CN102225958A - Scutellarin purifying method - Google Patents
Scutellarin purifying method Download PDFInfo
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- CN102225958A CN102225958A CN2011101433196A CN201110143319A CN102225958A CN 102225958 A CN102225958 A CN 102225958A CN 2011101433196 A CN2011101433196 A CN 2011101433196A CN 201110143319 A CN201110143319 A CN 201110143319A CN 102225958 A CN102225958 A CN 102225958A
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Abstract
The invention provides a scutellarin purifying method, which comprises steps of: first dissolving scutellarin crude product in an alkaline solution to change in a salt; then cooling and crystallizing in an aqueous solution to separate impurities; and acidifying to original molecule state to obtain a purified product with main content more than 99%. In the invention, solubility property of scutellarin sodium salt or sylvite is fully utilized to change a scutellarin refining process into a scutellarin salt separating and purifying process, so as to obtain the high-purity scutellarin product. The method of the invention has few operation steps and a high product yield, and is easy to operate and at low costs; besides water is used as a solvent of crystallization to avoid use of a large amount of organic solvents, so as to enhance production security and facilitate industrialized production.
Description
Technical field
The invention belongs to Chinese medicinal preparation method, relate to a kind of purification process of the scutellarin based on the salt purifying process.
Background technology
Scutellarin (Scutellarin) another name scutellarin, scutellarin, lamp-dish flower acetic, its chemical name is 4'-hydroxyl scutellarin-7-O-glucuronides, its plant origin has the leaf of the high root of large-flowered skullcap of labiate (Scutellaria altissima L.), stem, leaf and the Herba Scutellariae Barbatae of the root of large-flowered skullcap [S.baicalensis Georgi] (S. Barbara D. Don) herb etc.Clinical study is the result show, scutellarin has the reduction cerebral vascular resistance, improves the effect of brain circulation of blood, cerebral blood flow increasing amount and anti-platelet aggregation, clinically is used for the treatment of paralysing after the cerebro-vascular diseases.
Though scutellarin (lamp-dish flower acetic) has very clear and definite curative effect to the treatment of ischemic cerebrovascular disease and coronary heart disease, because the restriction of extraction process, lamp-dish flower acetic preparation ubiquity purity is not high at present, the unsettled situation of curative effect.Therefore, domestic in recent years industry is attached great importance to the research of the separating and purifying technology of scutellarin (lamp-dish flower acetic).Patent CN 101376669A proposes to separate with macroporous resin column the processing method of scutellarin, this technology is dissolved in scutellarin in the buck, and centrifugal rear filtrate joins on the D101 macroporous resin column, by the macroporous resin wash-out, use the anti-solvent crystallization of acetone of 10 times of amounts again, obtain Breviscarpine salt.Again its salt is dissolved with 50% acetone-water, use acid to transfer pH, get scutellarin to acid.Though this method can reach comparatively ideal refining effect, complex technical process causes production cost high, also exists potential safety hazard simultaneously.Patent CN 101830951 A then propose another kind of method of separating scutellarin as moving phase preparative liquid chromatography post with methyl alcohol-DMF-water, though products obtained therefrom purity than higher, the big and production cost of facility investment amount is difficult to industrial applications.It is the method for feedstock production high-purity wild baicalin with the Herba Erigerontis that patent CN 101497637 discloses a kind of.This method through steps such as solvent extraction, flocculation agent clarification, macroporous resin separation and membrane concentration, adopts the organic solvent deposit method to obtain the scutellarin product Herba Erigerontis at last.The weak point of this method is, the numerous length of technology, operation easier is big and unstable product quality.
Because the solubleness of scutellarin in the solvent of routine is less, the process for refining of employing solvent recrystallization is difficult to improve the efficient of industrial equipments.This is the common fault of existing preparation high-purity wild baicalin technology.Patent CN 1715288A, CN1727355A and CN 1718584A have proposed the processing method of the anti-solvent crystallization purifying of organic solvent scutellarin respectively.Though three kinds of technologies respectively have the characteristics of oneself, but technological line is identical, promptly transfer pH with alkali metal weak, make the crude extract dissolving of target product, be anti-solvent with a large amount of methyl alcohol, ethanol, acetone etc. again, separate out its salt crystallization, obtain the higher target product of purity by alkali extraction and acid precipitation technology then.The defective of above-mentioned anti-solvent process is: need to add the anti-solvent of several times volume, consumption of organic solvent is big; And under the alkaline condition, a large amount of methyl alcohol or ethanol are easy to associate with tannin, cause crystallization to be difficult to separate out or crystallization purity not high.
