CN111007162A - Method for simultaneously detecting contents of two impurities of cocarboxylase tetrahydrate - Google Patents
Method for simultaneously detecting contents of two impurities of cocarboxylase tetrahydrate Download PDFInfo
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- CN111007162A CN111007162A CN201911100004.6A CN201911100004A CN111007162A CN 111007162 A CN111007162 A CN 111007162A CN 201911100004 A CN201911100004 A CN 201911100004A CN 111007162 A CN111007162 A CN 111007162A
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
The invention provides an analysis method for detecting the content of cocarboxylase tetrahydrate impurity X and/or impurity A, which adopts a high performance liquid chromatograph, and the chromatographic conditions are as follows: a chromatographic column: octadecylsilane chemically bonded silica chromatographic column, mobile phase a: phosphate buffer solution containing sodium octane sulfonate or other similar ion pairs in efficiency, mobile phase B: one of methanol, acetonitrile, mobile phase a-methanol or mobile phase a-acetonitrile, mobile phase A, B performed according to a gradient program; column temperature: 30-50 ℃, flow rate: 0.8-1.2ml/min, detection wavelength: 240-270nm, sample injection amount: 20 μ l. The detection method has high accuracy and sensitivity, and is suitable for detecting the content of cocarboxylase tetrahydrate impurity X and/or impurity A in cocarboxylase tetrahydrate raw materials or vitamin preparations containing cocarboxylase tetrahydrate raw materials.
Description
Technical Field
The invention belongs to the field of analytical chemistry, and particularly relates to a high performance liquid analysis method for simultaneously detecting contents of two impurities in cocarboxylase tetrahydrate.
Background
The cocarboxylase tetrahydrate is a vitamin drug, participates in the oxidative decarboxylation reaction of pyruvic acid and a-ketoglutaric acid in sugar metabolism in vivo, is necessary for sugar metabolism, is clinically used for treating beriberi or Wernicke encephalopathy, can also be used for the adjuvant therapy of peripheral neuritis, dyspepsia and the like caused by the shortage of cocarboxylase tetrahydrate, and is also used as one raw material drug of a plurality of vitamins (12) for injection of a compound vitamin preparation product at present. Cocarboxylase tetrahydrate impurity X (formamidopyrimidine) and cocarboxylase tetrahydrate impurity A (thiamine monophosphate) are degradation products of cocarboxylase tetrahydrate, and the structural formulas are respectively as follows:
cocarboxylase tetrahydrate impurity X
Cocarboxylase tetrahydrate impurity A
The standard of cocarboxylase tetrahydrate is not collected in the domestic and foreign pharmacopoeia, in the examination of related substances of cocarboxylase tetrahydrate in the national standard (YBH03552014), the detection of cocarboxylase impurity A tetrahydrate is available, but the detection is suitable for the examination of raw materials, and the detection is not suitable for the examination of cocarboxylase impurity A tetrahydrate in a compound preparation product containing cocarboxylase tetrahydrate, such as a plurality of vitamins (12) for injection, the specificity does not meet the regulation, and the method for detecting cocarboxylase impurity A tetrahydrate in the literature is a derivation method, the detector is a fluorescence detector, the operation is complicated, and the sample processing method is not suitable. The cocarboxylase tetrahydrate impurity X is a degradation product of cocarboxylase tetrahydrate, and is usually present in a preparation containing cocarboxylase tetrahydrate, and in the detection of cocarboxylase tetrahydrate and related substances containing cocarboxylase tetrahydrate, the detection of cocarboxylase tetrahydrate impurity X and the content thereof is not described, and a method for simultaneously detecting cocarboxylase tetrahydrate impurity X and impurity A is not provided.
