CN103063779A - Detection method of simvastatin nicotinate tablet related impurities - Google Patents
Detection method of simvastatin nicotinate tablet related impurities Download PDFInfo
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- CN103063779A CN103063779A CN2013100035595A CN201310003559A CN103063779A CN 103063779 A CN103063779 A CN 103063779A CN 2013100035595 A CN2013100035595 A CN 2013100035595A CN 201310003559 A CN201310003559 A CN 201310003559A CN 103063779 A CN103063779 A CN 103063779A
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- simvastatin
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- relative substance
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Abstract
The invention provides a detection method of simvastatin nicotinate tablet related impurities. The method comprises the detection of nicotinic acid related impurities and the detection of simvastatin related impurities. With the method provided by the invention, nicotinic acid and impurities thereof can be effectively separated, and simvastatin and impurities thereof can be effectively separated. Simvastatin and related impurities/degradation product thereof causes no interference to the determination of nicotinic acid related impurities/degradation product. Nicotinic acid and related impurities/degradation product thereof causes no interference to the determination of simvastatin related impurities/degradation product. The specificity, linearity, accuracy, precision, quantification limit, detection limit, and the like of the method satisfy requirements.
Description
Technical field
The present invention relates to a kind of detection method of niacin simvastatin tablet relative substance, belong to the chemicals analysis field.
Background technology
Nicotinic acid is a kind of water miscible Cobastab, is to be used for the earliest one of medicine of transferring in fat, very strong increase high-density lipoprotein (HDL) (HDL) effect is arranged, but reduce a little less than low-density lipoprotein (LDL) effect.Simvastatin is a kind of Hydroxymethylglutaryl list acyl coenzyme A (HMG-CoA) reductase inhibitor, is a current line lipid-regulation medicine, has remarkable result to reducing LDL, but to a little less than the increase HDL effect.Both unite use, both can strengthen its effect for reducing blood fat, can reduce the medication number of times again, are used for the treatment of clinically hypercholesterolemia (II A type), combined hyperlipidemia familial (II Type B), hypertriglyceridemia.Particularly it is more more obvious than taking single preparations of ephedrine on to the curative effect of combined hyperlipidemia familial.
For guaranteeing quality and the security thereof of medicine, need set up detection method the niacin simvastatin tablet is controlled.At present, the detection of nicotinic acid relative substance does not have relevant detection method at Chinese Pharmacopoeia.The Simvastatin relative substance detects pharmacopeia and adopts the HPLC method, but because Simvastatin solution has instability, official method is only suitable for bulk drug and is not suitable for finished product, and the niacin simvastatin peak shape is bad, separates bad with relative substance.Therefore, must grope a kind of rational chromatographic system, make easy, detect the method for niacin simvastatin tablet relative substance fast and accurately, in order to effectively control the quality of niacin simvastatin tablet.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art part, a kind of detection method of niacin simvastatin tablet relative substance is provided.
The detection method of niacin simvastatin tablet relative substance of the present invention comprises the detection of nicotinic acid relative substance and the detection of Simvastatin relative substance,
The detection method of said nicotinic acid relative substance may further comprise the steps:
1) preparation of sample solution: the niacin simvastatin tablet is dissolved in water, is mixed with the solution that contains nicotinic acid 0.2mg/ml;
2) measure: extracting sample solution, sample introduction 50 μ L adopt the HPLC method, and the record chromatogram is also analyzed;
The chromatographic condition of described HPLC method is as follows:
Chromatographic column: the L8(nh 2 column);
Mobile phase: methanol-water mixtures, the volume ratio of water and methyl alcohol are (75-85): (15-25), transfer pH to 3-4 with glacial acetic acid;
Column temperature: 30-40oC;
Flow velocity: 0.8～2.0ml/min;
Detect wavelength: 258nm.
The detection method of said Simvastatin relative substance may further comprise the steps:
1) preparation of sample solution: the niacin simvastatin tablet dissolved is made the solution that contains Simvastatin 0.4mg/mL in acetonitrile; Room temperature preservation.
