CN103063779B - A kind of detection method of niacin simvastatin tablet relative substance - Google Patents
A kind of detection method of niacin simvastatin tablet relative substance Download PDFInfo
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Abstract
The invention provides a kind of detection method of niacin simvastatin tablet relative substance, comprise the detection of nicotinic acid relative substance and the detection of Simvastatin relative substance.Method of the present invention can be separated nicotinic acid and impurity thereof effectively, can also effectively be separated Simvastatin and impurity thereof, Simvastatin and its relative substance/catabolite can not produce interference to the mensuration of nicotinic acid relative substance/catabolite, nicotinic acid and its relative substance can not produce interference to the mensuration of Simvastatin relative substance/catabolite, specificity, linearly, accuracy and precision, quantitative limit, detectability etc. all meet the requirements.
Description
Technical field
The present invention relates to a kind of detection method of niacin simvastatin tablet relative substance, belong to chemicals analysis field.
Background technology
Nicotinic acid is a kind of water miscible Cobastab, is the earliest for one of medicine adjusting fat, have very strong increase high-density lipoprotein (HDL) (HDL) effect, but it is more weak to reduce 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 reduction LDL, but more weak to increase HDL effect.Both conbined usage, both can strengthen its effect for reducing blood fat, and can reduce times for spraying again, be used for the treatment of hypercholesterolemia (II A type), combined hyperlipidemia familial (II Type B), hypertriglyceridemia clinically.Particularly it is to more more obvious than taking single preparations of ephedrine in the curative effect of combined hyperlipidemia familial.
For ensureing quality and the security thereof of medicine, detection method need be set up niacin simvastatin tablet is controlled.At present, the detection of the nicotinic acid relative substance detection method of not being correlated with at Chinese Pharmacopoeia.Simvastatin relative substance detects pharmacopeia and adopts HPLC method, but has instability due to Simvastatin solution, and official method is only suitable for bulk drug and is not suitable for finished product, and niacin simvastatin peak shape is bad, is separated bad with relative substance.Therefore, a kind of reasonably chromatographic system must be groped, make easy, to detect niacin simvastatin tablet relative substance fast and accurately method, effectively to control the quality of niacin simvastatin tablet.
Summary of the invention
The object 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 comprises the following steps:
1) preparation of sample solution: be dissolved in water by niacin simvastatin tablet, is mixed with the solution containing nicotinic acid 0.2mg/ml;
2) measure: extracting sample solution, sample introduction 50 μ L, adopt HPLC method, record chromatogram is also analyzed;
The chromatographic condition of described HPLC method is as follows:
Chromatographic column: L8 (nh 2 column);
Mobile phase: methanol-water mixtures, the volume ratio of water and methyl alcohol is (75-85): (15-25), adjusts pH to 3-4 with glacial acetic acid;
Column temperature: 30-40 DEG C;
Flow velocity: 0.8 ~ 2.0ml/min;
Determined wavelength: 258nm.
The detection method of said Simvastatin relative substance comprises the following steps:
1) preparation of sample solution: niacin simvastatin tablet dissolved is made the solution containing Simvastatin 0.4mg/mL in acetonitrile; Room temperature preservation.
2) measure: extracting sample solution, sample introduction 50 μ L, adopt HPLC method, 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: 30-40 DEG C;
Flow velocity: 1-2mL/min;
Determined 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 is 80:20, adjusts pH to 3.15 ± 0.05 with glacial acetic acid;
Column temperature: 35 DEG C;
Flow velocity: 1ml/min;
Determined 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: 35 DEG C;
Flow velocity: 1.5mL/min;
Determined 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 Simvastatin can not produce interference to the mensuration of nicotinic acid relative substance/catabolite with its relative substance/catabolite, specificity, linearly, accuracy and precision, quantitative limit, detectabilities etc. all meet the requirements, can also effectively be separated Simvastatin and impurity thereof, the method can be easy, fast, detect Simvastatin relative substance exactly, and nicotinic acid and its relative substance can not produce interference to the mensuration of Simvastatin relative substance/catabolite, specificity, linearly, accuracy and precision, quantitative limit, detectabilities etc. all meet the requirements.Thus effectively can control product quality, avoid objectionable impurities and do not detect the hidden danger may brought to patient clinical drug safety.
2) by relative substance/catabolite in HPLC method inspection niacin simvastatin sustained-release sheet, adopt different chromatographic conditions, measure nicotinic acid relative substance and Simvastatin relative substance respectively, and do not interfere with each other." chemicals Quality Control Analysis method validation technological guidance principle " (governing principle numbering: (G) GPH-5-1) that verification method is announced according to State Food and Drug Administration's drug evaluation center.
