CN1297267C - Medicinal composition containing tanshinon II A sodium sulfonate and its quality control method - Google Patents
Medicinal composition containing tanshinon II A sodium sulfonate and its quality control method Download PDFInfo
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- CN1297267C CN1297267C CNB2005100204688A CN200510020468A CN1297267C CN 1297267 C CN1297267 C CN 1297267C CN B2005100204688 A CNB2005100204688 A CN B2005100204688A CN 200510020468 A CN200510020468 A CN 200510020468A CN 1297267 C CN1297267 C CN 1297267C
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Abstract
The present invention relates to a medicine composition containing tanshinone II A sodium sulfonate and a quality controlling method thereof, wherein the medicine composition is composed of tanshinone II A sodium sulfonate, carriers acceptable to pharmacy, auxiliary materials and additives. The quality controlling method adopts an efficient liquid chromatography method. Octadecylsilane chemically bonded silica is used as an immobile phase, and a mixed solvent compounded by water-soluble organic solvents, water, cations and reagents is used as a moving phase so as to measure the content of tanshinone II A sodium sulfonate in the medicine composition and check the content limitation of relevant substances of tanshinone I sodium sulfonate and tanshinone II A. The method has the advantages of simplicity, feasibility, high precision and good separation degree, precision and reproducibility. The medicine composition is better than that in the current national medicine standards. The present invention provides a new method for controlling the quality of the medicine composition containing tanshinone II A sodium sulfonate.
Description
Technical field
The present invention relates to a kind of Pharmaceutical composition and method of quality control thereof that contains sodium tanshinone IIA sulfate, belong to field of medicaments.
Background technology
Tanshinone is as the main component in the salviamiltiorrhizabung (Salvia miltiorrhiza Bunge), because its intestinal absorption is poor, clinical onset of action is slow, so its sulfonation is become water solublity sodium salt-DS-201 by people such as money name Kun, be sodium tanshinone IIA sulfate, successively make injection for zoopery and clinical use by Shanghai pharmacy one factory, Chinese medicine three factories etc.
Sodium tanshinone IIA sulfate has stronger anti-hypoxia, improves cardiac function, reduces effects such as thrombosis, can reduce the content of the myocardial mitochondria lipid peroxide that ischemia-reperfusion produces, improve the flowability of myocardial mitochondria film, also have coronary blood flow increasing, promote the effect that collateral circulation is set up.And the pharmacological action of Tanshinone I sodium sulfonate is mainly anti-inflammation and estrogen-like effects, and is far from each other with the sodium tanshinone IIA sulfate pharmacological action; Tanshinone is identical with the pharmacological action of sodium tanshinone IIA sulfate, but because it is a liposoluble constituent, and poor solubility in water is easily separated out precipitation behind the heat sterilization, the two safety and stability to the sodium tanshinone IIA sulfate injection all have harmful effect.
Therefore, Tanshinone I sodium sulfonate and tanshinone are the two kinds of major impurities (seeing national drug standards WS-10001-(HD-0923)-2002) in the sodium tanshinone IIA sulfate crude drug.At the sodium tanshinone IIA sulfate crude drug and to contain the content limit of checking Tanshinone I sodium sulfonate and tanshinone in the preparation of this crude drug significant to controlling sodium tanshinone IIA sulfate crude drug quality and containing the quality of the pharmaceutical preparations of this crude drug.The disclosed content assaying method of sodium tanshinone IIA sulfate crude drug and preparation sodium tanshinone IIA sulfate injection thereof is ultraviolet spectrophotometry (seeing national drug standards WS-10001-(HD-0923)-2002 and national drug standards WS-10001-(HD-1014)-2002) at present.Related substance inspection method about Tanshinone I sodium sulfonate and tanshinone in the disclosed sodium tanshinone IIA sulfate crude drug is thin layer chromatography (seeing national drug standards WS-10001-(HD-0923)-2002).
As follows in the national drug standards (trying) (standard No. WS-10001-(HD-0923)-2002) to the related substance and the content assaying method of sodium tanshinone IIA sulfate crude drug:
Related substance: get this product, add water and make the solution that contains 5mg among every 1ml, as need testing solution; Other gets the tanshinone reference substance, and chlorination is copied into the solution that contains 0.2mg among every 1ml, in contrast product solution (1); Get Tanshinone I sodium sulfonate reference substance, add water and make the solution product solution (2) in contrast that contains 0.2mg among every 1ml.Test according to thin layer chromatography (two appendix VB of Chinese Pharmacopoeia version in 2000), draw each 10 μ l of above-mentioned three kinds of solution, putting respectively on same silica gel g thin-layer plate, is developing solvent with chloroform-methanol (3: 1), after the expansion, dry, put under the fluorescent lamp and inspect, need testing solution is except that red principal spot, as showing the impurity speckle, compare with reference substance solution (1), (2), all must not be darker.
Assay: get the about 25mg of this product, the accurate title, decide, and puts in the 250ml measuring bottle, and thin up shakes up to scale.Precision is measured 5ml, puts in the 100ml measuring bottle, and thin up shakes up to scale, according to spectrophotography (two appendix IVA of Chinese Pharmacopoeia version in 2000), measures trap at wavelength 271nm place, presses C
19H
17NaO
6Trap (the E of S
1cm 1%) be 767 calculating, promptly.
