CN102936275A - Method for separating and purifying impurities in sodium tanshinone IIA sulfonate crude drug - Google Patents
Method for separating and purifying impurities in sodium tanshinone IIA sulfonate crude drug Download PDFInfo
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- CN102936275A CN102936275A CN201210452123XA CN201210452123A CN102936275A CN 102936275 A CN102936275 A CN 102936275A CN 201210452123X A CN201210452123X A CN 201210452123XA CN 201210452123 A CN201210452123 A CN 201210452123A CN 102936275 A CN102936275 A CN 102936275A
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Abstract
The invention relates to the technical field of medicines and discloses a method for separating and purifying impurities in a sodium tanshinone IIA sulfonate crude drug. Sodium tanshinone IIA sulfonate is widely used for treating cardiovascular and cerebrovascular diseases and other systemic disease at present. 1, 2-dehydrogenation sodium tanshinone IIA sulfonate, sodium tanshinone IIB sulfonate and 1-hydroxy sodium tanshinone IIA sulfonate are three major impurities in the sodium tanshinone IIA sulfonate crude drug. The method for separating and purifying the impurities in the sodium tanshinone IIA sulfonate crude drug is that a high-speed counter-current chromatography method is used for separating and purifying the three major impurities in the sodium tanshinone IIA sulfonate crude drug. The method has the advantages of being simple, fast, high in recovery rate, large in preparation quantity, high in separation efficiency, good in product purity, convenient and suitable for studying comparison products, and defects of cumbersome operations and long separation periods of traditional preparation methods are overcome.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind of from the sodium tanshinone IIA sulfate bulk drug separation and purification method of three kinds of major impurities wherein.
Background technology
Sodium tanshinone IIA sulfate (Sodium Tanshinone II A Sulfonate, Phenanthro[1,2-b] furan-2-sulfonicacid, 6,7,8,9,10,11-hexahydro-1,6,6-trimethyl-10,11-dioxo-, sodiumsalt) have promoting blood circulation and removing blood stasis, anticoagulant, reduction blood viscosity, expand arteriole, improve systemic microcirculation, remove oxyradical, improve histanoxia, the effect such as anti-inflammatory, be widely used in the treatment of cardiovascular and cerebrovascular diseases and other system disease at present.1,2-dehydrogenation sodium tanshinone IIA sulfate, Tanshinone II B sodium sulfonate and 1-hydroxyl sodium tanshinone IIA sulfate are three kinds of major impurities in the sodium tanshinone IIA sulfate bulk drug, their structural formula is respectively:
Correlative study for impurity in the sodium tanshinone IIA sulfate bulk drug significant (Li Jun etc., the research of Tanshinone II A sodium sulfonate related substances and assay method, Central-South pharmacy .2006,4(4): 291).When the sodium tanshinone IIA sulfate bulk drug is carried out quality approach, need to use the reference substance of related impurities that the impurity in the bulk drug is carried out the content monitoring, meet medicinal requirements to guarantee to prepare, can be used in and prepare the safely and effectively bulk drug of pharmaceutical preparation.
At present, domestic and international combine with normal pressure or middle compression leg chromatogram related impuritieses in the separation and purification sodium tanshinone IIA sulfate bulk drug of preparative high performance liquid chromatographies that adopt more, this class methods complex operation is consuming time, the organic solvent consumption is huge, and sample needs to transfer to preparative high performance liquid chromatography after column chromatography is separated after concentrated again, unavoidably can cause loss and pollution (the Wang B of sample, et al.Isolation and structurecharacterization of related impurities in Sodium Tanshinone IIA Sulfonate by LC/ESI-MSn andNMR, J Pharm Biom Anal.2012,36:67; Zou Q, et al.Identification, Isolation, andCharacterization of Impurities in Sodium Tanshinone IIA Sulfonate, J Liq Chrom Rel Tech.2009,32:2346).Therefore, if can directly separate preparation by the preparative high performance liquid chromatography technology to impurity without the conventional post chromatography process, then can effectively overcome above-mentioned limitation.Yet, because main ingredient and foreign matter content have big difference in the bulk drug, the content of impurity is but extremely humble when the main ingredient amount has overloaded, and can't be directly used in preparative high performance liquid chromatography, and the used stationary phase of preparative high performance liquid chromatography has the non-reversibility adsorption to sample.