3) change of mobile phase of the present invention and pH has a significant impact the degree of separation of impurity in test findings and peak shape.The volume of mixture ratio that nicotinic acid relative substance detects mobile phase methanol and water is (75-85): (15-25), preferred proportion 80:20, mobile phase glacial acetic acid regulates pH to 3.15 ± 0.05 can improve the degree of separation of impurity and improve peak shape.Simvastatin relative substance detection mobile phase acetonitrile and phosphate buffer volume are at (50-90): (10-50), better with gradient mixed effect, mobile phase phosphorus acid for adjusting pH to 3.00 ± 0.05 can be improved the degree of separation of impurity and improve peak shape.
Accompanying drawing explanation
Fig. 1 is the chromatogram carrying out the detection of nicotinic acid relative substance according to embodiment 1;
Fig. 2 is the chromatogram carrying out the detection of Simvastatin relative substance according to embodiment 2.
Fig. 3 is nicotinic acid relative substance linear relationship chart
Fig. 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 nicotinic acid relative substance and detects and the detection of Simvastatin relative substance,
The detecting step of nicotinic acid relative substance and catabolite is as follows:
1) preparation of sample solution: precision takes 10 niacin simvastatin tablets, adds about 700mL water in the volumetric flask of a 1000mL, stir 20 hours, mixes, be mixed with sample mother liquor with water constant volume.Sample thief mother liquor 10mL use water constant volume, to 250mL, is mixed with the sample solution containing nicotinic acid 0.2mg/mL, preserves under room temperature;
2) measure: extracting sample solution, sample introduction 50 μ L, adopt HPLC method, record chromatogram is also analyzed.
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), adjusts pH to 3.15 ± 0.05 with glacial acetic acid;
Column temperature: 35 DEG C;
Flow velocity: 1.0mL/min;
Determined wavelength: 258nm.
Testing result shows that every impurity is separated well with catabolite.Chromatogram is shown in Fig. 1.
The detecting step of Simvastatin relative substance and catabolite is as follows:
1) preparation of sample solution: 20mg/40mg tablet: precision takes niacin simvastatin tablet, solubilizer (acetonitrile: 0.3% glacial acetic acid solution=80:20) dissolves, stirring is not less than 4 hours, is mixed with the solution containing Simvastatin 0.4mg/ml, preserves under room temperature.
2) measure: extracting sample solution, sample introduction 50 μ L, adopt HPLC method, record chromatogram is also analyzed.
HPLC chromatographic condition is:
Instrument: Waters H-Class UPLC;
Chromatographic column: L1;
Detecting device: UV or PDA detecting device
Mobile phase: (volume ratio acetonitrile: phosphate buffer is (50-90): (10-50), adjusts pH to 3.00 ± 0.05 with phosphoric acid for acetonitrile and phosphate buffer gradient mixture;
Column temperature: 35 DEG C;
Flow velocity: 1.5mL/min;
Determined wavelength: 238nm.
Testing result shows that every impurity is separated well with catabolite.Chromatogram is shown in Fig. 2.
Embodiment 2 compliance test result
1, the method validation of nicotinic acid relative substance and catabolite
1.1 specificity tests
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 auxiliary material and be dissolved in water, stirs 20 hours, constant volume, be mixed with 1 times/2 times auxiliary material solution, detect with above-mentioned chromatographic condition, 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 impurities, and Choice tests assesses the degree of separation of simvastatin, Simvastatin known impurities and nicotinic acid.
Take Simvastatin relative substance Simvastatin hydroxy acid, dehydration Simvastatin, simvastatin dimer and Lovastatin respectively, nicotinic acid raw material, Simvastatin raw material, auxiliary material, solubilizer stirring and dissolving, be mixed with containing 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, and Simvastatin and its known impurities component all flow out near solvent peak, does not produce interference to nicotinic acid peak.Simvastatin, known impurities and nicotinic acid peak separate completely, and degree of separation is not less than 2.
1.1.3 force to degrade: force Degrading experiment to be the degree of separation verifying possible catabolite and nicotinic acid.Under oxidation, acid, alkali, ultraviolet light, visible ray, 60 DEG C of heat conditions, carry out strong Degrading experiment respectively, result shows, and 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 tests
Nicotinic acid without known impurities, so linear in the checking of impurity concentration scope with nicotinic acid.The range of linearity of checking is 0.1 μ g/mL ~ 1.0 μ g/mL (being equivalent to 0.05% ~ 0.5% nicotinic acid labelled amount).Linear verification result shows, in 0.1 μ g/mL ~ 1.0 μ g/mL concentration range, 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, accuracy (recovery) is determined at the recovery of nicotinic acid when auxiliary material and simvastatin exist.The checking scope of accuracy is between 0.1 μ g/mL ~ 1.0 μ g/mL.