Find that after deliberation in actual mechanical process, said method has the following disadvantages:
Ultraviolet spectrophotometry is as a kind of spectra methods, it does not have separation function, therefore during the content of the sodium tanshinone IIA sulfate in measuring sodium tanshinone IIA sulfate crude drug and sodium tanshinone IIA sulfate injection, can't get rid of influence such as other impurity components in crude drug and the preparation such as Tanshinone I sodium sulfonate, tanshinone etc. to its assay result, therefore its measurement result is bigger than normal than actual value, has certain positive error.
On the other hand, when the Tanshinone I sodium sulfonate in the employing thin layer chromatography inspection sodium tanshinone IIA sulfate crude drug and the content limit of tanshinone, the impurity speckle of judging test sample and the reference substance solution speckle of prescribed limit relative shade adopted is visual method, this method is subjected to operator, mode of operation and many such as Effect of Environmental such as temperature, humidity, and repeatability is relatively poor.Simultaneously because this method only the is a kind of range estimation formula decision method of limiting the quantity of, can not measure the accurate content of Tanshinone I sodium sulfonate and tanshinone in the sodium tanshinone IIA sulfate crude drug, therefore be difficult to reflect truly, exactly the mass change of sodium tanshinone IIA sulfate crude drug self, poor controllability.
High performance liquid chromatography has concurrently and separates and analytic function as a kind of chromatogram analysis method, can effectively separate under the prerequisite of different component, measures the content of each single component respectively.Up to now, do not see the bibliographical information of any employing high effective liquid chromatography for measuring sodium tanshinone IIA sulfate and Tanshinone I sodium sulfonate content both at home and abroad as yet.This is because sodium tanshinone IIA sulfate is comparatively similar to Tanshinone I sodium sulfonate structure, be diterpene quinone sulfonate form, polarity is big, can be dissociated into sodium ion and diterpene quinone sulfonate ion in water, be difficult on the octadecylsilane chemically bonded silica post, keep, can't measure it.
Summary of the invention
In order to address the above problem, technical scheme of the present invention has provided a kind of Pharmaceutical composition and method of quality control thereof that contains sodium tanshinone IIA sulfate, overcomes the defective that the existing Pharmaceutical composition that contains sodium tanshinone IIA sulfate is difficult to accurately measure sodium tanshinone IIA sulfate content and related substance Tanshinone I sodium sulfonate and tanshinone content limit.
The purpose of this invention is to provide a kind of injection that contains sodium tanshinone IIA sulfate, the percentage by weight of Tanshinone I sodium sulfonate and sodium tanshinone IIA sulfate is not higher than 4%, and the percentage by weight of tanshinone and sodium tanshinone IIA sulfate is not higher than 4%.
Wherein, described injection is injection, injectable powder (aseptic powder injection and freeze-dried powder), high capacity intravenous fluid.
The present invention also provides the method for quality control of the injection that contains sodium tanshinone IIA sulfate, is to adopt high performance liquid chromatography, and chromatographic condition is:
Immobile phase: octadecylsilane chemically bonded silica;
Mobile phase: the mixed solvent that water-miscible organic solvent, water and cation are formed reagent; Wherein, the percent by volume of forming each solvent of mobile phase is: water-miscible organic solvent: 50%～90%, and water: 10%～50%;
Flow velocity: 0.5～2.0ml/min;
Cation is to reagent: 0.2～20mmol/100ml water;
Detect wavelength: 240～280nm.
Wherein, described mobile phase middle-jiao yang, function of the spleen and stomach ion-pairing agent is the quaternary ammonium compound that alkyl replaces, and its general structure is as follows:
Wherein: R
1, R
2, R
3, R
4Be alkyl, M
-Expression anion I
-, Br
-, Cl
-, OH
-, HSO
4 -In a kind of.
As optimized technical scheme be: described R
1, R
2, R
3, R
4Be in methyl, ethyl, butyl, dodecyl, the cetyl one or more, M
-Expression anion I
-, Br
-, Cl
-, OH
-, HSO
4 -In a kind of.
Further preferred, mobile phase middle-jiao yang, function of the spleen and stomach ion-pairing agent is: tetramethyl ammonium chloride, 4 bromide, tetramethyl-ammonium iodide, the tetramethyl ammonium hydrogen sulfate, Tetramethylammonium hydroxide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethyl ammonium iodide, the tetraethyl ammonium hydrogen sulfate, tetraethyl ammonium hydroxide, tetrabutylammonium chloride, tetrabutyl ammonium bromide, tetrabutylammonium iodide, 4-butyl ammonium hydrogen sulfate, TBAH, Dodecyl trimethyl ammonium chloride, Dodecyl trimethyl ammonium chloride, hexadecyltrimethylammonium hydrogensulphate, in the cetyl trimethyl ammonium bromide one or more.
By in the mobile phase of high performance liquid chromatography, using cation, make polarity sodium tanshinone IIA sulfate and Tanshinone I sodium sulfonate big, that be difficult on the octadecylsilane chemically bonded silica post, keep reach separating effect preferably to reagent.
Wherein, the water-miscible organic solvent in the mixed solvent of described mobile phase is: methanol or acetonitrile, or acceptable water-miscible organic solvent in other liquid chromatograph.