High speed adverse current chromatogram (High-speed counter-current chromatography, HSCCC) be a kind of newer liquid liquid distribution chromatography technology, it need not any solid support or carrier and overcome the non-reversibility adsorption of traditional separation method to sample, thereby sample recovery rate is high, also have simultaneously the advantages such as applied range, instrumentation is simple, fractional dose is large, but yet there are no the separation and purification that high speed adverse current chromatogram is applied to related impurities in the sodium tanshinone IIA sulfate bulk drug at present both at home and abroad.
Summary of the invention
The object of the present invention is to provide a kind of preparation technology's Simple fast, the rate of recovery is high, purity is high and is suitable for three kinds of major impurities-1 of separation and purification from the sodium tanshinone IIA sulfate bulk drug of research of the chemical standard product, the method for 2-dehydrogenation sodium tanshinone IIA sulfate, Tanshinone II B sodium sulfonate and 1-hydroxyl sodium tanshinone IIA sulfate.
The invention provides the separation purification method of impurity in a kind of sodium tanshinone IIA sulfate bulk drug, with high speed adverse current chromatogram three kinds of major impurities-1 of separation and purification from the sodium tanshinone IIA sulfate bulk drug, 2-dehydrogenation sodium tanshinone IIA sulfate, Tanshinone II B sodium sulfonate and 1-hydroxyl sodium tanshinone IIA sulfate, the condition of described high speed adverse current chromatogram is with trichloromethane, propyl carbinol, methyl alcohol and the preparation of 0.5% saturated acetic acid aqueous ammonium consist of stationary phase, the solvent system of moving phase, static layering behind the shake well in separating funnel, upper is stationary phase mutually, lower is moving phase mutually, make first in the counter current chromatograph pillar and be full of stationary phase, main frame is rotated, pump into again moving phase, with the sodium tanshinone IIA sulfate bulk drug be dissolved in a small amount of lower mutually in, by the sampling valve sample introduction, receive flow point " I " according to the detector spectrogram, " II ", " III ", flow point " I " is 1,2-dehydrogenation sodium tanshinone IIA sulfate, flow point " II " is the Tanshinone II B sodium sulfonate, and flow point " III " is 1-hydroxyl sodium tanshinone IIA sulfate.
In the described solvent system, the consumption volume ratio of trichloromethane, propyl carbinol, methyl alcohol and 0.5% saturated acetic acid aqueous ammonium is 16 ~ 18 ︰, 0.2 ~ 0.4 ︰, 13 ~ 15 ︰ 8 ~ 10.
Preferably, the consumption volume ratio of trichloromethane, propyl carbinol, methyl alcohol and 0.5% saturated acetic acid aqueous ammonium is 17 ︰, 0.3 ︰, 14 ︰ 9 in the described solvent system.
Method concrete steps of the present invention are as follows:
With high speed adverse current chromatogram three kinds of major impurities of separation and purification from the sodium tanshinone IIA sulfate bulk drug: the solvent system that consists of high speed adverse current chromatogram stationary phase, moving phase is trichloromethane: propyl carbinol: methyl alcohol: 0.5% saturated acetic acid aqueous ammonium=16 ~ 18 ︰, 0.2 ~ 0.4 ︰, 13 ~ 15 ︰ 8 ~ 10.Static layering behind the shake well in separating funnel, upper is stationary phase mutually, lower is moving phase mutually.Behind stationary phase and the moving phase ultrasonic degas, be full of whole cylinder with stationary phase first, then open high-speed counter-current chromatograph, rotating speed is 800 ~ 1200rpm, with 1.0 ~ 3.0ml/min flow velocity moving phase is pumped in the post, after whole Establishing running balance, carry out again sample introduction; Preferred rotating speed is 950rpm, with the flow velocity of 2.0ml/min moving phase is pumped in the post.Get the sodium tanshinone IIA sulfate bulk drug and be dissolved in a small amount of lower phase, by the sampling valve sample introduction, receive flow point " I ", " II ", " III " according to the detector spectrogram.Adopt high performance liquid chromatography that the gained flow point is carried out purity detecting (areas of peak normalization method), record stream part " I " purity and be higher than 95%, stream part " II " purity is higher than 96%, and stream part " III " purity is higher than 96%.Volatilize behind the solvent to flow point " I ", " II ", " III " carry out MS,
1HNMR and
13CNMR analyzes, and carries out structural confirmation according to the data obtained, and flow point " I " is 1,2-dehydrogenation sodium tanshinone IIA sulfate, and flow point " II " is the Tanshinone II B sodium sulfonate, and flow point " III " is 1-hydroxyl sodium tanshinone IIA sulfate.