Summary of the invention
The present invention is directed to existing scutellarin purification technique process complexity, weak point that consumption of organic solvent is big, a kind of purification process of purifying scutellarin of novelty has been proposed, realize by following steps: at first at a certain temperature, the scutellarin crude product is put in the certain amount of solvent, transfer pH with alkaline solution, all be dissolved in the solution until scutellarin; Separate out crystallization by the method for evaporation or cooling then, filter, washing, drying obtains the intermediate of purified scutellarin salt; Reselect solvent, the crystalloid intermediate product is dissolved in wherein, add suitable acidic solution, the pH of regulator solution makes scutellarin salt change the scutellarin form into and separates out from solution; Again after filtration, washing, drying, obtain the scutellarin crystallization.The molecular structure of scutellarin of the present invention is:
Below the concrete steps of the inventive method:
(1) under 40 ~ 60 ℃, with the scutellarin crude product by weight volume ratio 1:5 ~ 1:20g/mL add in the solvent solution, with mass concentration is that 5 ~ 20% alkaline solution is transferred pH to 8.0 ~ 9.0, scutellarin is all dissolved, place crystallization down at 4 ~ 10 ℃ then, after 36 ~ 48 hours, filter, wash drying, the crystallization that gets intermediate scutellarin sodium salt or sylvite with water;
(2) under 10 ~ 35 ℃, crystallization with scutellarin sodium salt or sylvite, volume ratio 1:10 ~ 1:20g/mL joins in the solvent solution and dissolves by weight, with mass concentration is that 5 ~ 20% alkaline solution transfers pH to 8.0 ~ 9.0 that salt is all dissolved, and is 5 ~ 10% acid solution accent pH to 1.5 ~ 2.5 again with mass concentration, places 4 ~ 6 hours, filter, wash precipitation with water, drying obtains the scutellarin crystallization of purifying.
The used solvent of step (1) is selected water, ethanol, ethyl acetate or its mixture for use.Used alkaline solution is selected NaOH, NaHCO for use
3, Na
2CO
3, KOH, KHCO
3, K
2CO
3, phosphoric acid salt, ammoniacal liquor or basic aminoacids solution.The crystallization method of separating out the crystal form intermediate comprises decrease temperature crystalline or solvent evaporation crystallization or anti-solvent crystallization method.
The solvent of dissolving intermediate is selected water, methyl alcohol, ethanol, acetate, ethyl acetate or their mixture for use in the step (2), and wherein the weightmeasurement ratio of solute and solvent is 1:10 ~ 1:20g/mL.Used mineral acid or organic acid soln are selected sulfuric acid, hydrochloric acid, nitric acid or acetic acid water solution for use.
Adopt the reliable and stable high effective liquid chromatography for measuring intermediate and the content of the finished product among the present invention.Chromatographic condition is as follows, moving phase: methyl alcohol-0.4% phosphoric acid volume ratio 35:65; Flow rate of mobile phase: 1 mL/min; Detect wavelength: 335nm; Column oven temperature: 45 ℃.Scutellarin is by with its reference substance configuration standard solution, and the drawing standard curve is determined linearity range.Pass through one point external standard method, the content of principal constituent scutellarin in the working sample then.
Characteristics of the present invention are, by selecting suitable solvent and processing condition, make full use of the solubility properties of the sodium salt or the sylvite of scutellarin, and its salts solution separates scutellarin and impurity with the different solubility characteristics of impurity.Selected recrystallisation solvent can make most impurity stay in the solvent, and the scutellarin solution that reaches capacity is then along with the reduction crystallization of temperature is separated out.Compare with the separating and purifying technology of existing scutellarin, the method that the present invention proposes, operation steps is few, and is simple, with low cost, and makes water as the crystalline solvent, avoided the use of a large amount of organic solvents, increased the security of producing; Analyze through HPLC, the content of product principal constituent reaches more than 99%, and its foreign matter content also significantly reduces, the yield height, and constant product quality is convenient to suitability for industrialized production.Therefore, the highly purified scutellarin novel process of preparation proposed by the invention has significant technical superiority.