Method of quality control of the present invention, when measuring the content of sodium tanshinone IIA sulfate, the detection wavelength is 271 ± 2nm; When checking related substance Tanshinone I sodium sulfonate content limit, the detection wavelength is 246 ± 2nm; When checking the content limit of related substance tanshinone, the detection wavelength is 254 ± 2nm; When single injected sampling was measured the content of sodium tanshinone IIA sulfate in crude drug and the preparation simultaneously and checked the content limit of related substance Tanshinone I sodium sulfonate and tanshinone, the mensuration wavelength was 240～280nm.
The present invention has overcome when adopting ultraviolet spectrophotometry and thin layer chromatography control of quality in the existing national drug standards, be difficult to accurately measure the defective of sodium tanshinone IIA sulfate content and related substance Tanshinone I sodium sulfonate and tanshinone content limit, set up the high performance liquid chromatography quantitative approach, by in mobile phase, using cation to reagent, reach and separate sodium tanshinone IIA sulfate fully, the effect of Tanshinone I sodium sulfonate and tanshinone, and adopt UV-detector to measure its content respectively, accurately, convenient, favorable reproducibility, obviously be better than the ultraviolet spectrophotometry and the thin layer chromatography that are adopted in the disclosed national standard, having realized the effective mass control to the injection that contains sodium tanshinone IIA sulfate, is a kind of accuracy height, favorable reproducibility, the method that controllability is strong.
Description of drawings:
Fig. 1 is that (methanol-water (70: 30) (containing TBAH 2mmol in every 100mL water) is mobile phase to employing condition of the present invention, flow velocity 1mL/min detects wavelength 250nm) chromatogram of the Tanshinone I sodium sulfonate that detects, tanshinone, sodium tanshinone IIA sulfate mixing reference substance.
Fig. 2 is the chromatogram of Tanshinone I sodium sulfonate reference substance in the embodiment of the invention 1
Fig. 3 is the chromatogram of tanshinone reference substance in the embodiment of the invention 1
Fig. 4 is the chromatogram of sodium tanshinone IIA sulfate reference substance in the embodiment of the invention 1
Fig. 5 is the chromatogram of test sample in the embodiment of the invention 1
Fig. 6 is the chromatogram of test sample in the embodiment of the invention 2
The specific embodiment
Mode below by specific embodiment is further described the present invention; but should not be construed as is limiting the scope of the invention; all based on above-mentioned technological thought, the modification, replacement, the change that utilize ordinary skill knowledge and customary means to make all belong to scope of the present invention.
The present invention is by carrying out assay and check the content limit of its related substance Tanshinone I sodium sulfonate and tanshinone to sodium tanshinone IIA sulfate, and then realizes the effective mass control to the Pharmaceutical composition that contains sodium tanshinone IIA sulfate.
The present invention realizes by following two kinds of method of quality control.
Method of quality control 1
Measure by high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D), with octadecylsilane chemically bonded silica is filler, (cation is to reagent 2mmol in every 100mL water) is mobile phase with methanol-water (volume ratio 70: 30), flow velocity 1mL/min, and the detection wavelength is 246nm.Get Tanshinone I sodium sulfonate reference substance an amount of (self-control is through structural identification), the accurate title, decide, add mobile phase and make the solution that contains Tanshinone I sodium sulfonate 20 μ g among every 1mL, precision is measured Tanshinone I sodium sulfonate reference substance solution 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.Other gets test sample, adds mobile phase and makes the solution that contains sodium tanshinone IIA sulfate 500 μ g among every 1mL, and as need testing solution, precision is measured test liquid 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.The chromatographic peak area at the place of identical retention time with reference substance should be not more than the main peak area (content limit that is the Tanshinone I sodium sulfonate is no more than 4%) of reference substance in the test sample.
Measure by high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000), with octadecylsilane chemically bonded silica is filler, (cation is to reagent 2mmol in every 100mL water) is mobile phase with methanol-water (volume ratio 80: 20), flow velocity 1mL/min, and the detection wavelength is 254nm.Get tanshinone reference substance an amount of (available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute), the accurate title, decide, an amount of dissolving adds methylene chloride, add methanol and make the solution that contains tanshinone 20 μ g among every 1mL, precision is measured tanshinone reference substance solution 10 μ L injecting chromatographs, the record chromatogram calculates peak area.Other gets test sample, adds mobile phase and makes the solution that contains sodium tanshinone IIA sulfate 500 μ g among every 1mL, and as need testing solution, precision is measured test liquid 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.The chromatographic peak area at the place of identical retention time with reference substance should be not more than the main peak area (content limit that is tanshinone is no more than 4%) of reference substance in the test sample.
Assay is measured by high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica, and (cation is to reagent 2mmol in every 100mL water) is mobile phase with methanol-water (volume ratio 70: 30), and column temperature is a room temperature, detects wavelength 271nm.
Algoscopy is got the about 25mg of this product, puts in the 100mL measuring bottle, adds the mobile phase dissolving and is diluted to scale, shakes up; Precision is measured 5mL, puts in the 100mL measuring bottle, adds mobile phase and is diluted to scale, shakes up; Precision is measured 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.Other gets sodium tanshinone IIA sulfate reference substance (available from Chinese biological goods calibrating institute), measures with method, presses external standard method with calculated by peak area content.
