CN103076410A - Dissolution rate detection method for simvastatin - Google Patents
Dissolution rate detection method for simvastatin Download PDFInfo
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Abstract
The invention provides a dissolution rate detection method for simvastatin, which comprises the following steps: 1) preparation of dissolution medium: dissolving sodium phosphate dibasic dehydrate and sodium dodecyl sulfate in water, stirring, and adjusting the pH value to 6.95-7.005, so as to obtain the dissolution medium; 2 sample solution preparation: adding a nicotinic acid/simvastatin sustained release tablet in the dissolution medium obtained in the step 1), performing a dissolution experiment at the paddle rotating speed of 50 rounds/minute by adopting the paddle method and a tablet sedimentation method, so as to obtain the sample solution; 3) contrast solution preparation: weighing a simvastatin reference product, and adding into a mobile phase for dissolving, so as to obtain the contrast solution; 4) detection: taking the contrast solution and sample solutions at all dissolution time points, recording the chromatogram and analyzing; and 5) calculating the dissolution rate. The dissolution rate detection method can objectively reflect dissolution release action of the simvastatin, and can detect the dissolution rate of the simvastatin simply, conveniently, quickly and accurately, and can accurately detect the quality of the agent.
Description
Technical field
The present invention relates to a kind of detection method of Simvastatin dissolution rate, belong to the chemicals analysis field.
Background technology
Simvastatin is a kind of Hydroxymethylglutaryl list acyl coenzyme A (HMG-CoA) reductase inhibitor, is internationally recognized efficient blood lipid-lowering medicine.The strong curative effect of this medicine effect is high, and spinoff is slight, because its safety, characteristics efficient, low toxicity have become the most frequently used class blood lipid-lowering medicine in the present whole world.Simvastatin has remarkable result to reducing low-density lipoprotein (LDL), but to a little less than increasing high-density lipoprotein (HDL) (HDL) effect, and therefore, normal and nicotinic acid is united use on the preparation, makes the niacin simvastatin sustained-release sheet.Both unite use, both can strengthen its effect for reducing blood fat, can reduce spinoff 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.
The detection method of Simvastatin dissolution rate in the niacin simvastatin sustained-release sheet, Chinese Pharmacopoeia adopts the HPLC method, but existing method does not reflect Simvastatin emission and absorption situation in human body, therefore, must set up a kind of more rational determination method, the stripping situation that more objectively reflects Simvastatin is for the science safe medication provides foundation.
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 Simvastatin dissolution rate is provided.
The invention provides a kind of detection method of Simvastatin dissolution rate, may further comprise the steps:
1) preparation of dissolution medium: it is soluble in water to get two hypophosphite monohydrate sodium dihydrogens (10.8g/6L) and lauryl sodium sulfate (30g/6L), stir, regulate pH value to 7.00 ± 0.05, obtain dissolution medium, wherein the weight ratio of two hypophosphite monohydrate sodium dihydrogens and lauryl sodium sulfate is 10.8:30;
2) preparation of sample solution: get nicotinic acid/simvastatin slow-release tablet, add in the dissolution medium of step 1), use the oar method to add tablet sedimentation pendant, when the oar rotating speed is 50 rev/mins, carry out the stripping experiment, obtain sample solution; , wherein the weight ratio of nicotinic acid and Simvastatin is (25-50): 1;
3) preparation of reference substance solution: take by weighing the Simvastatin reference substance, be added in the mobile phase and dissolve, obtain reference substance solution;
4) measure: get respectively the sample solution of reference substance solution and each dissolution time point, adopt the HPLC method to measure, the record chromatogram is also analyzed;
5) calculate dissolution rate: Simvastatin dissolution rate (%LC) is as follows in the calculation sample:
To first time point:
To second and later time point:
Wherein, P
SplBe the peak area of Simvastatin in the sample solution, P
StdFor Simvastatin in the reference substance solution
Average peak area, W
StdBe Simvastatin reference substance quality (mg), P is Simvastatin reference substance purity (purity be 1.00 show purity 100%), V
wBe each sample volume (mL), LC is the labelled amount (mg) of Simvastatin.
