CN101393181B - Method for measuring relative material of sodium divalproate - Google Patents
Method for measuring relative material of sodium divalproate Download PDFInfo
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- CN101393181B CN101393181B CN200810231809XA CN200810231809A CN101393181B CN 101393181 B CN101393181 B CN 101393181B CN 200810231809X A CN200810231809X A CN 200810231809XA CN 200810231809 A CN200810231809 A CN 200810231809A CN 101393181 B CN101393181 B CN 101393181B
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- divalproex sodium
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Abstract
The invention discloses a method for mensurating relevant substances in sodium di-vedproate, The method comprises the following steps: sodium di-vedproate in a solid state is converted into valproic acid in a liquid state; a sodium di-vedproate sample is prepared; and according to contrast substances of butyric acid, valeric acid, diallyl acetic acid and (R,S)-2-isopropyl valerate, the relevant substances in the sodium di-vedproate are detected by a gas chromatograph instrument. The method can carry out relevant substances inspection on the sodium di-vedproate which exists in tablet dosages, capsule dosages, granular dosages, oral liquid dosages, needle dosages, film dosages, aerosol dosages or injection dosages and other dosages of a slow-release type, a controlled-release type and a common type, improve the quality standard of the prior sodium di-vedproate, and provide evidence for instituting a mensuration standard for the relevant substances of the sodium di-vedproate.
Description
Technical field
The present invention relates to a kind of detection method of medicine, particularly relate to method for determination related substances in a kind of divalproex sodium, this method is that the bioassay standard of China's formulation divalproex sodium provides foundation.
Background of invention
Divalproex sodium is a kind of mental disease class medication in U.S.'s listing, is a line medicine that is applied to treat epilepsy, adult's migraines and two-phase emotion type obstacle.
At present, the divalproex sodium that has gone on the market is not both at home and abroad all stipulated related substance inspection item and limit in quality standard, and this has constituted potential threat to clinical application safety.Therefore, for strictness control drug quality, guarantee that its safety of clinical administration is effective, the reply divalproex sodium carries out the related substance inspection, improves the quality standard of existing divalproex sodium.
Summary of the invention
The objective of the invention is to; Method for determination related substances in a kind of divalproex sodium is provided; This method adopts vapor-phase chromatography; With butyric acid that maybe be residual in the tester confrontation divalproex sodium, valeric acid, diallyl acetate, (R, S)-2-isopropyl valeric acid, valproic acid and other unknown impurities detect.
In order to realize above-mentioned task, the present invention takes following technical solution:
Method for determination related substances in a kind of divalproex sodium; It is characterized in that; This method changes into liquid valproic acid with the Solid Double sodium vedproate, preparation divalproex sodium sample, then with gas chromatograph according to contrast material butyric acid, valeric acid, diallyl acetate, (R; S)-2-isopropyl valeric acid detects the related substance in the divalproex sodium sample, specifically comprises the following steps:
1) select the contrast material:
The contrast material select butyric acid, valeric acid, diallyl acetate, (R, S)-2-isopropyl valeric acid, valproic acid;
2) specimen preparation:
It is an amount of to get the divalproex sodium raw material, is dissolved in water, and adds acid and makes the whole acidifyings of divalproex sodium in right amount, adds organic solvent again and extracts in right amount, volatilizes organic solvent, surplus debris;
3) chromatographic condition:
It is the polyglycol or the polyglycol improvement capillary chromatograph of strong polarity that the used capillary chromatographic column of gas chromatograph is selected stationary phase, and injector temperature is: 220 ℃～300 ℃; Column temperature: 100 ℃～200 ℃, carrier gas is helium, nitrogen or hydrogen;
4) measure:
Precision is measured debris 0.1～0.2 μ l, in the inject gas chromatograph, the record chromatogram, in the collection of illustrative plates if show impurity peaks, its each impurity peak area with must not surpass 3% of the total area.
In the preparation of above-mentioned sample, said acid is including, but not limited to organic acid and mineral acids such as phosphoric acid, hydrochloric acid, sulfuric acid, acetic acid.
In above-mentioned specimen preparation, said organic solvent is including, but not limited to volatile organic solvents of low boiling such as ether, sherwood oil, pentane, hexane, cyclohexane, octane, ethyl acetate, methylene chloride, methenyl cholorides.
The preferred temperature of injection port is: 245 ℃～275 ℃
The preferred temperature of column temperature is 130 ℃～160 ℃.