Method of quality control 2
Measure by high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D), with octadecylsilane chemically bonded silica is filler, (cation is to reagent 2mmol in every 100mL water) is mobile phase with methanol-water (volume ratio 75: 25), flow velocity 1mL/min, and the detection wavelength is 250nm.Get (the self-control of Tanshinone I sodium sulfonate reference substance, through structural identification) an amount of with tanshinone reference substance (available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute), the accurate title, decide, add methylene chloride and dissolve with methanol, add mobile phase and make the reference substance solution of mixing that contains Tanshinone I sodium sulfonate 20 μ g and tanshinone 20 μ g among every 1mL, precision is measured and is mixed reference substance solution 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.Other gets test sample, adds mobile phase and makes the solution that contains sodium tanshinone IIA sulfate 500 μ g among every 1mL, and as need testing solution, precision is measured test liquid 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.All should be not more than the main peak area (content limit that is tanshinone and Tanshinone I sodium sulfonate all is no more than 4%) of each reference substance in the test sample with the chromatographic peak area that mixes the identical retention time of reference substance place.
Assay homogenous quantities control method 1.
Particularly, the Pharmaceutical composition that contains sodium tanshinone IIA sulfate, comprise as sodium tanshinone IIA sulfate crude drug, the injection that contains sodium tanshinone IIA sulfate, lyophilized injectable powder that contains sodium tanshinone IIA sulfate and sterile powder injection, contain glucose (or sodium chloride) injection of sodium tanshinone IIA sulfate, also comprise the oral formulations and the external preparation that contain sodium tanshinone IIA sulfate.The present invention especially has a good application prospect in the quality control of above-mentioned Pharmaceutical composition.
In the method for quality control of the present invention, the mixed solvent that mobile phase can be formed with methanol or acetonitrile, water, tertiary amine (as trioctylamine, triethylamine etc.), according to this area general knowledge, select above-mentioned different water-miscible organic solvent proportioning, also can obtain good separation detection effect, the mixed solvent component as hereinbefore.
Further, the present invention can realize that also single injected sampling measures the sodium tanshinone IIA sulfate crude drug simultaneously and contain in the preparation of this raw material the content of two kinds of related substance Tanshinone I sodium sulfonates and tanshinone, thereby reaches the purpose of sodium tanshinone IIA sulfate crude drug and the preparation that contains this raw material being carried out quality control.
Fig. 1 is that (methanol-water (70: 30) (containing TBAH 2mmol in every 100mL water) is mobile phase to employing condition of the present invention, flow velocity 1mL/min detects wavelength 250nm) chromatogram of the Tanshinone I sodium sulfonate that detects, tanshinone, sodium tanshinone IIA sulfate mixing reference substance.From the figure as can be seen, the complete baseline separation of three, the theoretical tray number average is greater than 2000.(Tanshinone I sodium sulfonate retention time is that 4.03min, tanshinone retention time are that 22.25min, sodium tanshinone IIA sulfate retention time are 6.26min)
The methodological study result is as follows:
Separating degree is for test agent water or mobile phase dissolving back direct injected, and other components do not influence mensuration in the sample, and each component peaks all can reach baseline separation, and separating degree is greater than 1.5, and the main peak theoretical cam curve is greater than 2000.
The linearity and range sodium tanshinone IIA sulfate detects and is limited to 1.5ng, quantitatively is limited to 8ng, when sample size is in 8ng～320ng scope, its standard curve regression equation is that (A is a peak area to A=12355+4293.9m, m is a sample size, ng), and correlation coefficient r=0.9999.The Tanshinone I sodium sulfonate detects and to be limited to 2ng, quantitatively is limited to 10ng, and sample size is in 10ng～400ng scope the time, its standard curve regression equation be A=14313+3435.6m (A is a peak area, and m is a sample size, ng), correlation coefficient r=0.9998.Tanshinone detects and to be limited to 2ng, quantitatively is limited to 10ng, when sample size is in 10ng～400ng scope, its standard curve regression equation be A=5191.4m-3853.7 (A is a peak area, and m is a sample size, ng), correlation coefficient r=0.9999.Peak area and sample size are good linear relationship.
RSD=0.52% when withinday precision is measured sodium tanshinone IIA sulfate, n=5; RSD=0.81% when measuring the Tanshinone I sodium sulfonate, n=5; RSD=0.82% when measuring tanshinone, n=5.
RSD=1.23% when day to day precision is measured sodium tanshinone IIA sulfate, n=6; RSD=1.65% when measuring the Tanshinone I sodium sulfonate, n=5; RSD=1.73% when measuring tanshinone, n=5.
It is strong that day to day precision is measured explanation method of quality control repeatability of the present invention.
Average average recovery was 99.86% ± 0.38% when average recovery was measured sodium tanshinone IIA sulfate, n=9; Average average recovery is 99.23% ± 0.64% when measuring the Tanshinone I sodium sulfonate, n=9; Average average recovery is 99.24% ± 0.52% when measuring tanshinone, n=9.
Learn result of study as seen by said method, the inventive method is highly sensitive, precision good, easy and simple to handle, accurately and reliably, practical, be that the ideal of quality control that contains the Pharmaceutical composition of sodium tanshinone IIA sulfate is selected.
The embodiment of the invention is implemented by following operation.