Described step 2) the stripping temperature is 37.0 ± 0.5 ° of C in.
Mobile phase is phosphate buffer and acetonitrile in the described step 3), and its volume ratio is (250-350): (650-750).
The chromatographic condition of HPLC method is in the described step 4):
Chromatographic column: C18 chromatographic column, 4.6mm * 150mm, 5-m particle diameter;
Mobile phase is phosphate buffer and acetonitrile, and its volume ratio is (250-350): (650-750);
The detection wavelength is 238nm;
Column temperature is 35oC;
Flow rate of mobile phase is 1.5ml/min.
The preparation method of described phosphate buffer is: get two hypophosphite monohydrate sodium dihydrogens to volumetric flask, be dissolved in water, transfer pH to 4.00 ± 0.05 with phosphoric acid.
The volume ratio of described phosphate buffer and acetonitrile is 300:700.
The sampling method of sample solution is in the described step 4): take a sample respectively for detecting the rear medium fluid infusion with 37 ° of C constant temperature of sampling at 10,20,30,45,60 and 90 minutes dissolution time points; With 0.45-m water system filtering with microporous membrane, discard just filtrate of 2 mL, get subsequent filtrate and be used for analyzing.
The detection method of Simvastatin dissolution rate of the present invention has following technique effect:
1) the stripping release behavior of Simvastatin preparation can be objectively responded, the dissolution rate of Simvastatin can be detected easy, quickly and accurately, the quality of Accurate Determining preparation;
2) specificity is strong, and linear relationship is good, accuracy, and precision, scopes etc. all meet the requirements.
3) can react Simvastatin in release and the bioavilability of human body:
4) analytical approach is used HPLC, and is easy, quick, accurate
Description of drawings
Fig. 1 is Simvastatin stripping curve comparison diagram;
Fig. 2 is the linear relationship chart of Simvastatin peak area and concentration.
Embodiment
The invention will be further described below in conjunction with the drawings and specific embodiments, can be implemented so that those skilled in the art can better understand the present invention also, but illustrated embodiment is not as a limitation of the invention.
The mensuration of embodiment 1 Simvastatin dissolution rate
The mensuration of Simvastatin dissolution rate may further comprise the steps:
1) preparation of dissolution medium: take by weighing two hypophosphite monohydrate sodium dihydrogens, 10.8 g and lauryl sodium sulfate 30g and be dissolved in the degassed water of 6000 mL, stir with glass bar, the NaOH solution with 20% is transferred pH to 7.00 ± 0.05.
2) preparation of sample solution: get nicotinic acid/simvastatin slow-release tablet (500 mg/20 mg), add the dissolution medium in the step 1), use the oar method to add tablet sedimentation pendant, under 50 rev/mins of oar rotating speeds, carry out the stripping experiment, the stripping temperature is 37.0 ± 0.5 ° of C, obtains sample solution;
3) preparation of Simvastatin reference substance solution: precision takes by weighing the approximately volumetric flask of 22 mg to 100-mL of Simvastatin reference substance, adding the mobile 50 mL dissolving of making an appointment, and adds the mobile phase dilution and is settled to scale, and indicate mother liquor.Precision pipettes 5 mL mother liquors to the volumetric flask of 25-mL, adds the mobile phase dilution and is settled to scale.The concentration of Simvastatin is about 44 g/mL.Mobile phase is phosphate buffer and acetonitrile, and its volume ratio is 300:700.The preparation method of phosphate buffer is: take by weighing the volumetric flask of two hypophosphite monohydrate sodium dihydrogens, 4.5 g to 1000 mL, add the approximately water-soluble solution of 900 mL, transfer pH to 4.00 ± 0.05 with phosphoric acid, add water to 1000 mL, mixing.