Described polyglycol or polyglycol improvement capillary chromatograph is including, but not limited to several kinds of models like this: DB-WAX capillary chromatographic column (stationary phase is a polyglycol), AEPEG-20M capillary chromatographic column (stationary phase is a polyglycol), the general capillary column of FFAP (stationary phase is the polyglycol of nitroterephthalic acid (TPA) modification).
Method of the present invention detects accurately, sensitivity is higher; Specificity is strong; Can carry out the related substance inspection to the divalproex sodium in all kinds of formulations that are present in spacetabs type, control release type and medium-sized tablet, capsule, granule, oral liquid, injection, film, aerosol or injection; Improve the quality standard of existing divalproex sodium, for the determination of related substances standard of formulating divalproex sodium from now on provides foundation.
Description of drawings
Fig. 1 is the butyric acid gas chromatogram;
Fig. 2 is the valeric acid gas chromatogram;
Fig. 3 is a diallyl acetate gas chromatogram;
Fig. 4 is the valproic acid gas chromatogram;
Fig. 5 is the solvent chromatogram;
Fig. 6 is that acid destroys the sample gas chromatogram;
Fig. 7 is that alkali destroys the sample gas chromatogram;
Fig. 8 is that oxidation destroys the sample gas chromatogram;
Fig. 9 is that high temperature destroys the sample gas chromatogram;
Figure 10 is that limit of identification is confirmed gas chromatogram.
Through accompanying drawing and concrete experiment the present invention is described further below.
Embodiment
One, the related substance thin-layered chromatography is investigated experiment in the divalproex sodium
In order to guarantee the accuracy of testing result, the applicant has at first carried out related substance thin-layered chromatography investigation experiment in the divalproex sodium, and purpose is that the Solid Double sodium vedproate is changed into liquid valproic acid fully, and concrete grammar is:
1. specimen preparation:
Appearance 1: it is an amount of to get the divalproex sodium raw material, adds dissolve with ethanol;
Appearance 2: it is an amount of to get divalproex sodium, adds an amount of sulfuric acid, makees solvent with water, is mixed with the solution (in valproic acid) of volumetric molar concentration such as same 1;
Appearance 3: get and an amount of synthetic use the precursor valproic acid, add dissolve with ethanol, be mixed with the solution (in valproic acid) of volumetric molar concentration such as same 1;
Compound sample: equivalent is drawn above-mentioned kind 2, appearance 3 solution, mixing.
2. the selection of thin layer plate and developping agent:
Get above-mentioned 4 samples point sample under different thin-layer chromatography conditions, carry out separation test, see table 1.
Table 1 related substance thin-layered chromatography is investigated
3, conclusion:
Experimental study through adopting different thin layer plates and solvent polarity is found: divalproex sodium has only part to be converted into valproic acid in ethanol, and in acid solution, can all be converted into valproic acid.Therefore must adopt " acidifying " step in the sample treatment of confirming to be provided, the Solid Double sodium vedproate is changed into liquid valproic acid fully.
Two, other Study on Conditions of divalproex sodium determination of related substances method
1, injector temperature and column temperature confirms
Do contrast with butyric acid, valeric acid, diallyl acetate, valproic acid, mixed preparing is confirmed rational injector temperature and column temperature through the separation case of related substance in the biased sample.
Instrument: gas chromatograph.
Contrast material: butyric acid, valeric acid, diallyl acetate, valproic acid.
The preparation of sample: getting butyric acid, valeric acid, diallyl acetate respectively, to be dissolved in ether in right amount be contrast solution, and other gets each contrast solution and divalproex sodium is processed mixed solution.
Select DB-WAX capillary chromatographic column 30m*0.25mm*0.25 μ m for use; Carrier gas is a helium, shunts when identical each 3 pin of sample introduction contrast solution and biased sample respectively down of condition such as sample size, the appearance time mean value of contrast calculating related substance; Investigate injector temperature and column temperature, see table 2.
The investigation of table 2 detected temperatures (mean value, n=3)
Conclusion: visible from table 2 result: injector temperature is butyric acid, valeric acid, diallyl acetate, (R in 220 ℃～300 ℃ scopes, under the detected temperatures of column temperature in 100 ℃～200 ℃ scopes; S)-2-isopropyl valeric acid and valproic acid can reach effective separation, meet the mensuration requirement.
