put in a container, and is added with water of which the weight is two times of that of the breviscapine, and aqueous alkali of which the pH value is more than 9 is added so that the pH valve is adjusted into 4 to 8; thereby, the mixture is fully dissolved; a solvent of which the weight is three times of that of the breviscapine is added for deposition at the temperature of 18 to 35 DEG C, the mixture is statically placed and is filtered, and a deposit is washed by the solvent; the deposit is moved into a solution with 10 to 60 wt% of solvent, acid is added for acidification until the pH value is 1 to 2, and the mixture is deposited, filtered and washed by water so as to be neutralized, and then is dried; thus, breviscapine raw material medicine with high purity is obtained.
Description
Technical field
The present invention relates to the preparation technology of bulk drug in a kind of pharmaceutical industry, especially the preparation technology of high-purity raw medicine.
Background technology
The Herba Erigerontis prime system is isolated flavonoid effective ingredient from Herba Erigerontis Erigeron breviscapus (Vant.) Hand-Mazz herb, wherein be mainly lamp-dish flower acetic and (have another name called scutellarin, scutellarin, hereinafter to be referred as the second element), chemical name is 4 ' 5,6-trihydroxyflavone-7-O-glucuronides, the Breviscarpine bulk drug of buying is from the market at present analyzed through HPLC, the second cellulose content is about 90%, the various preparations of deutero-have been widely used in the treatment cardiovascular and cerebrovascular diseases clinically, evident in efficacy, but its injection liquid poor stability, period of storage is short, caloric response is arranged when individual patient is with the back clinically, skin pruritus, phenomenons such as fash take place, the appearance of these phenomenons does not eliminate in process of production mainly due to bulk drug due to the some of them impurity, and this problem fails over more than 30 year to solve since the Herba Erigerontis product comes out always.
To the extraction of breviscapine B raw material medicine, it is described only is to use activated carbon treatment and add the EDTA used as stabilizers in " drug standard " promulgated by the ministries or commissions of the Central Government record Breviscapini injection, and lamp-dish flower acetic content reaches 90%.About not putting down in writing report in document and the Patent data, do not report the raising of lamp-dish flower acetic purity and the elimination of side effect to the lamp-dish flower acetic process for refining yet.
Summary of the invention
Purpose of the present invention is intended to overcome the shortcoming of prior art, and a kind of preparation technology of high-purity medicine with lamp-dish flower acetic as raw material is provided.
Technology of the present invention is to carry out technological design with the physico-chemical property and the feature on the chemical structure of lamp-dish flower acetic, lamp-dish flower acetic is insoluble in water, solubleness in methyl alcohol, ethanol, acetone is also very little, is infeasible so carry out a large amount of recrystallizations with these solvents.The impurities reason that is difficult to remove wherein, still main owing to due to the structural carboxyl of lamp-dish flower acetic and a plurality of hydroxyl, forms a strong electrified body, because its electrostatic effect easily produces association, complexing with some other composition, so be difficult to separate.According to this factor, the present invention adopts following particular design, utilize structural hydroxyl to be made into special salts solution, pass through screening system, find that some salt can generate the salt of solubility with lamp-dish flower acetic, or complex compound, this salt is insoluble in organic solvent, utilizes solvent precipitation to precipitate, reach the plain and isolating purpose of other impurity of second, throw out dissociates through acidifying, is reduced into lamp-dish flower acetic, and above step can once be used, also can repeatedly use repeatedly, analyze with HPLC, the purity of lamp-dish flower acetic can reach more than 99%, even can reach more than 99.9%.
The preparation technology of high-purity medicine with lamp-dish flower acetic as raw material of the present invention is made up of following steps:
One, gets Breviscarpine and place container to add the above water of 2 times of weight, add pH value and regulate PH to 4-8, make dissolving fully greater than 9 alkaline solution;
Two, adding weight again is that solvent more than three times precipitates under 18-35 ℃ of temperature condition, leaves standstill, and filters the throw out solvent wash;
Three, precipitation moves to and contains in the solution that weight percent is the 10-60% solvent, is acidified with acid the 1-2 to PH, and precipitation filters, and is washed to neutrality, and drying promptly obtains high-purity medicine with lamp-dish flower acetic as raw material.