Wherein used instrument and reagent are:
High performance liquid chromatograph (Tianjin, island SPD-10A), infusion pump (LC-10AT
VP), UV-detector (SPD-10A
VP), chromatography post (C
18-ODS, Di Ma company), chromatographic work station (N-2000 of Zhejiang University).
Methanol (chromatographically pure, Hanbon Sci. ﹠ Tech. Co., Ltd.)
Acetonitrile (chromatographically pure, Fisher chemical reagents corporation)
TBAH (Shanghai reagent one factory)
Tetramethyl ammonium hydrogen sulfate (Hanbon Sci. ﹠ Tech. Co., Ltd.)
4-butyl ammonium hydrogen sulfate (Hanbon Sci. ﹠ Tech. Co., Ltd.)
Tetraethyl ammonium hydrogen sulfate (Hanbon Sci. ﹠ Tech. Co., Ltd.)
Hexadecyltrimethylammonium hydrogensulphate (Hanbon Sci. ﹠ Tech. Co., Ltd.)
Triethylamine (Tianjin chemical reagent factory)
The related substance inspection and the assay of embodiment 1 sodium tanshinone IIA sulfate crude drug
Related substance
Measure by high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D), with octadecylsilane chemically bonded silica is filler, with methanol-water (volume ratio 70: 30) (containing TBAH 2mmol in every 100mL water) is mobile phase, flow velocity 1mL/min, and the detection wavelength is 246nm.Get Tanshinone I sodium sulfonate reference substance an amount of (self-control is through structural identification), the accurate title, decide, add mobile phase and make the solution that contains Tanshinone I sodium sulfonate 20 μ g among every 1mL, precision is measured Tanshinone I sodium sulfonate reference substance solution 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.Other gets sodium tanshinone IIA sulfate crude drug (self-control), adds mobile phase and makes the solution that contains sodium tanshinone IIA sulfate 500 μ g among every 1mL, and as need testing solution, precision is measured test liquid 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.The chromatographic peak area at the place of identical retention time with reference substance should be not more than the main peak area of reference substance in the test sample.(being that Tanshinone I sodium sulfonate content is no more than 4%) chromatogram is seen Fig. 2 (Tanshinone I sodium sulfonate retention time is 4.03min).
Measure by high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D), with octadecylsilane chemically bonded silica is filler, with methanol-water (volume ratio 80: 20) (containing TBAH 2mmol in every 100mL water) is mobile phase, flow velocity 1mL/min, and the detection wavelength is 254nm.Get tanshinone reference substance an amount of (available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute), the accurate title, decide, dissolving adds methylene chloride, add methanol and make the solution that contains tanshinone 20 μ g among every 1mL, precision is measured tanshinone reference substance solution 10 μ L injecting chromatographs, the record chromatogram calculates peak area.Other gets sodium tanshinone IIA sulfate crude drug (self-control), adds mobile phase and makes the solution that contains sodium tanshinone IIA sulfate 500 μ g among every 1mL, and as need testing solution, precision is measured test liquid 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.The chromatographic peak area at the place of identical retention time with reference substance should be not more than the main peak area of reference substance in the test sample.(being that tanshinone content is no more than 4%) chromatogram is seen Fig. 3 (the tanshinone retention time is 15.85min).
Assay
Measure by high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica, with methanol-water (volume ratio 70: 30) (containing TBAH 2mmol in every 100mL water) is mobile phase, column temperature is a room temperature, and flow velocity 1mL/min detects wavelength 271nm.
Algoscopy is got the about 25mg of sodium tanshinone IIA sulfate crude drug (self-control), puts in the 100mL measuring bottle, adds the mobile phase dissolving and is diluted to scale, shakes up; Precision is measured 5mL, puts in the 100mL measuring bottle, adds mobile phase and is diluted to scale, shakes up; Precision is measured 10 μ L injecting chromatographs, the record chromatogram, and (chromatogram is seen Fig. 4, and the sodium tanshinone IIA sulfate retention time is 6.26min) calculates peak area.It is an amount of that other gets sodium tanshinone IIA sulfate reference substance (available from Chinese biological goods calibrating institute), add the mobile phase dissolving, be mixed with every 1mL and contain the reference substance solution of sodium tanshinone IIA sulfate 12.5 μ g, measure with method, (chromatogram is seen Fig. 5 to the record chromatogram, the sodium tanshinone IIA sulfate retention time is 6.26min), press external standard method with calculated by peak area content.The content that records for sodium tanshinone IIA sulfate in the test agent is 97.3%.
The related substance inspection and the assay of embodiment 2 sodium tanshinone IIA sulfate crude drug
Related substance
Measure by high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D), with octadecylsilane chemically bonded silica is filler, with methanol-water (volume ratio 75: 25) (containing TBAH 2mmol in every 100mL water) is mobile phase, flow velocity 1mL/min, and the detection wavelength is 250nm.Get (the self-control of Tanshinone I sodium sulfonate reference substance, through structural identification) an amount of with the tanshinone reference substance, the accurate title, decide, add methylene chloride and dissolve with methanol, add mobile phase and make the reference substance solution of mixing that contains Tanshinone I sodium sulfonate 20 μ g and tanshinone 20 μ g among every 1mL, precision is measured and is mixed reference substance solution 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.Other gets the sodium tanshinone IIA sulfate crude drug, adds mobile phase and makes the solution that contains sodium tanshinone IIA sulfate 500 μ g among every 1mL, and as need testing solution, precision is measured test liquid 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.Should be not more than the main peak area of each reference substance in the test sample with the chromatographic peak area that mixes the identical retention time of reference substance place.(being that Tanshinone I sodium sulfonate and tanshinone content all are no more than 4%) chromatogram is seen chromatogram 6 (Tanshinone I sodium sulfonate retention time is that 3.43min, tanshinone retention time are that 17.05min, sodium tanshinone IIA sulfate retention time are 5.16min)
Assay is with embodiment 1.