4) measure: the accurate solution of difference label taking and each point in time sampling product solution, sample introduction 50 μ L adopt the HPLC method to measure, and the record chromatogram is also analyzed.The sample solution sampling method is: 10,20, dissolution time point was taken a sample respectively for detecting in 30,45,60 and 90 minutes, used constant temperature in the medium fluid infusion of 37 ° of C after the sampling; At above-mentioned each point in time sampling 5 mL, with 0.45-m water system filtering with microporous membrane, discard just filtrate of 2 mL, get the subsequent filtrate analysis.
The chromatographic condition of HPLC method is as follows:
Instrument: Waters H-Class UPLC;
Chromatographic column: C18,4.6mm * 150mm, 5-m particle diameter;
Detecting device: UV or PDA detecting device
Mobile phase is phosphate buffer and acetonitrile, and its volume ratio is 300:700.The preparation method of phosphate buffer is: take by weighing the volumetric flask of two hypophosphite monohydrate sodium dihydrogens, 4.5 g to 1000 mL, add the approximately water-soluble solution of 900 mL, transfer pH to 4.00 ± 0.05 with phosphoric acid, add water to 1000 mL, mixing.
The detection wavelength is 238nm;
Column temperature is 35oC;
Flow rate of mobile phase is 1.5ml/min.
5) calculate: Simvastatin dissolution rate (%LC) is as follows in the calculation sample:
To first time point:
To second and later time point:
Wherein,
| P spl | The peak area of Simvastatin in the sample solution |
| P std | The average peak area of Simvastatin in the reference substance solution |
| W std | Simvastatin reference substance quality (mg) |
| P | Simvastatin reference substance purity (purity be 1.00 |
| V w | Each sample volume (mL) |
| LC | The labelled amount of Simvastatin (mg) |
Get the nicotinic acid/simvastatin slow-release tablet (500 mg/20 mg) (batch I1000001) of Changtai, Jiangsu pharmaceutcal corporation, Ltd research and development, the niacin simvastatin sustained-release sheet of the reference medicine U.S. Abbott of having gone on the market (500 mg/20 mg) (lot number: 09048AA) each 12 tablet is done Simvastatin dissolution rate curve relatively, its average dissolution rate (% labelled amount) and percentage relative deviation (%RSD) comparative result such as table 1:
Table 1 Simvastatin dissolution determination result
The above results explanation, in each dissolution time point sampling and measuring, measurement result is reliable and stable, and RSD is less.Correlativity between Changtai research and development and reference substance reaches 83%, meets the requirements, and correlativity stripping curve comparison diagram is seen Fig. 1.In the time of 90 minutes, the dissolution rate of Simvastatin illustrates that more than 90% this assay method is feasible.This dissolving-out method may be used for predicting that Simvastatin is at the release behavior of human body in this preparation.
The checking of dissolution determination method:
The test of 1 specificity
Press the sample compound method, take by weighing 1 times/2 times auxiliary material and nicotinic acid raw material, be mixed with 1 times/2 times auxiliary material solution, according to stripping experiment flow and determination method, in the time of 60 minutes, sampling, centrifugal, get the supernatant liquor analysis.Adopt above-mentioned chromatographic condition to detect and analyze, result's demonstration, in medium, auxiliary material solution (1 times) and auxiliary material solution (2 times) chromatogram, medium and auxiliary material solution are noiseless in the Simvastatin retention time.
The test of 2 linear relationships
Precision take by weighing Simvastatin approximately 22mg place the 100-mL volumetric flask, add the mobile phase dissolved dilution to scale, shake up, press the liquor analysis of table 2 preparation linear criterion, concentration is about 2.2～66 μ g/mL, each concentration arranges two standard models, takes the mean.With sample introduction gained peak area each time concentration is done linear regression analysis, the results are shown in Figure 2, Fig. 2 and show, in 2.2～66 μ g/mL concentration ranges, Simvastatin peak area and concentration are good linear relationship, and its linearly dependent coefficient is 0.99999.