The present invention adopts high speed adverse current chromatogram three kinds of major impurities of separation and purification from the sodium tanshinone IIA sulfate bulk drug, method Simple fast and the rate of recovery are high, overcome the shortcomings such as traditional preparation method's complex operation, separation cycle be long, and have have that preparation amount is large, separation efficiency is high, good product purity, easy, be applicable to the advantage such as research of the chemical standard product.
Description of drawings
Fig. 1 is the color atlas of the high speed adverse current chromatogram (HSCCC) of sodium tanshinone IIA sulfate bulk drug;
Fig. 2 is the high-efficient liquid phase chromatogram of sodium tanshinone IIA sulfate bulk drug;
Fig. 3 is that HSCCC separates flow point " I " (impurity 1) high-efficient liquid phase chromatogram;
Fig. 4 is that HSCCC separates flow point " II " (impurity 2) high-efficient liquid phase chromatogram;
Fig. 5 is HSCCC separated flow part " III " (impurity 3) high-efficient liquid phase chromatogram.
Embodiment
Now in conjunction with the embodiments and accompanying drawing, the invention will be further described, but enforcement of the present invention is not limited in this.
Embodiment 1:
Use high speed adverse current chromatogram (Shenzhen is with the biochemical company limited in field) separation and purification three kinds of major impurities wherein from the sodium tanshinone IIA sulfate bulk drug: the solvent system that consists of high speed adverse current chromatogram stationary phase, moving phase is San Lv Jia Wan ︰ Zheng Ding Chun ︰ Jia Chun ︰ 0.5% saturated acetic acid aqueous ammonium=17 ︰, 0.3 ︰, 14 ︰ 9(volume ratios).Static layering behind the shake well in separating funnel, upper is stationary phase mutually, lower is moving phase mutually.Make first in the counter current chromatograph pillar and be full of stationary phase, main frame is rotated, pump into moving phase again, the adverse current chromatogram column volume is 300ml, stationary phase retention rate 75%, flow velocity 2.0ml/min, rotating speed 950rpm detects wavelength 280nm, get during sodium tanshinone IIA sulfate bulk drug 100mg is dissolved under the 20ml mutually, by the sampling valve sample introduction, receive flow point " I ", " II ", " III " according to the detector spectrogram, see Fig. 1.
This part is carried out HPLC the analysis showed that " I ", " II ", " III " are single chromatographic peak, peak purity is respectively 95.60%, 96.47%, 97.03%.The HPLC analysis condition is chromatographic column Diamonsil C18 (250 * 4.6mm, 5 μ m); Moving phase is the A=20mM ammonium acetate, B=methyl alcohol; The gradient elution mode is: T (min)/%B:0/45,10/60,20/60,25/75,30/4545/45; Flow velocity 1.0ml/min; 25 ℃ of column temperatures; Detect wavelength 270nm.Each high-efficient liquid phase chromatogram of gained is seen Fig. 2, Fig. 3, Fig. 4, Fig. 5 with this understanding.
" I ", " II ", " III " flow point that separation is obtained volatilize, and get flow point " I " brown powder 26.43mg, and yield is 26.43%; Flow point " II " yellow powder 18.61mg, yield is 18.61%; The brick-red powder 32.23mg of flow point " III ", yield is 32.23%.Flow point " I ", " II ", " III " on Varian INOVA-500 type nuclear magnetic resonance analyser and Varian MAT-212 type mass spectrograph, are carried out
1HNMR,
13CNMR and MS analyze, and determine that through structure elucidation flow point " I " is 1,2-dehydrogenation sodium tanshinone IIA sulfate, and flow point " II " is the Tanshinone II B sodium sulfonate, and flow point " III " is 1-hydroxyl sodium tanshinone IIA sulfate.