2, carrier gas confirms
With butyric acid, valeric acid, (R, S)-2-isopropyl valeric acid, valproic acid do contrast, confirm desirable carrier gas through the separation case of related substance in the biased sample.
Instrument: gas chromatograph.
Contrast material: butyric acid, valeric acid, diallyl acetate and valproic acid.
The preparation of sample: getting butyric acid, valeric acid, diallyl acetate respectively, to be dissolved in ether in right amount be contrast solution, and other gets each contrast solution and divalproex sodium is processed mixed solution.
Chromatographic condition DB-WAX capillary chromatographic column 30m*0.25mm*0.25 μ m; Injector temperature: 260 ℃; Column temperature: 145 ℃.Be carrier gas with helium, hydrogen, nitrogen respectively, each 3 pin of difference sample introduction contrast solution and biased sample.
The result: contrast material appearance time basically identical under the different carrier gas conditions of three, all can effectively separate.
Conclusion: helium, hydrogen, nitrogen are all comparatively desirable as the carrier gas of this chromatogram testing conditions, but preferred carrier gas is a helium.
Three, measure the research of the capillary chromatograph of divalproex sodium related substance
1, method
Do contrast with butyric acid, valeric acid, diallyl acetate, valproic acid, confirm detected temperatures through the separation case of related substance in the biased sample.
2, preparation
Contrast material: butyric acid, valeric acid, diallyl acetate and valproic acid.
The preparation of sample: getting butyric acid, valeric acid, diallyl acetate respectively, to be dissolved in ether in right amount be contrast solution, and other gets each contrast solution and divalproex sodium is processed mixed solution.
3, the investigation of different capillary chromatograph separation case
Each 3 pin of sample introduction contrast solution and biased sample contrast and calculate related substance appearance time mean value respectively, investigate the separation case of capillary chromatograph to related substance, and the result sees table 3.
The separation of the different capillary chromatographs of table 3 (mean value, n=3)
| Appearance time (min)/capillary chromatograph | Butyric acid | Valeric acid | Valproic acid | Diallyl acetate | Separation case |
| The DB-WAX capillary chromatograph | 4.4 | 6.1 | 11.0 | 18.0 | Effectively separate |
| The general capillary column of FFAP | 4.0 | 7.3 | 12.1 | 17.3 | Effectively separate |
| The AEPEG-20M capillary chromatographic column | 4.7 | 6.1 | ?11.2 | ?18.8 | Effectively separate |
Conclusion: visible with table 3 result: stationary phase such as DB-WAX capillary chromatographic column, the general capillary column of FFAP, AEPEG-20M capillary chromatographic column are the polyglycol or the polyglycol improvement capillary chromatograph of strong polarity; Butyric acid, valeric acid, diallyl acetate and valproic acid are reached separation fully, meet the mensuration requirement.
The acid of four, specimen preparation process and the screening study of organic solvent
Mainly comprise the screening of two materials among the preparation method of divalproex sodium sample: the acid of acidified sample, the organic solvent of extraction valproic acid.With the content of divalproex sodium, the measured quantity and the separation case in the determination of related substances process of related substance serves as to investigate index, and screening study is carried out in acid and organic solvent, sees table 4:
Chromatographic column: DB-WAX capillary chromatographic column 30m*0.25mm*0.25 μ m; Injector temperature: 260 ℃; Column temperature: 145 ℃; Carrier gas: helium.
Specimen preparation: get the about 2g of divalproex sodium, add water 50ml, heating for dissolving adds sour 1ml after cooling, add organic solvent 15ml again, and jolting is placed and made layering.Get organic solvent layer, volatilize, surplus debris is surveyed diallyl acetate.
The acid of table 4 sample preparation methods and organic solvent are confirmed
Conclusion: visible: in specimen preparation, should select phosphoric acid, hydrochloric acid, sulfuric acid or acidifying with acetic acid sample for use, select ether, sherwood oil, pentane, hexane, cyclohexane, octane, ethyl acetate, methylene chloride for use, trichlorine is first-class or low melting point organic solvent extraction, extraction sample with table 4 result.
Five, divalproex sodium determination of related substances Study on standards
1, chromatographic condition
DB-WAX capillary chromatographic column 30m*0.25mm*0.25 μ m.
Injector temperature: 260 ℃; Column temperature: 145 ℃; Carrier gas: helium.