At Breviscarpine described in the above-mentioned processing step () is at commercially available Breviscarpine, add entry amount be more than 2 times, its upper limit can be unrestricted, just the water yield that adds is big more, the quantity of solvent that should add in the step afterwards also increases thereupon, consider from industrial cost and feasibility angle, generally doubly be advisable with 2-15; The described alkaline solution of step () is a pH value greater than 9 alkaline solution, from test, can find out, as long as the alkaline solution that added be pH value greater than 9 alkaline solution and can make the Breviscarpine dissolving all can, preferably phosphoric acid benzene disodium, sodium ethylate, three (methylol) amido methane, nitrilotriacetic acid(NTA) sodium solution in the present invention.Above-mentioned several basic solutions can only add a kind of, also can add simultaneously.Considering from the industrial angle of being convenient to operate, obviously is a kind of for good to add.The mode of its adding can directly add, and also can be mixed with the aqueous solution and add, and the amount of adding is with the pH value degree of being of final adjusting; The organic solvent of solvent described in step (two) and (three) for mixing with arbitrary proportion with water, as: one or more in methyl alcohol, ethanol, acetone, the tetrahydrofuran (THF), the amount that solvent adds in the step (two) is relevant with the water yield in the step (), be tied to form proportional relation, generally the 3-15 with Breviscarpine described in the step () doubly is advisable; Leaving standstill in the step (two) mainly is to make precipitation and liquid phase separation, and the time was generally 5-30 hour.The acid that is added in the step (three), main effect are acidifying disassociation throw outs, the reduction lamp-dish flower acetic is advisable with strong acid, and as hydrochloric acid, sulfuric acid etc., the described weight percent that contains is the aqueous solution that the solution of 10-60% solvent is meant solvent.Said process can carry out at normal temperatures, also can carry out below the boiling temperature of solvent for use, but be the best with 10-45 ℃.
Processing step of the present invention is simple, is easy to suitability for industrialized production, and prepared lamp-dish flower acetic is analyzed through high pressure liquid chromatography (HPLC) HPLC, and lamp-dish flower acetic purity has obtained the success of beyond thought effect and coml more than 99%.High-purity scutellarin has extremely important value at industrial especially pharmacy field, and it has solved Breviscarpine does not have the technical barrier that solves in nearly 30 years clinical application, has solved the unstable of injection that is:; Eliminated that this product exists feel cold, untoward reactions such as heating, fash, skin pruritus; Reduce toxicity, improved the security of curative effect and use, LD
50Bring up to 1794.98mg/kg by original 1314mg/kg.
The obtained product of the present invention not only can be used as bulk drug, also can be used as reference substance.
Description of drawings
Accompanying drawing is an embodiment of the invention liquid chromatogram.
Use Yi device type: liquid chromatogram gradient mode: constant current detector: outside the Zi
Yi type number: LC-10A wavelength (nm): 335 column temperatures (℃): 30
Zhu Xing number: Phenomenx Xing Prodigy (250*4.6mm) 5u ODS3 100R
Integration method: area normalization method
The analysis result table
| Peak number | The peak name | Retention time | Peak height | Peak area | Content |
| 1 2 3 4 | 4.148 9.832 13.232 15.648 | 25.444 69.073 38.412 21125.418 | 310.600 1558.100 933.300 674148.813 | 0.0459 0.2302 0.1379 99.5861 | |
| The Zong meter | 21258.347 | 676950.812 | 100.0000 |
The peak parameter list
| Peak width | Xie leads | Drift | Minimum area | Time becomes ginseng | Locking time | Dwell time | Example weight |
| 10 | 17.822 | 0.000 | 10.000 | 0.000 | 4.000 | 40.090 | 0.0000 |
Embodiment
Embodiment 1:
Claim commercially available Breviscarpine bulk drug 1000g, add the water of 10 times of weight, transfer pH value to 7 with 30% disodium phenyl phosphate solution, make dissolving fully, filter, filtrate adds 8 times of acetone precipitations under 25 ℃, the limit edged stirs, and makes precipitation fully, leaves standstill 12 hours, filter, add washing with acetone three times, again throw out is moved in another container, add 6 times of amount 40% acetone, stir evenly, adding 25% hydrochloric acid adjustment acidity again is PH 1-2, leaves standstill suction filtration 10 hours, be washed with water to neutrality, add ethanol again and wash once, oven dry is refining lamp-dish flower acetic, analyzing the second cellulose content through HPLC is 99.5861%, as shown in drawings.
Embodiment 2:
Claim commercially available Breviscarpine bulk drug 1000g, add the water of 15 times of weight, transfer pH value to 7, make dissolving fully with 20% alcohol sodium solution, filter, filtrate adds 10 times of acetone precipitations under 25 ℃, and the limit edged stirs, make precipitation fully, left standstill 12 hours, filter, add washing with acetone three times, again throw out is moved in another container, add 6 times of amount 40% acetone, stir evenly, adding 25% hydrochloric acid adjustment acidity again is PH 1-2, leaves standstill 10 hours, suction filtration is washed with water to neutrality, adds ethanol again and washes once.According to above working method 2-3 time repeatedly, oven dry is refining lamp-dish flower acetic with the gained product.
Detection method: (with octadecyl silane is weighting agent: methyl alcohol-0.1% phosphoric acid solution (40: 60) is a moving phase for chromatographic condition and system suitability test; The detection wavelength is 335nm.Number of theoretical plate calculates by the scutellarin peak should not be lower than 5000).Get this product, add water 1ml dissolving, add methyl alcohol and make the solution that every 1ml contains scutellarin 0.4mg approximately, as need testing solution according to every 10mg scutellarin; Precision is measured need testing solution 1.0ml, puts in the 100ml measuring bottle, adds methyl alcohol to scale, mixing, solution in contrast.Get contrast solution 5ul and inject liquid chromatograph, regulate detection sensitivity, the peak height that makes the principal constituent chromatographic peak is 10% of a full range.Get need testing solution 5ul again and inject liquid chromatograph, the record color atlas is to 2.5 of principal constituent peak retention time.Measure each impurity peak area on the need testing solution color atlas and with the peak area ratio of contrast solution principal constituent, calculate lamp-dish flower acetic purity.