Embodiment 2:
According to the high-speed countercurrent chromatography operation steps of embodiment 1 separation and purification three kinds of major impurities wherein from the sodium tanshinone IIA sulfate bulk drug: the solvent system that consists of high speed adverse current chromatogram stationary phase, moving phase is San Lv Jia Wan ︰ Zheng Ding Chun ︰ Jia Chun ︰ 0.5% saturated acetic acid aqueous ammonium=18 ︰, 0.2 ︰, 15 ︰ 8.The method of the separation and purification of three kinds of impurity, purity detecting and Structural Identification, step are with embodiment 1.1,2-dehydrogenation sodium tanshinone IIA sulfate yield is 24.8%, and purity is 95.07%; Tanshinone II B sodium sulfonate yield is 17.46%, and purity is 96.14%; 1-hydroxyl sodium tanshinone IIA sulfate yield is 29.45%, and purity is 97.57%.
Above demonstration and described ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in above-described embodiment and the specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (5)
1. the separation purification method of impurity in the sodium tanshinone IIA sulfate bulk drug, it is characterized in that, the method is with high speed adverse current chromatogram separation and purification 1 from the sodium tanshinone IIA sulfate bulk drug, 2-dehydrogenation sodium tanshinone IIA sulfate, Tanshinone II B sodium sulfonate and 1-hydroxyl sodium tanshinone IIA sulfate, the condition of described high speed adverse current chromatogram is with trichloromethane, propyl carbinol, methyl alcohol and the preparation of 0.5% saturated acetic acid aqueous ammonium consist of stationary phase, the solvent system of moving phase, static layering behind the shake well in separating funnel, upper is stationary phase mutually, lower is moving phase mutually, make first in the counter current chromatograph pillar and be full of stationary phase, main frame is rotated, pump into again moving phase, with the sodium tanshinone IIA sulfate bulk drug be dissolved in a small amount of lower mutually in, by the sampling valve sample introduction, receive flow point " I " according to the detector spectrogram, " II ", " III ", flow point " I " is 1,2-dehydrogenation sodium tanshinone IIA sulfate, flow point " II " is the Tanshinone II B sodium sulfonate, flow point " III " is 1-hydroxyl sodium tanshinone IIA sulfate.
2. the separation purification method of impurity in a kind of sodium tanshinone IIA sulfate bulk drug according to claim 1, it is characterized in that, in the described solvent system, the consumption volume ratio of trichloromethane, propyl carbinol, methyl alcohol and 0.5% saturated acetic acid aqueous ammonium is 16 ~ 18 ︰, 0.2 ~ 0.4 ︰, 13 ~ 15 ︰ 8 ~ 10.
3. the separation purification method of impurity in a kind of sodium tanshinone IIA sulfate bulk drug according to claim 1, it is characterized in that, in the described solvent system, the consumption volume ratio of trichloromethane, propyl carbinol, methyl alcohol and 0.5% saturated acetic acid aqueous ammonium is 17 ︰, 0.3 ︰, 14 ︰ 9.
4. the separation purification method of impurity in a kind of sodium tanshinone IIA sulfate bulk drug according to claim 1 and 2 is characterized in that, static layering behind the shake well in separating funnel, and upper is stationary phase mutually, lower is moving phase mutually; Behind stationary phase and the moving phase ultrasonic degas, be full of whole cylinder with stationary phase first, then open high-speed counter-current chromatograph, rotating speed is 800 ~ 1200rpm, with 1.0 ~ 3.0ml/min flow velocity moving phase is pumped in the post, after whole Establishing running balance, carry out again sample introduction; Preferred rotating speed is 950rpm, with the flow velocity of 2.0ml/min moving phase is pumped in the post; Get the sodium tanshinone IIA sulfate bulk drug and be dissolved in a small amount of lower phase, by the sampling valve sample introduction, receive flow point " I ", " II ", " III " according to the detector spectrogram.