Take simvastatin stock and adjunct in volumetric flask, prepare 0.1 μ g/mL, 0.2 μ g/mL, the horizontal Nicotinic test of 1.0 μ g/mL tri-, recovery result meets the requirements.
1.4 precision test
Preparation and detection 3 parallel sample, do method precision and Intermediate precision test respectively, result shows, method precision and Intermediate precision the result meet the requirements.
1.5 Quantitation Limit and detection limit value
Nicotinic acid relative substance Quantitation Limit (QL) is 0.1 μ g/mL or 0.05% nicotinic acid labelled amount.
Nicotinic acid relative substance detects the nicotinic acid labelled amount that limit value (DL) is 0.05 μ g/mL or 0.025%.
2, the method validation of Simvastatin relative substance and catabolite
2.1 specificity tests
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: by sample preparation method, be mixed with 1 times/2 times auxiliary material solution, detect with above-mentioned chromatographic condition, 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 nicotinic acid, Simvastatin known impurities, nicotinic acid raw material respectively, Simvastatin raw material, and auxiliary material, add acetonitrile stirring and dissolving, be mixed with and be about 20mg/mL, Simvastatin about 800 μ g/mL, the selectivity solution of each 4 μ g/mL of Simvastatin known impurities containing containing nicotinic acid.Detect with above-mentioned chromatographic condition, nicotinic acid, Simvastatin and known impurities single needle sample introduction confirm the retention time of each component.Result shows, and nicotinic acid retention time is near solvent peak, and each known impurities of Simvastatin and other impurity separate completely, and degree of separation is not less than 2.The result meets the requirements.
2.1.3 degraded is forced: force Degrading experiment to be whether the possible unknown catabolite of checking has interference to Simvastatin impurity determination.Nicotinic acid is taken respectively with formula rate, Simvastatin, auxiliary material, mix and grind and evenly make sample powder, strong Degrading experiment is carried out respectively under acid, alkali, oxidation, ultraviolet light, visible ray, 60 DEG C of heat conditions, result shows, and Simvastatin peak purity angle is less than purity threshold value (spectrum is even).The result illustrates the method tool specificity.
2.2 linear relationship tests
Simvastatin linear verification scope is set to 0.4 μ g/mL to 6.0 μ g/mL (being equivalent to 0.1% ~ 1.5% Simvastatin labelled amount).Test findings shows, in 0.4 μ g/mL ~ 6.0 μ g/mL concentration range, 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
Accuracy (recovery) has been determined at auxiliary material and Simvastatin when existing, Simvastatin hydroxy acid, dehydration Simvastatin, the recovery of simvastatin dimer.Recovery the result meets the requirements:
2.4 precision test
Preparation and detection 6 parts of sample solutions, do method precision and Intermediate precision test respectively, result shows, the distribution of 6 increment product impurity is close with numerical value, the difference of method precision experiment and Intermediate precision experiment gained total impurities mean value is 0.01%, be not more than 0.3%, method precision the result meets the requirements.
2.5 Quantitation Limit and detection limit value
The Quantitation Limit of Simvastatin impurity is the least concentration limit meeting acceptable standard in linear verification and recovery checking.Test findings is as following table.
Simvastatin is known/unknown impuritie Quantitation Limit table
Claims (3)
1. a detection method for 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 comprises the following steps:
1) preparation of sample solution: be dissolved in water by niacin simvastatin tablet, is mixed with the solution containing nicotinic acid 0.2mg/ml;
2) measure: extracting sample solution, sample introduction 50 μ L, adopt HPLC method, 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 is (75-85): (15-25), adjusts pH to 3-4 with glacial acetic acid;
Column temperature: 30-40 DEG C;
Flow velocity: 0.8 ~ 2.0ml/min;
Determined wavelength: 258nm;
The detection method of said Simvastatin relative substance comprises the following steps:
1) preparation of sample solution: niacin simvastatin tablet dissolved is made the solution containing Simvastatin 0.4mg/mL in acetonitrile; Room temperature preservation;
2) measure: extracting sample solution, sample introduction 50 μ L, adopt HPLC method, 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: 30-40 DEG C;
Flow velocity: 1-2mL/min;
Determined 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 is 80:20, adjusts pH to 3.15 ± 0.05 with glacial acetic acid;
Column temperature: 35 DEG C;
Flow velocity: 1ml/min;
Determined 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: 35 DEG C;
Flow velocity: 1.5mL/min;
Determined wavelength: 238nm.
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