The related substance inspection and the assay of embodiment 3 sodium tanshinone IIA sulfate injectable powder
Related substance
Measure by high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D), with octadecylsilane chemically bonded silica is filler, with acetonitrile-water (volume ratio 50: 50) (containing tetramethyl ammonium hydrogen sulfate 0.2mmol in every 100mL water) is mobile phase, flow velocity 2mL/min, the detection wavelength is 246nm.Get Tanshinone I sodium sulfonate reference substance an amount of (self-control is through structural identification), the accurate title, decide, add mobile phase and make the solution that contains Tanshinone I sodium sulfonate 20 μ g among every 1mL, precision is measured Tanshinone I sodium sulfonate reference substance solution 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.Other gets Tanshinone I I A sodium sulfonate injectable powder (self-control), adds mobile phase and makes the solution that contains sodium tanshinone IIA sulfate 500 μ g among every 1mL, and as need testing solution, precision is measured test liquid 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.The chromatographic peak area at the place of identical retention time with reference substance should be not more than the main peak area of reference substance in the test sample.(being that Tanshinone I sodium sulfonate content is no more than 4%)
Measure by high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D), with octadecylsilane chemically bonded silica is filler, with acetonitrile-water (60: 40) (containing tetramethyl ammonium hydrogen sulfate 0.5mmol in every 100mL water) is mobile phase, flow velocity 1.5mL/min, and the detection wavelength is 254nm.Get tanshinone reference substance an amount of (available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute), the accurate title, decide, dissolving adds methylene chloride, add methanol and make the solution that contains tanshinone 20 μ g among every 1mL, precision is measured tanshinone reference substance solution 10 μ L injecting chromatographs, the record chromatogram calculates peak area.Other gets sodium tanshinone IIA sulfate injectable powder (self-control), adds mobile phase and makes the solution that contains sodium tanshinone IIA sulfate 500 μ g among every 1mL, and as need testing solution, precision is measured test liquid 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.The chromatographic peak area at the place of identical retention time with reference substance should be not more than the main peak area of reference substance in the test sample.(being that tanshinone content is no more than 4%)
Assay
Measure by high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica, are mobile phase with acetonitrile-water (60: 40) (containing tetramethyl ammonium hydrogen sulfate 1mmol in every 100mL water), and column temperature is a room temperature, and flow velocity 1mL/min detects wavelength 271nm.
Algoscopy is got the about 25mg of sodium tanshinone IIA sulfate injectable powder (self-control), puts in the 100mL measuring bottle, adds the mobile phase dissolving and is diluted to scale, shakes up; Precision is measured 5mL, puts in the 100mL measuring bottle, adds mobile phase and is diluted to scale, shakes up; Precision is measured 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.It is an amount of that other gets sodium tanshinone IIA sulfate reference substance (available from Chinese biological goods calibrating institute), adds the mobile phase dissolving, is mixed with the reference substance solution that every 1mL contains sodium tanshinone IIA sulfate 12.5 μ g, measures with method, presses external standard method with calculated by peak area content.The content that records for sodium tanshinone IIA sulfate in the test agent is 96.3%.
The related substance inspection and the assay of embodiment 4 sodium tanshinone IIA sulfate injectable powder
Related substance
Measure by high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D), with octadecylsilane chemically bonded silica is filler, with methanol-water (75: 25) (containing hexadecyltrimethylammonium hydrogensulphate 2mmol in every 100mL water) is mobile phase, flow velocity 1mL/min, the detection wavelength is 250nm.Get (the self-control of Tanshinone I sodium sulfonate reference substance, through structural identification) an amount of with the tanshinone reference substance, the accurate title, decide, add methylene chloride and dissolve with methanol, add mobile phase and make the reference substance solution of mixing that contains Tanshinone I sodium sulfonate 20 μ g and tanshinone 20 μ g among every 1mL, precision is measured and is mixed reference substance solution 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.Other gets the sodium tanshinone IIA sulfate injectable powder, adds mobile phase and makes the solution that contains sodium tanshinone IIA sulfate 500 μ g among every 1mL, and as need testing solution, precision is measured test liquid 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.Should be not more than the main peak area (being that Tanshinone I sodium sulfonate and tanshinone content all are no more than 4%) of each reference substance in the test sample with the chromatographic peak area that mixes the identical retention time of reference substance place.
Assay is with embodiment 3.