5. the separation purification method of impurity in a kind of sodium tanshinone IIA sulfate bulk drug according to claim 4, it is characterized in that, receive flow point " I ", " II ", " III " afterwards according to the detector spectrogram, adopt high performance liquid chromatography that the gained flow point is carried out purity detecting; Volatilize behind the solvent to flow point " I ", " II ", " III " carry out MS,
1HNMR and
13CNMR analyzes, and carries out structural confirmation according to the data obtained, and flow point " I " is 1,2-dehydrogenation sodium tanshinone IIA sulfate, and flow point " II " is the Tanshinone II B sodium sulfonate, and flow point " III " is 1-hydroxyl sodium tanshinone IIA sulfate.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103736296A (en) * | 2013-12-30 | 2014-04-23 | 浙江大学 | Double-column circulating separation system and method for preparing high-purity tanshinone compound |
| CN103768826A (en) * | 2013-12-30 | 2014-05-07 | 浙江大学 | Three-column cyclic separation system for preparing high-purity tanshinone compound and method thereof |
| CN103772478A (en) * | 2013-12-30 | 2014-05-07 | 浙江大学 | Single-column cyclic separation system for preparing high-purity tanshinone compounds and method thereof |
| CN103819532A (en) * | 2014-03-14 | 2014-05-28 | 上海第一生化药业有限公司 | Preparation method and application of sodium tanshinone II B sulfonate |
| CN103819533A (en) * | 2014-03-14 | 2014-05-28 | 上海第一生化药业有限公司 | Preparation method and application of sodium methyl tanshinonate sulfonate |
| CN103864884A (en) * | 2014-03-14 | 2014-06-18 | 上海第一生化药业有限公司 | Method for preparing przewaquinone sodium sulfonate |
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| CN1394870A (en) * | 2001-07-05 | 2003-02-05 | 北京天纯维通生物技术有限公司 | Method for separating and purifying tanshinone |
| CN102167721A (en) * | 2011-03-24 | 2011-08-31 | 聊城大学 | Method for extracting and purifying tanshinone monomeric compounds from red sage root |
-
2012
- 2012-11-13 CN CN201210452123.XA patent/CN102936275B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1394870A (en) * | 2001-07-05 | 2003-02-05 | 北京天纯维通生物技术有限公司 | Method for separating and purifying tanshinone |
| CN102167721A (en) * | 2011-03-24 | 2011-08-31 | 聊城大学 | Method for extracting and purifying tanshinone monomeric compounds from red sage root |
Non-Patent Citations (3)
| Title |
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| WANG BAOLIN等: "Isolation and structure characterization of related impurities in Sodium Tanshinone IIA Sulfonate by LC/ESI-MSn and NMR", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103736296A (en) * | 2013-12-30 | 2014-04-23 | 浙江大学 | Double-column circulating separation system and method for preparing high-purity tanshinone compound |
| CN103768826A (en) * | 2013-12-30 | 2014-05-07 | 浙江大学 | Three-column cyclic separation system for preparing high-purity tanshinone compound and method thereof |
| CN103772478A (en) * | 2013-12-30 | 2014-05-07 | 浙江大学 | Single-column cyclic separation system for preparing high-purity tanshinone compounds and method thereof |
| CN103736296B (en) * | 2013-12-30 | 2015-12-30 | 浙江大学 | A kind of twin columns circulation separation system and method thereof preparing tanshinone compound |
| CN103768826B (en) * | 2013-12-30 | 2016-03-02 | 浙江大学 | A kind of three post circulation separation system and methods thereof preparing tanshinone compound |
| CN103819532A (en) * | 2014-03-14 | 2014-05-28 | 上海第一生化药业有限公司 | Preparation method and application of sodium tanshinone II B sulfonate |
| CN103819533A (en) * | 2014-03-14 | 2014-05-28 | 上海第一生化药业有限公司 | Preparation method and application of sodium methyl tanshinonate sulfonate |
| CN103864884A (en) * | 2014-03-14 | 2014-06-18 | 上海第一生化药业有限公司 | Method for preparing przewaquinone sodium sulfonate |
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