The invention content is as follows:
in order to solve the problems, the invention provides a method for simultaneously detecting the content of cocarboxylase tetrahydrate impurity X (formamidopyrimidine) and/or cocarboxylase tetrahydrate impurity A, which is suitable for detecting cocarboxylase tetrahydrate raw materials and vitamin preparation products containing cocarboxylase tetrahydrate raw materials. The technical scheme of the application is as follows:
an analysis method for detecting the content of cocarboxylase tetrahydrate impurity X and/or cocarboxylase tetrahydrate impurity A is characterized in that the method adopts a high performance liquid chromatograph to determine, and the chromatographic conditions are as follows:
a chromatographic column: octadecylsilane chemically bonded silica chromatographic column;
mobile phase A: a phosphate washing solution containing sodium octane sulfonate or an ion pair with the effect similar to sodium sulfonate;
mobile phase B: one of methanol, acetonitrile, mobile phase a-methanol or mobile phase a-acetonitrile;
column temperature: 30-50 ℃;
flow rate: 0.8-1.2 ml/min;
detection wavelength: 240-270 nm;
sample introduction amount: 20 mu l of the mixture;
the mobile phase A, B was performed in a gradient program.
Wherein, the preferred chromatographic column is a Thermo BDS HYPERSIL C18 column, a 250mm multiplied by 4.6mm, a 5 μm or equivalent performance chromatographic column;
preferably, the mobile phase A is 0.01mol/L-0.1mol/L phosphate buffer solution, the concentration of sodium octane sulfonate is 1g/L-4g/L, the pH value of the mobile phase A is adjusted to 2.0-5.0 by phosphoric acid, the ion-pairing agent in the mobile phase A can be other ion-pairing agents similar to the action of sodium octane sulfonate, such as sodium sulfonate ion-pairing agents including sodium heptane sulfonate, sodium hexane sulfonate and the like, and the phosphate can be potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate and the like.
Preferably, in the mobile phase B, the ratio of the mobile phase A to the methanol or the acetonitrile is 20-40: 80-60 parts of;
the preferred flow rate is 1.0ml/min
The preferred column temperature is 40 ℃;
the preferred detection wavelength is 245 nm;
the injection gradient elution procedure was:
the method can be used for detecting the content of cocarboxylase tetrahydrate impurity X and/or cocarboxylase tetrahydrate impurity A in cocarboxylase tetrahydrate raw material or preparation containing cocarboxylase tetrahydrate raw material such as vitamin preparation for injection, thereby controlling the quality of cocarboxylase tetrahydrate impurity X and/or cocarboxylase tetrahydrate impurity A in raw material or preparation.
The invention has the following beneficial effects:
1) the invention simultaneously detects the cocarboxylase tetrahydrate impurity X and cocarboxylase tetrahydrate impurity A for the first time.
2) The invention provides a method for detecting the content of cocarboxylase tetrahydrate impurity X and/or cocarboxylase tetrahydrate impurity A in cocarboxylase tetrahydrate by using the technology of a high performance liquid chromatograph, and the method has the advantages of easily obtained consumables, high accuracy and high sensitivity.
3) The known quantity of cocarboxylase tetrahydrate impurity X reference substance and cocarboxylase tetrahydrate impurity A reference substance are added into the sample, and the measured recovery rates are respectively 100.1% and 99.82%, and the accuracy of the method is good.
Description of the drawings:
FIG. 1 is a chromatogram for detecting a sample to be tested in example 2
The specific implementation mode is as follows:
example 1 determination of recovery
Taking a proper amount of an impurity X reference substance and a proper amount of a cocarboxylase tetrahydrate impurity A reference substance, precisely weighing, adding a mobile phase A to dissolve, quantitatively diluting to prepare a solution containing 0.3mg/ml of the impurity X and the cocarboxylase tetrahydrate impurity A in each 1ml, and shaking up;
taking 1ml of the solution in the step (1), putting the solution in a 50ml measuring flask, adding the mobile phase A to dilute the solution to a scale, and shaking up the solution to be used as a reference substance mixed solution;
and (3) precisely weighing about 750mg of multivitamin (12) for injection, placing the multivitamin in a 50ml measuring flask, adding the mobile phase A to dissolve and dilute the multivitamin to a scale, and shaking up to obtain a sample solution.