2) measure: extracting sample solution, sample introduction 50 μ L adopt the HPLC method, and the record chromatogram is also analyzed.The chromatographic condition of described HPLC method is as follows:
Chromatographic column: C18 chromatographic column;
Mobile phase: acetonitrile and phosphate buffer gradient mixture, acetonitrile and phosphate buffer volume ratio are (50-90): (10-50), with phosphoric acid adjust pH to 2.5～3.5;
Column temperature: 30-40oC;
Flow velocity: 1-2 mL/min;
Detect wavelength: 238nm.
Preferably,
The chromatographic condition of the HPLC method in the detection method of described nicotinic acid relative substance is as follows:
Chromatographic column: Hilic-NH
2Chromatographic column;
Mobile phase: methanol-water mixtures, the volume ratio of water and methyl alcohol are 80:20, transfer pH to 3.15 ± 0.05 with glacial acetic acid;
Column temperature: 35oC;
Flow velocity: 1ml/min;
Detect wavelength: 258nm.
The chromatographic condition of the HPLC method in the detection method of described Simvastatin relative substance is as follows:
Chromatographic column: C18 chromatographic column;
Mobile phase: acetonitrile and phosphate buffer gradient mixture, acetonitrile and phosphate buffer volume ratio are (50-90): (10-50), with phosphoric acid adjust pH to 3.00 ± 0.05;
Column temperature: 35oC;
Flow velocity: 1.5 mL/min;
Detect wavelength: 238nm.
The detection method of niacin simvastatin tablet relative substance of the present invention has following technique effect:
1) the method can be separated nicotinic acid and impurity thereof effectively, and the relative substance/catabolite of Simvastatin and it can not produce the mensuration of nicotinic acid relative substance/catabolite and disturbs, specificity, linear, accuracy and precision, quantitative limit, detectabilities etc. all meet the requirements, and can also effectively separate Simvastatin and impurity thereof, and the method can be easy, fast, detect exactly the Simvastatin relative substance, and nicotinic acid and its relative substance can not produce to the mensuration of Simvastatin relative substance/catabolite interference, specificity, linearity, accuracy and precision, quantitative limit, detectability etc. all meet the requirements.Thereby can effectively control product quality, avoid objectionable impurities not detect the hidden danger that bring for the patient clinical drug safety.
2) by relative substance/catabolite in the HPLC method check niacin simvastatin sustained-release sheet, adopt different chromatographic conditions, measure respectively nicotinic acid relative substance and Simvastatin relative substance, and do not interfere with each other." the chemicals Quality Control Analysis method validation technological guidance principle " that verification method is announced according to State Food and Drug Administration drug evaluation center (governing principle numbering: (G) GPH-5-1).
3) variation of mobile phase of the present invention and pH has a significant impact degree of separation and the peak shape of impurity in the test findings.The volume of mixture ratio that the nicotinic acid relative substance detects mobile phase methanol and water is (75-85): (15-25), preferred proportion 80:20, mobile phase regulate pH to 3.15 ± 0.05 with glacial acetic acid and can improve the degree of separation of impurity and improve peak shape.The Simvastatin relative substance detect mobile phase with acetonitrile and phosphate buffer volume at (50-90): (10-50) better with the gradient mixed effect, mobile phase can improve the degree of separation of impurity and improve peak shape with phosphorus acid for adjusting pH to 3.00 ± 0.05.
Description of drawings
Fig. 1 is for carrying out the chromatogram that the nicotinic acid relative substance detects according to embodiment 1;
Fig. 2 is for carrying out the chromatogram that the Simvastatin relative substance detects according to embodiment 2.
Fig. 3 is nicotinic acid relative substance linear relationship chart
Figure: 4 is Simvastatin relative substance linear relationship chart
Embodiment
The detection of embodiment 1 niacin simvastatin tablet relative substance
The detection of niacin simvastatin tablet relative substance comprises that the nicotinic acid relative substance detects and the Simvastatin relative substance detects,
The detecting step of nicotinic acid relative substance and catabolite is as follows:
1) preparation of sample solution: precision takes by weighing 10 niacin simvastatin tablets, adds about 700 mL water in the volumetric flask of a 1000mL, stirs 20 hours, and water constant volume and mixing are mixed with the sample mother liquor.Sample thief mother liquor 10mL water constant volume is mixed with the sample solution that contains nicotinic acid 0.2mg/mL to 250mL, preserves under the room temperature;
2) measure: extracting sample solution, sample introduction 50 μ L adopt the HPLC method, and the record chromatogram is also analyzed.