Different with the existing processes technology, technical thought of the present invention is the isolation and purification that the scutellarin treating process is converted into its salt.Different with anti-solvent process, the present invention becomes the crude extract of target product into scutellarin salt under proper condition, and direct decrease temperature crystalline in the aqueous solution reaches the purpose of removing various impurity then.Sodium salt or sylvite return to the initial molecule state by acidifying again behind the purifying, thereby obtain the high-purity wild baicalin product.Therefore, technological line provided by the invention is more succinct, and facility investment is less, and running cost reduces.
Description of drawings
Fig. 1 is the high-efficient liquid phase chromatogram of scutellarin raw material drug.
Fig. 2 is the high-efficient liquid phase chromatogram of refining scutellarin.
Embodiment
Embodiment 1:
Take by weighing 5.13g content and be 90% scutellarin crude product (its high-efficient liquid phase chromatogram is referring to Fig. 1), join in the 60mL water, under 50-60 ℃, the NaOH with 5% transfers pH to 8.0 ~ 9.0, and sample is dissolved fully, solution is placed 4 ℃ of following decrease temperature crystalline 36h, filter, it is 7.5 that precipitation is washed with water to pH, drying, obtain intermediate precipitation 4.40g, the gained intermediate all joins in the 44mL10% aqueous ethanolic solution, transfers pH to 8.0 ~ 9.0 with 10%KOH solution, makes whole dissolvings, transfer pH to 2.5 with 10% HCl or acetum again, filter, washing with water and being precipitated to pH is 6.8-7.5, drying, obtain purified scutellarin 4.10g, its high-efficient liquid phase chromatogram is referring to Fig. 2.As calculated, the content of scutellarin is 99.8%, and the treating process product yield is 88.6%.
Embodiment 2:
Take by weighing 5.10g content and be 90% scutellarin crude product (its high-efficient liquid phase chromatogram is referring to Fig. 1), join in the 100mL water, handle according to the operation steps of embodiment 1 then, obtain containing the purified product 3.98g of 99.0% scutellarin, product yield 85.8%.
Embodiment 3:
Take by weighing 5.28g content and be 90% scutellarin crude product, join in the aqueous ethanolic solution of 75mL10%, under 50-60 ℃, the Na with 10%
2CO
3Transfer pH to 8.0 ~ 9.0, sample is dissolved fully, evaporation makes liquor capacity dwindle half under vacuum condition, and concentrated solution places 8 ℃ of following decrease temperature crystalline 24h again, filters, and it is 7.5 that precipitation is washed with water to pH, and drying obtains scutellarin sodium salt precipitation 4.38g.The scutellarin sodium salt is joined in the 60mL water, use Na
2CO
3Solution is transferred pH to 8.0 ~ 9.0, makes whole dissolvings, uses rare H again
2SO
4Transferring pH to 1.5-2.0, filter, is 6.8-7.5 with the pure water washing precipitation to pH, and drying obtains purity and be 99.0% scutellarin 4.13g, product yield 86.0%.
Embodiment 4:
Take by weighing 5.30g content and be 90% scutellarin crude product, joining 50mL contains in the aqueous solution of 2mL ethyl acetate, under 50-60 ℃, arginine solution with 30% is transferred pH to 8.0 ~ 9.0, and sample is dissolved fully, and solution is placed 4 ℃ of following decrease temperature crystalline 32h, filter, it is 7.5 that precipitation is washed with water to pH, and drying obtains intermediate precipitation 4.59g.The gained intermediate all joins in the 45mL10% aqueous ethanolic solution, transfer pH to 8.0 ~ 9.0 with 10%KOH solution, make whole dissolvings, transfer pH to 2.8 with 10% acetum again, filter, washing with water and being precipitated to pH is 6.5-7.5, drying, obtain purity and be 99.5% scutellarin 4.14g, product yield 86.3%.