Table 2 linear criterion solution preparation table
| Standard solution | Concentration (μ g/mL) | Mother liquor pipettes (mL) | Volumetric flask (mL) |
| Mark 1 | 2.2 | 1 | 100 |
| Mark 2 | 8.8 | 4 | 100 |
| Mark 3 | 22 | 10 | 100 |
| Mark 4 | 44 | 10 | 50 |
| Mark 5 | 66 | 15 | 50 |
3 accuracy tests
Precision takes by weighing the approximately volumetric flask of 22mg to 100-mL of Simvastatin, adds acetonitrile 30mL dissolving, adds stripping medium constant volume, is mixed with recovery mother liquor.Take by weighing respectively a certain amount of nicotinic acid and auxiliary material, precision pipettes recovery mother liquor, and concussion is 60 minutes in the 37oC water-bath, use the medium constant volume, mixing is mixed with 2.2 μ g/mL, 44 μ g/mL, three concentration recovery of 66 μ g/mL solution, and each concentration is prepared respectively 3 samples.Recovery the result sees Table 3, and the result shows, average recovery rate is all more than 95%, and RSD in 3%, all meets the requirements.
Table 3 recovery the result
4 precision tests
Method precision: get 6 tablets, press dissolution determination method and take a sample at 60 minutes points, sample 0.45-μ m water system filtering with microporous membrane, and discard just filtrate of 2 mL.
Middle precision: get 6 tablets, on different working days, use different digestion instruments by another analyst, different chromatographic columns and various criterion solution operate with method precision.
Test findings sees Table 4.6 tablet stripping mean values of method precision experiment are 85%, and 6 tablet mean values are 83% in the middle Precision Experiment, and the difference of mean value is 2%, and the method precision the result meets the requirements.
Table 4 precision result, 500 mg/20 mg
5 scopes
The quantitative scope of linear, the recovery and precision demonstration validation is approximately between 2.2 to 66 μ g/mL, is equivalent to approximately 10%LC(20mg labelled amount) to the 150%LC(40mg labelled amount) stripping of Simvastatin.
Claims (7)
1. the detection method of a Simvastatin dissolution rate is characterized in that, may further comprise the steps:
1) preparation of dissolution medium: it is soluble in water to get two hypophosphite monohydrate sodium dihydrogens (10.8g/6L) and lauryl sodium sulfate (30g/6L), stir, regulate pH value to 7.00 ± 0.05, obtain dissolution medium, wherein the weight ratio of two hypophosphite monohydrate sodium dihydrogens and lauryl sodium sulfate is 10.8:30;
2) preparation of sample solution: get nicotinic acid/simvastatin slow-release tablet, add in the dissolution medium of step 1), use the oar method to add tablet sedimentation pendant, when the oar rotating speed is 50 rev/mins, carry out the stripping experiment, obtain sample solution; , wherein the weight ratio of nicotinic acid and Simvastatin is (25-50): 1;
3) preparation of reference substance solution: take by weighing the Simvastatin reference substance, be added in the mobile phase and dissolve, obtain reference substance solution;
4) measure: get respectively the sample solution of reference substance solution and each dissolution time point, adopt the HPLC method to measure, the record chromatogram is also analyzed;
5) calculate dissolution rate: Simvastatin dissolution rate (%LC) is as follows in the calculation sample:
To first time point:
To second and later time point:
Wherein, P
SplBe the peak area of Simvastatin in the sample solution, P
StdFor Simvastatin in the reference substance solution
Average peak area, W
StdBe Simvastatin reference substance quality (mg), P is Simvastatin reference substance purity (purity be 1.00 show purity 100%), V
wBe each sample volume (mL), LC is the labelled amount (mg) of Simvastatin.
2. the detection method of Simvastatin dissolution rate according to claim 1 is characterized in that, described step 2) in the stripping temperature be 37.0 ± 0.5 ° of C.
3. the detection method of Simvastatin dissolution rate according to claim 1 is characterized in that, mobile phase is phosphate buffer and acetonitrile in the described step 3), and its volume ratio is (250-350): (650-750).