Taking 750mg of the multivitamin (12) for injection, precisely weighing, placing in a 50ml measuring flask, precisely adding a proper amount of the solution in the step (1), adding the mobile phase A to dilute to a scale, and shaking up to obtain a recovery rate solution;
and (5) precisely measuring 20 mu l of the solution, respectively injecting the solution into a liquid chromatograph, and recording a chromatogram. According to an external standard method, the contents of the impurity X and the cocarboxylase tetrahydrate impurity A in the test sample are calculated according to peak areas, the recovery rates of the cocarboxylase tetrahydrate impurity X and the cocarboxylase tetrahydrate impurity A are respectively 100.02% and 99.8%, and the method is good in accuracy.
EXAMPLE 2 determination of the content of impurity X and/or cocarboxylase tetrahydrate impurity A in multivitamin for injection (12)
Step 1, preparation of solution
Preparing a reference substance solution: taking appropriate amount of impurity X reference substance and tetrahydrate cocarboxylase impurity A reference substance, precisely weighing, adding mobile phase A to dissolve, quantitatively diluting to obtain solution containing 6 μ g/ml impurity X and tetrahydrate cocarboxylase impurity A per 1ml, and shaking;
preparing a test solution: precisely weighing about 750mg of multivitamin (12) for injection, placing into a 50ml measuring flask, adding mobile phase A, dissolving and diluting to scale, and shaking. The prescription composition of multivitamin for injection (12) is referred to patent CN 107898805A.
And 2, the liquid chromatography conditions are as follows:
a chromatographic column: a Thermo BDS HYPERSIL C18 column, 250mm x 4.6mm, 5 μm or equivalent performance chromatography column;
mobile phase A: the concentration of the phosphate buffer solution of sodium octane sulfonate is 0.01-0.1mol/L, the pH value is adjusted to 2.0-5.0 by using phosphoric acid, the concentration of the sodium octane sulfonate is 1g/L-4g/L, and sodium sulfonate ion pair reagents with similar effects such as sodium heptane sulfonate, sodium hexane sulfonate and the like can also be used;
mobile phase B: mobile phase B: any one of methanol, acetonitrile, mobile phase a-methanol, or mobile phase a-acetonitrile;
when the mobile phase B is mobile phase A-methanol or mobile phase A-acetonitrile, the ratio of the mobile phase A to the methanol or the acetonitrile is 20-40: 80-60 parts of;
flow rate: 0.8-1.2 ml/min;
column temperature: 35-45 ℃;
detection wavelength: 240-270 nm;
sample introduction amount: 20 mu l of the mixture;
the mobile phase A, B was performed in a gradient program.
Precisely measuring the above solutions at 20 μ l, respectively injecting into liquid chromatograph, and recording chromatogram, which is shown in figure 1 of the specification. According to an external standard method, the content of cocarboxylase tetrahydrate impurity X in the test solution accounts for 0.13% of cocarboxylase tetrahydrate, and the content of cocarboxylase tetrahydrate impurity A accounts for 1.7%.
EXAMPLE 3 determination of the content of impurity X and/or impurity A in the cocarboxylase tetrahydrate starting Material
Step 1, preparation of solution
Preparing a reference substance solution: taking appropriate amount of impurity X reference substance and tetrahydrate cocarboxylase impurity A reference substance, precisely weighing, adding mobile phase A to dissolve, quantitatively diluting to obtain solution containing 6 μ g/ml impurity X and tetrahydrate cocarboxylase impurity A per 1ml, and shaking;
preparing a test solution: taking a proper amount of cocarboxylase tetrahydrate raw material, precisely weighing, placing in a proper measuring flask, adding mobile phase A to dissolve and dilute to scale, shaking up, and preparing into a solution containing 0.12mg of cocarboxylase tetrahydrate in each 1 ml.