Embodiment 5:
Take by weighing 5.33g content and be 90% scutellarin crude product, join in the methanol aqueous solution of 60mL10%, under 50-60 ℃, KOH with 5% transfers pH to 8.0 ~ 9.0, sample is dissolved fully, place rotatory evaporator to remove the closely solvent of half solution, separate out scutellarin sylvite, gently be cooled to 4 ℃ then, further decrease temperature crystalline filters, and it is 7.5 that precipitation is washed with water to pH, drying obtains intermediate precipitation 4.85g.The gained intermediate all joins in the 45mL10% aqueous ethanolic solution, transfer pH to 8.0 ~ 9.0 with 10%KOH solution, make whole dissolvings, transfer pH to 2.8 with 10% hydrochloric acid soln again, filter, washing with water and being precipitated to pH is 6.5-7.5, drying, obtain purity and be 99.1% scutellarin 4.20g, product yield 86.7%.
Claims (7)
1. the purification process of a scutellarin is characterized in that, realizes by following steps:
(1) under 40 ~ 60 ℃, with the scutellarin crude product by weight volume ratio 1:5 ~ 1:20g/mL add in the solvent solution, with mass concentration is that 5 ~ 20% alkaline solution is transferred pH to 8.0 ~ 9.0, scutellarin is all dissolved, place crystallization down at 4 ~ 10 ℃ then, after 36 ~ 48 hours, filter, wash drying, the crystallization that gets intermediate scutellarin sodium salt or sylvite with water;
(2) under 10 ~ 35 ℃, crystallization with scutellarin sodium salt or sylvite, volume ratio 1:10 ~ 1:20g/mL joins in the solvent solution and dissolves by weight, is that 5 ~ 20% alkaline solution transfers pH to 8.0 ~ 9.0 that salt is all dissolved with mass concentration, is 5 ~ 10% HCl or H again with mass concentration
2SO
4Solution is transferred pH to 1.5 ~ 2.5, places 4 ~ 6 hours, filters, and washes precipitation with water, and drying obtains the scutellarin crystallization of purifying; The molecular structure of described scutellarin is:
2. the purification process of a kind of scutellarin according to claim 1 is characterized in that, the used solvent of step (1) is selected water, ethanol, ethyl acetate or its mixture for use.
3. the purification process of a kind of scutellarin according to claim 1 is characterized in that, the used alkaline solution of step (1) is selected NaOH, NaHCO for use
3, Na
2CO
3, KOH, KHCO
3, K
2CO
3, phosphoric acid salt, ammoniacal liquor or basic aminoacids solution.
4. the purification process of a kind of scutellarin according to claim 1 is characterized in that, step (1) crystalline method is selected decrease temperature crystalline, solvent evaporation crystallization or anti-solvent crystallization method for use.
5. the purification process of a kind of scutellarin according to claim 1, it is characterized in that, used solvent is selected water, methyl alcohol, ethanol, acetate, ethyl acetate or its mixture for use in the step (2), and wherein the weightmeasurement ratio of solute and solvent is 1:10 ~ 1:20g/mL.
6. the purification process of a kind of scutellarin according to claim 1 is characterized in that, acid solution used in the step (2) is mineral acid or organic acid, selects sulfuric acid, hydrochloric acid, nitric acid or acetic acid water solution for use.