The HPLC chromatographic condition is:
Instrument: Waters H-Class UPLC;
Chromatographic column: L8 chromatographic column;
Detecting device: UV or PDA detecting device
Mobile phase: methanol-water mixtures (volume ratio water: methyl alcohol=80:20), transfer pH to 3.15 ± 0.05 with glacial acetic acid;
Column temperature: 35oC;
Flow velocity: 1.0 mL/min;
Detect wavelength: 258nm.
Testing result shows that every impurity separates well with catabolite.Chromatogram is seen Fig. 1.
The detecting step of Simvastatin relative substance and catabolite is as follows:
1) preparation of sample solution: 20mg/40mg tablet: precision takes by weighing the niacin simvastatin tablet, solubilizer (acetonitrile: 0.3% glacial acetic acid solution=80:20) dissolving, stirring is not less than 4 hours, is mixed with the solution that contains Simvastatin 0.4mg/ml, preserves under the room temperature.
2) measure: extracting sample solution, sample introduction 50 μ L adopt the HPLC method, and the record chromatogram is also analyzed.The HPLC chromatographic condition is:
Instrument: Waters H-Class UPLC;
Chromatographic column: L1;
Detecting device: UV or PDA detecting device
Mobile phase: (the volume ratio acetonitrile: phosphate buffer is (50-90): (10-50), transfer pH to 3.00 ± 0.05 with phosphoric acid for acetonitrile and phosphate buffer gradient mixture;
Column temperature: 35oC;
Flow velocity: 1.5 mL/min;
Detect wavelength: 238nm.
Testing result shows that every impurity separates well with catabolite.Chromatogram is seen Fig. 2.
Embodiment 2 compliance test results
1, the method validation of nicotinic acid relative substance and catabolite
1.1 specificity test
The specificity checking comprises the interference of (1) solvent (water) and auxiliary material, (2) selectivity, and (3) force degraded.
1.1.1 the interference of solvent (water) and auxiliary material: take by weighing auxiliary material and be dissolved in water, stirred 20 hours, constant volume is mixed with 1 times/2 times auxiliary material solution, detects with above-mentioned chromatographic condition, and the result shows that the position at nicotinic acid peak is without any interference in solvent and auxiliary material solution.The result meets the requirements.
1.1.2 selectivity: selectivity checking Simvastatin, Simvastatin known impurities are to the interference of nicotinic acid impurity analysis.Nicotinic acid is without known impurity, and Choice tests is assessed the degree of separation of simvastatin, Simvastatin known impurities and nicotinic acid.
Take by weighing respectively Simvastatin relative substance Simvastatin hydroxy acid, dehydration Simvastatin, simvastatin dimer and Lovastatin, the nicotinic acid raw material, Simvastatin raw material, auxiliary material, the solubilizer stirring and dissolving, be mixed with and contain the 200 μ g/mL nicotinic acid of having an appointment, 8 μ g/mL Simvastatins, the selectivity solution of 0.04 each Simvastatin known impurities of μ g/mL.Testing result shows that Simvastatin and its known impurities component all flow out near solvent peak, the nicotinic acid peak is not produced and disturb.Simvastatin, known impurities and nicotinic acid peak separate fully, and degree of separation is not less than 2.
1.1.3 force degraded: forcing Degrading experiment is the possible catabolite of checking and the degree of separation of nicotinic acid.Carry out strong Degrading experiment respectively under oxidation, acid, alkali, ultraviolet light, visible light, 60 ℃ of heat conditions, the result shows that in control solution and each degraded solutions, nicotinic acid peak purity angle is less than purity threshold value (spectrum is even).Simvastatin, the degree of separation at known/unknown impuritie and nicotinic acid peak is not less than 2.
1.2 linear relationship test
Nicotinic acid is without known impurity, so linear in the checking of impurity concentration scope with nicotinic acid.The range of linearity of checking is that 0.1 μ g/mL～1.0 μ g/mL(are equivalent to 0.05%～0.5% nicotinic acid labelled amount).Linear verification is the result show, in 0.1 μ g/mL～1.0 μ g/mL concentration ranges, Nicotinic and peak area are good linear relationship, and its linearly dependent coefficient is 0.9997, as shown in Figure 3.