And 2, the liquid chromatography conditions are as follows:
a chromatographic column: a Thermo BDS HYPERSIL C18 column, 250mm x 4.6mm, 5 μm or equivalent performance chromatography column;
mobile phase A: the concentration of the phosphate buffer solution of sodium octane sulfonate is 0.01-0.1mol/L, the pH value is adjusted to 2.0-5.0 by using phosphoric acid, the concentration of the sodium octane sulfonate is 1g/L-4g/L, and sodium sulfonate ion pair reagents with similar effects such as sodium heptane sulfonate, sodium hexane sulfonate and the like can also be used;
mobile phase B: mobile phase B: any one of methanol, acetonitrile, mobile phase a-methanol, or mobile phase a-acetonitrile;
when the mobile phase B is mobile phase A-methanol or mobile phase A-acetonitrile, the ratio of the mobile phase A to the methanol or the acetonitrile is 20-40: 80-60 parts of;
flow rate: 0.8-1.2 ml/min;
column temperature: 35-45 ℃;
detection wavelength: 240-270 nm;
sample introduction amount: 20 mu l of the mixture;
the mobile phase A, B was performed in a gradient program.
Precisely measuring 20 μ l of each solution, respectively injecting into a liquid chromatograph, recording chromatogram, and calculating by peak area according to external standard method to obtain a sample solution containing 0.01% of cocarboxylase tetrahydrate impurity X and 0.2% of cocarboxylase tetrahydrate impurity A.
EXAMPLE 4 determination of impurity X content in multivitamin for injection (12)
Step 1, preparation of solution
Preparing a reference substance solution: taking appropriate amount of each impurity X reference substance, precisely weighing, adding mobile phase A for dissolving, quantitatively diluting to obtain solution containing 6 μ g/ml impurity X per 1ml, and shaking;
preparing a test solution: precisely weighing about 750mg of multivitamin (12) for injection, placing into a 50ml measuring flask, adding mobile phase A, dissolving and diluting to scale, and shaking. The prescription composition of multivitamin for injection (12) is referred to patent CN 107898805A.
And 2, the liquid chromatography conditions are as follows:
a chromatographic column: a Thermo BDS HYPERSIL C18 column, 250mm x 4.6mm, 5 μm or equivalent performance chromatography column;
mobile phase A: the concentration of the phosphate buffer solution of sodium octane sulfonate is 0.01-0.1mol/L, the pH value is adjusted to 2.0-5.0 by using phosphoric acid, the concentration of the sodium octane sulfonate is 1g/L-4g/L, and sodium sulfonate ion pair reagents with similar effects such as sodium heptane sulfonate, sodium hexane sulfonate and the like can also be used;
mobile phase B: mobile phase B: any one of methanol, acetonitrile, mobile phase a-methanol, or mobile phase a-acetonitrile;
when the mobile phase B is mobile phase A-methanol or mobile phase A-acetonitrile, the ratio of the mobile phase A to the methanol or the acetonitrile is 20-40: 80-60 parts of;
flow rate: 0.8-1.2 ml/min;
column temperature: 35-45 ℃;
detection wavelength: 240-270 nm;
sample introduction amount: 20 mu l of the mixture;
the mobile phase A, B was performed in a gradient program.
Precisely measuring the above solutions at 20 μ l each, injecting into liquid chromatograph, and recording chromatogram. According to an external standard method, the content of cocarboxylase tetrahydrate impurity X in the test solution accounts for 0.2% of cocarboxylase tetrahydrate.
Claims (10)
1. The cocarboxylase tetrahydrate raw material containing cocarboxylase tetrahydrate impurity X is characterized in that the content of impurity X is not higher than 1.0%, and the structural formula of the impurity X is as follows:
2. a vitamin formulation comprising the source of cocarboxylase tetrahydrate of claim 1, wherein the level of impurity X is no greater than 6.0% of the source of cocarboxylase tetrahydrate.
3. A method for detecting cocarboxylase tetrahydrate impurity a and/or impurity X in a cocarboxylase tetrahydrate raw material or a vitamin preparation containing cocarboxylase tetrahydrate raw material of claim 1 or 2, by high performance liquid chromatography, wherein the chromatographic conditions are as follows:
mobile phase A: a phosphate washing solution containing sodium octane sulfonate or an ion pair with the effect similar to sodium sulfonate;
mobile phase B: one of methanol, acetonitrile, mobile phase a-methanol or mobile phase a-acetonitrile;
the mobile phase A, B was run according to a gradient program, elution program:
column temperature: 30-50 ℃;
flow rate: 0.8-1.2 ml/min;
detection wavelength: 240-270 nm;
sample introduction amount: 20 mu l of the mixture;
the impurity A is thiamine monophosphate.