2, methodological study
2.1 failure test
2.1.1 acid destroys the preparation of sample solution
The about 2g of these article of getting adds water 50ml, adds dilute sulfuric acid 5ml, placed 30 minutes, and the 15ml that adds diethyl ether again, jolting is placed and is made layering, gets ether layer and volatilizes, debris 0.2 μ l sample introduction, record chromatogram.
2.1.2 alkali destroys the preparation of sample solution:
The about 2g of these article of getting adds water 50ml, adds 0.1mol NaOH 5ml, places 30 minutes, transfers pH value to neutral with dilute sulfuric acid, adds dilute sulfuric acid 5ml, the 15ml that adds diethyl ether again, and jolting is placed and is made layering, gets ether layer and volatilizes, debris 0.2 μ l sample introduction, record chromatogram.
2.1.3 oxidation destroys the preparation of sample solution:
The about 2g of these article of getting adds water 50ml, adds 2 of 1% superoxols, places 30 minutes, adds dilute sulfuric acid 5ml, the 15ml that adds diethyl ether again, and jolting is placed and is made layering, gets ether layer and volatilizes, debris 0.2 μ l sample introduction, record chromatogram.
2.1.4 high temperature destroys the preparation of sample solution:
The about 2g of these article of getting adds water 50ml, and heated and boiled 30 minutes cools and adds dilute sulfuric acid 5ml, the 15ml that adds diethyl ether again, and jolting is placed and is made layering, gets ether layer and volatilizes, debris 0.2 μ l sample introduction, record chromatogram.
Sample solution before above four kinds of solution and the destruction by above-mentioned chromatographic condition difference inject gas chromatograph, is write down chromatogram, and the degree of separation of each impurity peaks and main peak all meets the requirements as a result, sees accompanying drawing 1,2,3,4,5,6,7,8,9.
2.2 minimum detectable activity
Precision takes by weighing divalproex sodium 0.05890g; Add dissolve with ethanol and be diluted to the solution of 0.5890mg/ml, 0.05890mg/ml, 0.02945mg/ml, 0.008835mg/ml; Get 0.2 μ l inject gas chromatograph; Learn with collection of illustrative plates, be about 3 times of baseline noise when concentration records the main peak peak height during for 0.008835mg/ml, so minimum detectable activity is 1.767ng (seeing accompanying drawing 10).
3, divalproex sodium determination of related substances research on standard
(1) chromatographic condition:
DB-WAX capillary chromatographic column 30m*0.25mm*0.25 μ m.
Injector temperature: 260 ℃; Column temperature: 145 ℃; Carrier gas: helium.
(2) specimen preparation:
Get the about 2g of divalproex sodium, add water 50ml, heating for dissolving cools and adds dilute sulfuric acid 5ml, the 15ml that adds diethyl ether again, and jolting is placed and is made layering.Get ether layer, volatilize ether, surplus debris.
(3) assay method
Precision is measured debris 0.2 μ l, in the inject gas chromatograph, and 2 times of record chromatogram to major component peak retention time.In the test sample collection of illustrative plates as show impurity peaks, each impurity peak area with must not surpass 3% of the total area.
Below be the inventor provide according to the method described above to the specific embodiment of divalproex sodium determination of related substances, the invention is not restricted to these embodiment.
Embodiment 1:
(1) chromatographic condition
AEPEG-20M capillary chromatographic column 30m*0.25mm*0.25 μ m.
Injector temperature: 240 ℃; Column temperature: 130 ℃; Carrier gas: hydrogen.
(2) specimen preparation
Get the about 1g of divalproex sodium, add water 30ml, heating for dissolving cools and adds watery hydrochloric acid 3ml, adds cyclohexane 10ml again, and jolting is placed and made layering.Get the cyclohexane layer, volatilize, surplus debris.
(3) determination method
Precision is measured debris 0.1 μ l, in the inject gas chromatograph, and 2 times of record chromatogram to major component peak retention time.In the test sample spectrogram as show impurity peaks, each impurity peak area with must not surpass 3% of the total area.
Embodiment 2:
(1) chromatographic condition
DB-WAX capillary chromatographic column 30m*0.25mm*0.25 μ m.
Injector temperature: 220 ℃; Column temperature: 150 ℃; Carrier gas: nitrogen.
(2) specimen preparation
Get the about 5g of divalproex sodium, add water 100ml, heating for dissolving cools and adds phosphoric acid solution 2.5ml, adds sherwood oil 35ml again, and jolting is placed and made layering.Get sherwood oil, volatilize, surplus debris.