4. the detection method of Simvastatin dissolution rate according to claim 1 is characterized in that, the chromatographic condition of HPLC method is in the described step 4):
Chromatographic column: C18 chromatographic column, 4.6mm * 150mm, 5-m particle diameter;
Mobile phase is phosphate buffer and acetonitrile, and its volume ratio is (250-350): (650-750);
The detection wavelength is 238nm;
Column temperature is 35oC;
Flow rate of mobile phase is 1.5ml/min.
5. according to claim 3 or the detection method of 4 described Simvastatin dissolution rates, it is characterized in that, the preparation method of described phosphate buffer is: get two hypophosphite monohydrate sodium dihydrogens to volumetric flask, be dissolved in water, transfer pH to 4.00 ± 0.05 with phosphoric acid.
6. according to claim 3 or the detection method of 4 described Simvastatin dissolution rates, it is characterized in that, the volume ratio of described phosphate buffer and acetonitrile is 300:700.
7. the detection method of Simvastatin dissolution rate according to claim 1, it is characterized in that, the sampling method of sample solution is in the described step 4): take a sample respectively for detecting the rear medium fluid infusion supplementing solvent with 37 ° of C constant temperature of sampling at 10,20,30,45,60 and 90 minutes dissolution time points; With 0.45-m water system filtering with microporous membrane, discard just filtrate of 2 mL, get subsequent filtrate and be used for analyzing.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103336071A (en) * | 2013-06-18 | 2013-10-02 | 润泽制药(苏州)有限公司 | Method for determining dissolution rates of atorvastatin calcium preparation |
| CN105158188A (en) * | 2015-07-06 | 2015-12-16 | 长春中医药大学 | Release detection method of aniracetam sustained release tablet |
| CN106053663A (en) * | 2016-07-08 | 2016-10-26 | 海南华益泰康药业有限公司 | Method for determining releasing rate of enteric sustained-release tablet |
| CN106483203A (en) * | 2015-08-27 | 2017-03-08 | 扬子江药业集团南京海陵药业有限公司 | Epalrestat tablet dissolution determination method |
| CN108414656A (en) * | 2018-01-29 | 2018-08-17 | 四川省食品药品检验检测院 | A method of measuring the stripping curve of Simvastatin Tablets |
| CN110133134A (en) * | 2019-05-17 | 2019-08-16 | 南通联亚药业有限公司 | A kind of analysis method measuring Quetiapine fumarate sustained-release tablets release |
| CN112034118A (en) * | 2020-07-29 | 2020-12-04 | 北京诺康达医药科技股份有限公司 | Method for rapidly detecting dissolution rate of solid preparation |
| CN112114052A (en) * | 2019-06-21 | 2020-12-22 | 上海信谊万象药业股份有限公司 | Method for determining dissolution rate of simvastatin tablets |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103336071A (en) * | 2013-06-18 | 2013-10-02 | 润泽制药(苏州)有限公司 | Method for determining dissolution rates of atorvastatin calcium preparation |
| CN105158188A (en) * | 2015-07-06 | 2015-12-16 | 长春中医药大学 | Release detection method of aniracetam sustained release tablet |
| CN106483203A (en) * | 2015-08-27 | 2017-03-08 | 扬子江药业集团南京海陵药业有限公司 | Epalrestat tablet dissolution determination method |
| CN106053663A (en) * | 2016-07-08 | 2016-10-26 | 海南华益泰康药业有限公司 | Method for determining releasing rate of enteric sustained-release tablet |
| CN108414656A (en) * | 2018-01-29 | 2018-08-17 | 四川省食品药品检验检测院 | A method of measuring the stripping curve of Simvastatin Tablets |
| CN110133134A (en) * | 2019-05-17 | 2019-08-16 | 南通联亚药业有限公司 | A kind of analysis method measuring Quetiapine fumarate sustained-release tablets release |
| CN112114052A (en) * | 2019-06-21 | 2020-12-22 | 上海信谊万象药业股份有限公司 | Method for determining dissolution rate of simvastatin tablets |
| CN112034118A (en) * | 2020-07-29 | 2020-12-04 | 北京诺康达医药科技股份有限公司 | Method for rapidly detecting dissolution rate of solid preparation |
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Application publication date: 20130501 |