Claims (4)
1, a kind of preparation technology of high-purity medicine with lamp-dish flower acetic as raw material is characterized in that being made up of following steps:
(1), getting Breviscarpine places container to add the above water of 2 times of weight, add pH value and regulate PH to 4-8 greater than 9 alkaline solution, make dissolving fully, described alkaline solution is disodium phenyl phosphate, sodium ethylate, three (methylol) amido methane, nitrilotriacetic acid(NTA) sodium solution;
(2), again the solvent that adds weight and be more than three times precipitates under 18-35 ℃ of temperature condition, leaves standstill, and filters, and throw out solvent wash, described solvent are the organic solvent that can mix with arbitrary proportion with water;
(3), precipitation moves to and contains in the solution that weight percent is the 10-60% organic solvent that can mix with arbitrary proportion with water, is acidified with acid to PH1-2, precipitation filters, and is washed to neutrality, drying promptly obtains high-purity medicine with lamp-dish flower acetic as raw material.
2, according to the preparation technology of the described high-purity medicine with lamp-dish flower acetic as raw material of claim 1, the amount that it is characterized in that adding in the step () entry be 2-15 doubly.
3,, it is characterized in that the described organic solvent that can mix with arbitrary proportion with water is one or more in methyl alcohol, ethanol, acetone, the tetrahydrofuran (THF) according to the preparation technology of the described high-purity medicine with lamp-dish flower acetic as raw material of claim 1.
4,, it is characterized in that the solvent adding amount described in the step (two) is 3-15 times according to the preparation technology of the described high-purity medicine with lamp-dish flower acetic as raw material of claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100107230A CN100352826C (en) | 2005-04-01 | 2005-04-01 | Process for preparing high purity scutellarin raw materials |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2005100107230A CN100352826C (en) | 2005-04-01 | 2005-04-01 | Process for preparing high purity scutellarin raw materials |
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| Publication Number | Publication Date |
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| CN1840537A CN1840537A (en) | 2006-10-04 |
| CN100352826C true CN100352826C (en) | 2007-12-05 |
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| CNB2005100107230A Active CN100352826C (en) | 2005-04-01 | 2005-04-01 | Process for preparing high purity scutellarin raw materials |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101747395B (en) * | 2009-12-25 | 2013-01-30 | 中国医药集团总公司四川抗菌素工业研究所 | Method for preparing high-purity scutellarin |
| CN102225958A (en) * | 2011-05-27 | 2011-10-26 | 浙江大学 | Scutellarin purifying method |
| CN103374050B (en) * | 2012-04-18 | 2015-09-23 | 昆明制药集团股份有限公司 | One prepares 5,6, the method for 4 '-trihydroxyflavone-7-0-D-glucuronic acid |
| CN102659875B (en) * | 2012-04-27 | 2014-12-10 | 段志雄 | Extracting method of breviscapine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1053609A (en) * | 1990-01-25 | 1991-08-07 | 云南省生物制药厂 | The extraction process of Herba Erigerontis tablet bulk drug |
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2005
- 2005-04-01 CN CNB2005100107230A patent/CN100352826C/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1053609A (en) * | 1990-01-25 | 1991-08-07 | 云南省生物制药厂 | The extraction process of Herba Erigerontis tablet bulk drug |
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| CN1840537A (en) | 2006-10-04 |
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Assignee: Beijing Chuangli-Kechuang Pharmacy Technology Development Co., Ltd. Assignor: Fan Xiane Contract fulfillment period: 2009.4.8 to 2025.3.31 Contract record no.: 2009990000566 Denomination of invention: Process for preparing high-purity scutellarin bulk drug Granted publication date: 20071205 License type: Exclusive license Record date: 20090527 |
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Effective date of registration: 20100512 Address after: 650106 No. 2188 Gao Lu, hi tech Zone, Yunnan, Kunming Patentee after: Kunming Longjin Pharmaceutical Co., Ltd. Address before: 650228, Yunnan City, Kunming province road under the five pile of Kunming Long Jin Pharmaceutical Co., Ltd. Patentee before: Fan Xiane |
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Address after: 650500 No. 789, Lanmao Road, majinpu sub district office, Kunming high tech Zone, Kunming, Yunnan Patentee after: KUNMING LONGJIN PHARMACEUTICAL Co.,Ltd. Address before: 650106 No. 2188 Kegao Road, high tech Zone, Kunming, Yunnan Patentee before: KUNMING LONGJIN PHARMACEUTICAL Co.,Ltd. |
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