The related substance inspection and the assay of embodiment 5 sodium tanshinone IIA sulfate glucose (or sodium chloride) injection
Related substance
Measure by high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D), with octadecylsilane chemically bonded silica is filler, with methanol-water (80: 20) (containing tetraethyl ammonium hydrogen sulfate 20mmol in every 100mL water) is mobile phase, flow velocity 0.5mL/min, and the detection wavelength is 246nm.Get Tanshinone I sodium sulfonate reference substance an amount of (self-control is through structural identification), the accurate title, decide, add mobile phase and make the solution that contains Tanshinone I sodium sulfonate 20 μ g among every 1mL, precision is measured Tanshinone I sodium sulfonate reference substance solution 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.Other gets sodium tanshinone IIA sulfate glucose (or sodium chloride) injection (self-control), add mobile phase and make the solution that contains sodium tanshinone IIA sulfate 500 μ g among every 1mL, as need testing solution, precision is measured test liquid 10 μ L injecting chromatographs, the record chromatogram calculates peak area.The chromatographic peak area at the place of identical retention time with reference substance should be not more than the main peak area of reference substance in the test sample.(being that Tanshinone I sodium sulfonate content is no more than 4%)
Measure by high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D), with octadecylsilane chemically bonded silica is filler, with methanol-water (90: 10) (containing tetraethyl ammonium hydrogen sulfate 20mmol in every 100mL water) is mobile phase, flow velocity 0.5mL/min, and the detection wavelength is 254nm.Get tanshinone reference substance an amount of (available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute), the accurate title, decide, dissolving adds methylene chloride, add methanol and make the solution that contains tanshinone 20 μ g among every 1mL, precision is measured tanshinone reference substance solution 10 μ L injecting chromatographs, the record chromatogram calculates peak area.Other gets sodium tanshinone IIA sulfate glucose (or sodium chloride) injection (self-control), add mobile phase and make the solution that contains sodium tanshinone IIA sulfate 500 μ g among every 1mL, as need testing solution, precision is measured test liquid 10 μ L injecting chromatographs, the record chromatogram calculates peak area.The chromatographic peak area at the place of identical retention time with reference substance should be not more than the main peak area of reference substance in the test sample.(being that tanshinone content is no more than 4%)
Assay
Measure by high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica, are mobile phase with methanol-water (80: 20) (containing tetraethyl ammonium hydrogen sulfate 20mmol in every 100mL water), and column temperature is a room temperature, and flow velocity 1mL/min detects wavelength 271nm.
It is an amount of that algoscopy is got sodium tanshinone IIA sulfate glucose (or sodium chloride) injection (self-control), adds mobile phase and make the solution that every 1mL contains sodium tanshinone IIA sulfate 12.5 μ g, and precision is measured 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.It is an amount of that other gets sodium tanshinone IIA sulfate reference substance (available from Chinese biological goods calibrating institute), adds the mobile phase dissolving, is mixed with the reference substance solution that every 1mL contains sodium tanshinone IIA sulfate 12.5 μ g, measures with method, presses external standard method with calculated by peak area content.The content that records for sodium tanshinone IIA sulfate in the test agent is 98.3%.
The related substance inspection and the assay related substance of embodiment 6 sodium tanshinone IIA sulfate glucose (or sodium chloride) injection
Measure by high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D), with octadecylsilane chemically bonded silica is filler, with acetonitrile-water (80: 20) (containing 4-butyl ammonium hydrogen sulfate 10mmol in every 100mL water) is mobile phase, flow velocity 1mL/min, and the detection wavelength is 250nm.Get (the self-control of Tanshinone I sodium sulfonate reference substance, through structural identification) an amount of with tanshinone reference substance (available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute), the accurate title, decide, add methylene chloride and dissolve with methanol, add mobile phase and make the reference substance solution of mixing that contains Tanshinone I sodium sulfonate 20 μ g and tanshinone 20 μ g among every 1mL, precision is measured and is mixed reference substance solution 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.Other gets sodium tanshinone IIA sulfate glucose (or sodium chloride) injection (self-control), add mobile phase and make the solution that contains sodium tanshinone IIA sulfate 500 μ g among every 1mL, as need testing solution, precision is measured test liquid 10 μ L injecting chromatographs, the record chromatogram calculates peak area.Should be not more than the main peak area of each reference substance in the test sample with the chromatographic peak area that mixes the identical retention time of reference substance place.(being that Tanshinone I sodium sulfonate and tanshinone content all are no more than 4%)
Assay is with embodiment 5.
The related substance inspection and the assay of embodiment 7 sodium tanshinone IIA sulfate injection
Related substance
Measure by high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D), with octadecylsilane chemically bonded silica is filler, with methanol-water (70: 30) (containing TBAH 1mmol, hexadecyltrimethylammonium hydrogensulphate 1mmol in every 100mL water) is mobile phase, flow velocity 1mL/min, the detection wavelength is 246nm.Get Tanshinone I sodium sulfonate reference substance an amount of (self-control is through structural identification), the accurate title, decide, add mobile phase and make the solution that contains Tanshinone I sodium sulfonate 20 μ g among every 1mL, precision is measured Tanshinone I sodium sulfonate reference substance solution 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.Other gets sodium tanshinone IIA sulfate injection (self-control), adds mobile phase and makes the solution that contains sodium tanshinone IIA sulfate 500 μ g among every 1mL, and as need testing solution, precision is measured test liquid 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.The chromatographic peak area at the place of identical retention time with reference substance should be not more than the main peak area of reference substance in the test sample.(being that Tanshinone I sodium sulfonate content is no more than 4%)
Measure by high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D), with octadecylsilane chemically bonded silica is filler, with methanol-water (80: 20) (containing TBAH 1mmol, hexadecyltrimethylammonium hydrogensulphate 1mmol in every 100mL water) is mobile phase, flow velocity 1mL/min, the detection wavelength is 254nm.Get tanshinone reference substance an amount of (available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute), the accurate title, decide, dissolving adds methylene chloride, add methanol and make the solution that contains tanshinone 20 μ g among every 1mL, precision is measured tanshinone reference substance solution 10 μ L injecting chromatographs, the record chromatogram calculates peak area.Other gets sodium tanshinone IIA sulfate injection (self-control), adds mobile phase and makes the solution that contains sodium tanshinone IIA sulfate 500 μ g among every 1mL, and as need testing solution, precision is measured test liquid 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.The chromatographic peak area at the place of identical retention time with reference substance should be not more than the main peak area of reference substance in the test sample.(being that tanshinone content is no more than 4%)
Assay
Measure by high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica, with methanol-water (volume ratio 70: 30) (containing TBAH 1mmol, hexadecyltrimethylammonium hydrogensulphate 1mmol in every 100mL water) is mobile phase, column temperature is a room temperature, flow velocity 1mL/min detects wavelength 271nm.