1.3 accuracy test
Because nicotinic acid does not have known relative substance/catabolite, the recovery of nicotinic acid when accuracy (recovery) is determined at auxiliary material and simvastatin and exists.The checking scope of accuracy is between 0.1 μ g/mL～1.0 μ g/mL.
Take by weighing the simvastatin stock and adjunct in volumetric flask, prepare 0.1 μ g/mL, 0.2 μ g/mL, three horizontal Nicotinic tests of 1.0 μ g/mL, recovery result meets the requirements.
1.4 precision test
The preparation and detect 3 parallel sample, make respectively method precision and middle precision test, the result shows that method precision and middle precision the result meet the requirements.
1.5 quantitative limit value and detection limit value
The quantitative limit value of nicotinic acid relative substance (QL) is 0.1 μ g/mL or 0.05% nicotinic acid labelled amount.
It is the nicotinic acid labelled amount of 0.05 μ g/mL or 0.025% that the nicotinic acid relative substance detects limit value (DL).
2, the method validation of Simvastatin relative substance and catabolite
2.1 specificity test
The specificity checking comprises the interference of (1) solvent (acetonitrile) and auxiliary material, (2) selectivity, and (3) force degraded.
2.1.1 the interference of solvent (acetonitrile) and auxiliary material: press the sample compound method, be mixed with 1 times/2 times auxiliary material solution, detect with above-mentioned chromatographic condition, the result shows that in solvent and auxiliary material solution the retention time of Simvastatin, Simvastatin known impurities is not obviously disturbed.
2.1.2 selectivity: take by weighing respectively nicotinic acid, Simvastatin known impurities, nicotinic acid raw material, Simvastatin raw material, and auxiliary material, add the acetonitrile stirring and dissolving, be mixed with and contain about 20 mg/mL of nicotinic acid, the about 800 μ g/mL of Simvastatin, the selectivity solution of each 4 μ g/mL of Simvastatin known impurities.Detect with above-mentioned chromatographic condition, nicotinic acid, Simvastatin and known impurities single needle sample introduction are confirmed the retention time of each component.The result shows that the nicotinic acid retention time is near solvent peak, and each known impurities of Simvastatin and other impurity separate fully, and degree of separation is not less than 2.The result meets the requirements.
2.1.3 force degraded: force Degrading experiment is whether the possible unknown catabolite of checking has interference to the Simvastatin impurity determination.Take by weighing respectively nicotinic acid, Simvastatin, auxiliary material with formula rate, mixing is also ground and is evenly made sample powder, carry out strong Degrading experiment respectively under acid, alkali, oxidation, ultraviolet light, visible light, 60 ℃ of heat conditions, the result shows that Simvastatin peak purity angle is less than purity threshold value (spectrum is even).The result explanation the method tool specificity.
2.2 linear relationship test
Simvastatin linear verification scope is made as 0.4 μ g/mL to 6.0 μ g/mL (being equivalent to 0.1%～1.5% Simvastatin labelled amount).Test findings shows that in 0.4 μ g/mL～6.0 μ g/mL concentration ranges, Simvastatin, Simvastatin hydroxy acid, dehydration Simvastatin, simvastatin dimer and peak area are good linear relationship, and its linearly dependent coefficient is 0.9999.
2.3 accuracy test
When accuracy (recovery) has been determined at auxiliary material and Simvastatin and has existed, Simvastatin hydroxy acid, dehydration Simvastatin, the recovery of simvastatin dimer.Recovery the result meets the requirements:
2.4 precision test
Prepare and detect 6 duplicate samples solution, make respectively method precision and middle precision test, the result shows, distribution and the numerical value of 6 duplicate samples impurity are close, the difference of method precision experiment and middle Precision Experiment gained total impurities mean value is 0.01%, be not more than 0.3%, the method precision the result meets the requirements.
2.5 quantitative limit value and detection limit value
The quantitative limit value of Simvastatin impurity is for meeting the least concentration limit of acceptable standard in linear verification and recovery checking.Test findings such as following table.