(3) determination method
Precision is measured debris 0.1 μ l, in the inject gas chromatograph, and 2 times of record chromatogram to major component peak retention time.In the spectrogram as show impurity peaks, each impurity peak area with must not surpass 3% of the total area.
Embodiment 3:
(1) chromatographic condition
DV-17 capillary column 30m*0.25mm*0.25 μ m.
Injector temperature: 250 ℃; Column temperature: 170 ℃; Carrier gas: hydrogen.
(2) specimen preparation
Get the about 1.5g of divalproex sodium, add water 30ml, heating for dissolving cools and adds acetum 2.5ml, adds methenyl choloride 18ml again, and jolting is placed and made layering.Get methenyl choloride, volatilize, surplus debris.
(3) determination method
Precision is measured debris 0.2 μ l, in the inject gas chromatograph, and 2 times of record chromatogram to major component peak retention time.In the spectrogram as show impurity peaks, its each impurity peak area with must not surpass 3% of the total area.
Claims (5)
1. method for determination related substances in the divalproex sodium; It is characterized in that; This method changes into liquid valproic acid with the Solid Double sodium vedproate, preparation divalproex sodium sample, then with gas chromatograph according to contrast material butyric acid, valeric acid, diallyl acetate, (R; S)-2-isopropyl valeric acid detects the related substance in the divalproex sodium sample, specifically comprises the following steps:
1) select the contrast material:
The contrast material select butyric acid, valeric acid, diallyl acetate, (R, S)-2-isopropyl valeric acid, valproic acid;
2) specimen preparation:
It is an amount of to get the divalproex sodium raw material, is dissolved in water, and adds acid and makes the whole acidifyings of divalproex sodium in right amount, adds organic solvent again and extracts in right amount, volatilizes organic solvent, surplus debris;
3) chromatographic condition:
It is the polyglycol or the polyglycol improvement capillary chromatograph of strong polarity that capillary chromatographic column is selected stationary phase; Injector temperature is: 245 ℃～275 ℃; Column temperature: 130 ℃～160 ℃, carrier gas is helium, nitrogen or hydrogen;
4) measure:
Precision is measured debris 0.1～0.2 μ l, in the inject gas chromatograph, the record chromatogram, in the collection of illustrative plates if show impurity peaks, its each impurity peak area with must not surpass 3% of the total area.
2. assay method as claimed in claim 1 is characterized in that, described chromatographic column is DB-WAX capillary chromatographic column or AEPEG-20M capillary chromatographic column or the general capillary column of FFAP.
3. assay method as claimed in claim 1 is characterized in that described acid comprises phosphoric acid, hydrochloric acid, sulfuric acid or acetic acid.
4. assay method as claimed in claim 1 is characterized in that described organic solvent comprises ether, sherwood oil, pentane, hexane, cyclohexane, octane, ethyl acetate, methylene chloride or methenyl choloride.
5. assay method as claimed in claim 1 is characterized in that, described divalproex sodium is present in all kinds of formulations of spacetabs type, control release type or medium-sized tablet, capsule, granule, oral liquid, injection, film, aerosol or injection.
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| CN103454369A (en) * | 2013-09-09 | 2013-12-18 | 上海兰卫临床检验有限公司 | Method for detecting sodium valproate content of blood through high performance liquid chromatography |
| CN109580828A (en) * | 2018-12-28 | 2019-04-05 | 四川健能制药有限公司 | A kind of related substance-measuring method of sodium vedproate oral administration solution |
| CN109580831B (en) * | 2018-12-28 | 2022-05-13 | 四川健能制药有限公司 | Method for measuring related substances of sodium valproate oral solution |
| CN110687223B (en) * | 2019-09-29 | 2022-08-05 | 四川健能制药有限公司 | Method for measuring content of sodium valproate raw material methyl acetoacetate |
| CN113252803A (en) * | 2020-09-30 | 2021-08-13 | 四川健能制药有限公司 | Method for determining process and degradation impurities in sodium valproate raw material |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20020127277A1 (en) * | 2000-12-22 | 2002-09-12 | Yihong Qiu | Solid dosage forms of divalproex sodium |
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| US20020127277A1 (en) * | 2000-12-22 | 2002-09-12 | Yihong Qiu | Solid dosage forms of divalproex sodium |
Non-Patent Citations (1)
| Title |
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| council of Europe.SODIUM VALPROATE.《EUROPEAN PHARMACOPOEIA 5.0》.2005,第2457－2458页. * |
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