7. the purification process of a kind of scutellarin according to claim 1 is characterized in that, the chromatographic condition of high-performance liquid chromatogram determination is moving phase: methyl alcohol-0.4% phosphoric acid volume ratio 35:65; Flow rate of mobile phase: 1 mL/min; Detect wavelength: 335nm; Column oven temperature: 45 ℃.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584917A (en) * | 2011-12-29 | 2012-07-18 | 昆明龙津药业股份有限公司 | Preparation method of high-purity scutellarin crude drug |
| CN104650165A (en) * | 2015-02-27 | 2015-05-27 | 山东省分析测试中心 | Preparation method of high-purity baicalin |
| CN105273018A (en) * | 2014-06-17 | 2016-01-27 | 昆明制药集团股份有限公司 | Scutellarin dihydrate crystal II and preparation method thereof |
| CN105399788A (en) * | 2015-12-29 | 2016-03-16 | 云南生物谷药业股份有限公司 | Scutellarin sodium salt crystal I and preparation method thereof |
| CN106950318A (en) * | 2017-04-20 | 2017-07-14 | 广西壮族自治区梧州食品药品检验所 | A kind of method that ASE HPLC methods determine baicalin in Scutellaria baicalensis Georgi content |
| CN104592184B (en) * | 2014-12-15 | 2017-09-29 | 云南省药物研究所 | Scutellarein crystal formation and preparation method thereof |
| CN107513086A (en) * | 2017-09-08 | 2017-12-26 | 珠海易嘉贸易有限公司 | A kind of method and scutellarin that separating high-purity scutellarin is extracted from Scullcap stem and leaf |
| CN109705179A (en) * | 2019-03-15 | 2019-05-03 | 李小冬 | A method of the extraction purification high-purity scutellarin from radix scutellariae seed shell |
| CN115819477A (en) * | 2022-11-21 | 2023-03-21 | 楚雄云植药业有限公司 | Process for extracting and purifying breviscapine |
Citations (1)
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| CN1840537A (en) * | 2005-04-01 | 2006-10-04 | 樊献俄 | Process for preparing high purity scutellarin raw materials |
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2011
- 2011-05-27 CN CN2011101433196A patent/CN102225958A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1840537A (en) * | 2005-04-01 | 2006-10-04 | 樊献俄 | Process for preparing high purity scutellarin raw materials |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584917A (en) * | 2011-12-29 | 2012-07-18 | 昆明龙津药业股份有限公司 | Preparation method of high-purity scutellarin crude drug |
| CN102584917B (en) * | 2011-12-29 | 2014-03-12 | 昆明龙津药业股份有限公司 | Preparation method of high-purity scutellarin crude drug |
| CN105273018B (en) * | 2014-06-17 | 2018-11-27 | 昆药集团股份有限公司 | A kind of lamp-dish flower acetic dihydrate crystallization II and preparation method thereof |
| CN105273018A (en) * | 2014-06-17 | 2016-01-27 | 昆明制药集团股份有限公司 | Scutellarin dihydrate crystal II and preparation method thereof |
| CN104592184B (en) * | 2014-12-15 | 2017-09-29 | 云南省药物研究所 | Scutellarein crystal formation and preparation method thereof |
| CN107501223A (en) * | 2014-12-15 | 2017-12-22 | 云南省药物研究所 | Scutellarein crystal formation and preparation method thereof |
| US10172824B2 (en) | 2014-12-15 | 2019-01-08 | Yunnan Institute Of Materia Medica | Crystal forms of scutellarin aglycone and preparation thereof |
| CN104650165B (en) * | 2015-02-27 | 2017-10-13 | 山东省分析测试中心 | A kind of preparation method of scutelloside |
| CN104650165A (en) * | 2015-02-27 | 2015-05-27 | 山东省分析测试中心 | Preparation method of high-purity baicalin |
| CN105399788A (en) * | 2015-12-29 | 2016-03-16 | 云南生物谷药业股份有限公司 | Scutellarin sodium salt crystal I and preparation method thereof |
| CN106950318A (en) * | 2017-04-20 | 2017-07-14 | 广西壮族自治区梧州食品药品检验所 | A kind of method that ASE HPLC methods determine baicalin in Scutellaria baicalensis Georgi content |
| CN107513086A (en) * | 2017-09-08 | 2017-12-26 | 珠海易嘉贸易有限公司 | A kind of method and scutellarin that separating high-purity scutellarin is extracted from Scullcap stem and leaf |
| CN107513086B (en) * | 2017-09-08 | 2020-05-01 | 珠海易嘉贸易有限公司 | Method for extracting and separating high-purity scutellarin from scutellaria baicalensis stem and leaf and scutellarin |
| CN109705179A (en) * | 2019-03-15 | 2019-05-03 | 李小冬 | A method of the extraction purification high-purity scutellarin from radix scutellariae seed shell |
| CN115819477A (en) * | 2022-11-21 | 2023-03-21 | 楚雄云植药业有限公司 | Process for extracting and purifying breviscapine |
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Application publication date: 20111026 |