Simvastatin is known/the quantitative limit value table of unknown impuritie
Claims (3)
1. the detection method of a niacin simvastatin tablet relative substance comprises the detection of nicotinic acid relative substance and the detection of Simvastatin relative substance, it is characterized in that,
The detection method of said nicotinic acid relative substance may further comprise the steps:
1) preparation of sample solution: the niacin simvastatin tablet is dissolved in water, is mixed with the solution that contains nicotinic acid 0.2mg/ml;
2) measure: extracting sample solution, sample introduction 50 μ L adopt the HPLC method, and the record chromatogram is also analyzed;
Wherein, the chromatographic condition of described HPLC method is as follows:
Chromatographic column: L8 chromatographic column;
Mobile phase: methanol-water mixtures, the volume ratio of water and methyl alcohol are (75-85): (15-25), transfer pH to 3-4 with glacial acetic acid;
Column temperature: 30-40oC;
Flow velocity: 0.8～2.0ml/min;
Detect wavelength: 258nm;
The detection method of said Simvastatin relative substance may further comprise the steps:
1) preparation of sample solution: the niacin simvastatin tablet dissolved is made the solution that contains Simvastatin 0.4mg/mL in acetonitrile; Room temperature preservation;
2) measure: extracting sample solution, sample introduction 50 μ L adopt the HPLC method, and the record chromatogram is also analyzed;
The chromatographic condition of described HPLC method is as follows:
Chromatographic column: L1 chromatographic column;
Mobile phase: acetonitrile and phosphate buffer gradient mixture, acetonitrile and phosphate buffer volume ratio are (50-90): (10-50), with phosphoric acid adjust pH to 2.5～3.5;
Column temperature: 30-40oC;
Flow velocity: 1-2 mL/min;
Detect wavelength: 238nm.
2. the detection method of niacin simvastatin tablet relative substance according to claim 1 is characterized in that, the chromatographic condition of the HPLC method in the detection method of described nicotinic acid relative substance is as follows:
Chromatographic column: L8 nh 2 column;
Mobile phase: methanol-water mixtures, the volume ratio of water and methyl alcohol are 80:20, transfer pH to 3.15 ± 0.05 with glacial acetic acid;
Column temperature: 35oC;
Flow velocity: 1ml/min;
Detect wavelength: 258nm.
3. the detection method of niacin simvastatin tablet relative substance according to claim 1 is characterized in that, the chromatographic condition of the HPLC method in the detection method of described Simvastatin relative substance is as follows:
Chromatographic column: L1;
Mobile phase: acetonitrile and phosphate buffer gradient mixture, acetonitrile and phosphate buffer volume ratio are (50-90): (10-50), with phosphoric acid adjust pH to 3.00 ± 0.05;
Column temperature: 35oC;
Flow velocity: 1.5 mL/min;
Detect wavelength: 238nm.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106568881A (en) * | 2015-10-12 | 2017-04-19 | 北大方正集团有限公司 | Analysis method of preparation process of statin compound |
| CN111983113A (en) * | 2020-09-23 | 2020-11-24 | 海南通用三洋药业有限公司 | Method for detecting content of 6-oxosimvastatin in ezetimibe simvastatin tablets |
| CN114235975A (en) * | 2021-11-05 | 2022-03-25 | 宜昌东阳光长江药业股份有限公司 | Method for determining simvastatin related substances |
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2013
- 2013-01-06 CN CN201310003559.5A patent/CN103063779B/en active Active
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106568881A (en) * | 2015-10-12 | 2017-04-19 | 北大方正集团有限公司 | Analysis method of preparation process of statin compound |
| CN111983113A (en) * | 2020-09-23 | 2020-11-24 | 海南通用三洋药业有限公司 | Method for detecting content of 6-oxosimvastatin in ezetimibe simvastatin tablets |
| CN111983113B (en) * | 2020-09-23 | 2022-03-22 | 海南通用三洋药业有限公司 | Method for detecting content of 6-oxosimvastatin in ezetimibe simvastatin tablets |
| WO2022062961A1 (en) * | 2020-09-23 | 2022-03-31 | 海南通用三洋药业有限公司 | Method for detecting content of 6-oxosimvastatin in ezetimibe-simvastatin tablets |
| CN114235975A (en) * | 2021-11-05 | 2022-03-25 | 宜昌东阳光长江药业股份有限公司 | Method for determining simvastatin related substances |
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