It is an amount of that algoscopy is got sodium tanshinone IIA sulfate injection (self-control), adds mobile phase and make the solution that every 1mL contains sodium tanshinone IIA sulfate 12.5 μ g, and precision is measured 10 μ L injecting chromatographs, and the record chromatogram calculates peak area.It is an amount of that other gets sodium tanshinone IIA sulfate reference substance (available from Chinese biological goods calibrating institute), adds the mobile phase dissolving, is mixed with the reference substance solution that every 1mL contains sodium tanshinone IIA sulfate 12.5 μ g, measures with method, presses external standard method with calculated by peak area content.The content that records for sodium tanshinone IIA sulfate in the test agent is 97.3%.
To sum up, method of quality control of the present invention has overcome when adopting ultraviolet spectrophotometry and thin layer chromatography control of quality in the existing national drug standards, be difficult to accurately measure the defective of sodium tanshinone IIA sulfate content and related substance Tanshinone I sodium sulfonate and tanshinone content limit, set up high performance liquid chromatography accurate, convenient, favorable reproducibility, realized effective mass control the injection that contains sodium tanshinone IIA sulfate.
Claims (3)
1, a kind of control contains the method for quality of the injection of sodium tanshinone IIA sulfate, it is characterized in that: it is to adopt high performance liquid chromatography, and chromatographic condition is:
Immobile phase: octadecylsilane chemically bonded silica;
Mobile phase: the mixed solvent that water-miscible organic solvent, water and cation are formed reagent; Wherein, the percent by volume of forming each solvent of mobile phase is: water-miscible organic solvent: 50%～90%, and water: 10%～50%;
Flow velocity: 0.5～2.0ml/min;
Cation is to reagent: 0.2～20mmol/100ml water;
Detect wavelength: 240～280nm;
Wherein, described water-miscible organic solvent is: methanol or acetonitrile, or acceptable water-miscible organic solvent in other liquid chromatograph;
Described mobile phase middle-jiao yang, function of the spleen and stomach ion-pairing agent is the quaternary ammonium compound that alkyl replaces, and its general structure is as follows:
R in the general formula
1, R
2, R
3, R
4Be in methyl, ethyl, butyl, dodecyl, the cetyl one or more; M
-Expression anion I
-, Br
-, Cl
-, OH
-, HSO
4 -In a kind of.
2, the method of the quality control of the injection that contains sodium tanshinone IIA sulfate according to claim 1, it is characterized in that: mobile phase middle-jiao yang, function of the spleen and stomach ion-pairing agent is: tetramethyl ammonium chloride, 4 bromide, tetramethyl-ammonium iodide, the tetramethyl ammonium hydrogen sulfate, Tetramethylammonium hydroxide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethyl ammonium iodide, the tetraethyl ammonium hydrogen sulfate, tetraethyl ammonium hydroxide, tetrabutylammonium chloride, tetrabutyl ammonium bromide, tetrabutylammonium iodide, 4-butyl ammonium hydrogen sulfate, TBAH, Dodecyl trimethyl ammonium chloride, Dodecyl trimethyl ammonium chloride, hexadecyltrimethylammonium hydrogensulphate, cetyl trimethyl ammonium bromide, in the triethylamine one or more.
3, the method for the quality control of the injection that contains sodium tanshinone IIA sulfate according to claim 1 is characterized in that: when measuring the content of sodium tanshinone IIA sulfate, the detection wavelength is 271 ± 2nm; When checking related substance Tanshinone I sodium sulfonate content limit, the detection wavelength is 246 ± 2nm; When checking the content limit of related substance tanshinone, the detection wavelength is 254 ± 2nm; When single injected sampling was measured the content limit of related substance Tanshinone I sodium sulfonate and tanshinone in crude drug and the preparation simultaneously, the mensuration wavelength was 240～280nm.
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| CN1337397A (en) * | 2000-08-07 | 2002-02-27 | 香港生物科技研究院有限公司 | High-speed countercurrent chromatographic process of separating and purifying tanshinol |
| 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 |
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| CN1337397A (en) * | 2000-08-07 | 2002-02-27 | 香港生物科技研究院有限公司 | High-speed countercurrent chromatographic process of separating and purifying tanshinol |
| 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 |
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