4. A process as claimed in claim 3, wherein the chromatography column is a Thermo BDS HYPERSIL C18 column, 250mm x 4.6mm, 5 μm or a column of comparable performance to the chromatography column.
5. The method according to claim 3, wherein the concentration of sodium octane sulfonate in the mobile phase A is 1g/L-4g/L, and the concentration of phosphate buffer solution is 0.01mol/L-0.1 mol/L; adjusting the pH value of the mobile phase A to 2.0-5.0 by using phosphoric acid; the ion pair with similar efficacy is sodium sulfonate ion pair reagents such as sodium heptanesulfonate, sodium hexanesulfonate and the like, and the phosphate can be potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate and the like.
6. The method according to claim 3, wherein the mobile phase B is mobile phase A-methanol or mobile phase A-acetonitrile, and the ratio of the mobile phase A to the methanol or the acetonitrile is 20-40: 80-60.
7. The method of claim 3, wherein the flow rate is 1.0 ml/min; the column temperature is 40 ℃; the detection wavelength is 248 nm.
8. A method according to claim 3, wherein the method is used to determine the amount of cocarboxylase tetrahydrate impurity X in a cocarboxylase tetrahydrate feedstock or a cocarboxylase tetrahydrate-containing preparation.
9. A method according to claim 3, wherein the method is used to determine the level of cocarboxylase tetrahydrate impurity X and/or impurity A in a cocarboxylase tetrahydrate feedstock or a cocarboxylase tetrahydrate-containing preparation.
10. The method of claim 9, wherein the formulation is a vitamin formulation comprising cocarboxylase tetrahydrate.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116008439A (en) * | 2023-02-20 | 2023-04-25 | 山东绿叶制药有限公司 | Method for detecting impurities in 2, 6-dioxaspiro [4,5] decane compounds or salts thereof |
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| CH441322A (en) * | 1957-09-28 | 1967-08-15 | Merck Ag E | Process for the preparation of the tetrahydrate of cocarboxylase |
| CN101787049A (en) * | 2009-09-23 | 2010-07-28 | 北京京卫信康医药科技发展有限公司 | Novel crystal form of cocarboxylase tetrahydrate and preparation method thereof |
| CN104603115A (en) * | 2012-08-21 | 2015-05-06 | 帝斯曼知识产权资产管理有限公司 | Method for preparation of thiazole derivatives |
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2019
- 2019-11-12 CN CN201911100004.6A patent/CN111007162A/en active Pending
Patent Citations (3)
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|---|---|---|---|---|
| CH441322A (en) * | 1957-09-28 | 1967-08-15 | Merck Ag E | Process for the preparation of the tetrahydrate of cocarboxylase |
| CN101787049A (en) * | 2009-09-23 | 2010-07-28 | 北京京卫信康医药科技发展有限公司 | Novel crystal form of cocarboxylase tetrahydrate and preparation method thereof |
| CN104603115A (en) * | 2012-08-21 | 2015-05-06 | 帝斯曼知识产权资产管理有限公司 | Method for preparation of thiazole derivatives |
Non-Patent Citations (3)
| Title |
|---|
| WILLIAM H. AMOS 等: "Isolation and identification of 3-(2"-methyl-4"-amino-5"-pyrimidylmethyl)-4-methylthiazole-5-acetic acid (thiamine acetic acid) and 2-methyl-4-amino-5-formylaminomethylpyrimidine as metabolites of thiamine in the rat", 《THE JOURNAL OF BIOLOGICAL CHEMISTRY》 * |
| 戴海平 等: "膜组合技术浓缩辅羧酶", 《中国医药工业杂志》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116008439A (en) * | 2023-02-20 | 2023-04-25 | 山东绿叶制药有限公司 | Method for detecting impurities in 2, 6-dioxaspiro [4,5] decane compounds or salts thereof |
| CN116008439B (en) * | 2023-02-20 | 2023-10-27 | 山东绿叶制药有限公司 | Method for detecting impurities in 2, 6-dioxaspiro [4,5] decane compounds or salts thereof |
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