WO2022062961A1 - Method for detecting content of 6-oxosimvastatin in ezetimibe-simvastatin tablets - Google Patents

Abstract

Disclosed is a method for detecting the content of 6-oxosimvastatin in Ezetimibe-Simvastatin tablets, which uses high performance liquid chromatography for detection. The present invention may not only quantitatively determine the content of 6-oxosimvastatin in Ezetimibe-Simvastatin tablets, but also completely separate 6-oxosimvastatin from impurities, and has a good peak shape, thus meeting the requirements of Chinese Pharmacopoeia. Moreover, the method has a low detection limit, effectively controls the quality of raw materials in Ezetimibe-Simvastatin tablets, has strong specificity, a high degree of separation, high sensitivity and good accuracy.

Description

A method for detecting the content of 6-oxosimvastatin in ezetimibe simvastatin tablets technical field

The invention belongs to the technical field of chemical substance detection, and relates to the detection of degraded impurities in medicines, in particular to the detection of 6-oxosimvastatin content in ezetimibe simvastatin tablets.

Background technique

Ezetimibe Simvastatin Tablets is a compound preparation composed of ezetimibe and simvastatin, ezetimibe is a selective cholesterol absorption inhibitor, which can inhibit the absorption of exogenous cholesterol. Simvastatin can competitively inhibit the activity of HMG-CoA reductase and reduce the synthesis of free cholesterol in cells. The compound preparation is suitable for the treatment of patients with primary hypercholesterolemia or mixed hyperlipidemia.

6-Oxosimvastatin is the degradation impurity of ezetimibe and simvastatin tablets. It is an impurity generated in the process of synthesizing compound preparations of ezetimibe and simvastatin, which may be transferred to the finished product during the production process. . Therefore, in order to better control the impurity content of 6-oxosimvastatin in ezetimibe simvastatin tablets, it is necessary to select a simple, accurate, repeatable, high sensitivity and low detection limit method for detection. On the premise of ensuring the safety and reliability of the product, the quality of 6-oxosimvastatin in ezetimibe simvastatin tablets is effectively controlled.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide a method for detecting the content of 6-oxosimvastatin in ezetimibe simvastatin tablets, which can quantitatively determine 6-oxosimvastatin in ezetimibe simvastatin tablets statin content, and has a lower detection limit and higher sensitivity.

In order to accomplish the above object, the present invention adopts the following technical solutions:

A method for detecting the content of 6-oxosimvastatin in ezetimibe simvastatin tablets adopts high performance liquid chromatography for detection.

The further improvement of the technical solution of the present invention is that the detection conditions of the high performance liquid chromatography are as follows:

Stationary phase: The stationary phase is octadecylsilane bonded silica gel;

The detection wavelength is 290nm;

Mobile phase A: sodium dihydrogen phosphate solution with a concentration of 0.025mol/L, the sodium dihydrogen phosphate solution is adjusted to pH 4.0 with 10% phosphoric acid solution, and then mixed with acetonitrile to prepare a solution with a volume ratio of 80:20;

Mobile phase B: acetonitrile;

Elution mode: gradient elution;

The procedure for the elution gradient is:

0min, the volume fraction of mobile phase A is 100%, and the volume fraction of mobile phase B is 0;

27.00min, the volume fraction of mobile phase A is 46%, and the volume fraction of mobile phase B is 54%;

27.01min, the volume fraction of mobile phase A is 100%, and the volume fraction of mobile phase B is 0;

37.00min, the volume fraction of mobile phase A is 100%, and the volume fraction of mobile phase B is 0;

The flow rate is 1.5ml/min;

The injection volume is 100 μl;

The column temperature was 30°C.

A further improvement of the technical solution of the present invention is, comprising the following steps:

A: Preparation of the test solution: Weigh the ezetimibe simvastatin tablets as the test sample to _be ground into a powder and place it in a _dilute ml volumetric flask, add the solvent after ultrasonic treatment at room temperature and add The solvent is adjusted to the scale to prepare the test solution, which is ready for use;

B: preparation of reference substance solution: take by weighing BHA (butylated hydroxyanisole), dissolve it with acetonitrile and then dilute it with solvent to prepare a reference substance solution with a concentration of C _contrast , for use;

C: measure: respectively measure the need testing solution and the reference solution and inject it into a high-performance liquid chromatograph to measure, to obtain the chromatographic peak area of ezetimibe and the chromatographic peak area of 6-oxosimvastatin in the test solution. Chromatographic peak area A _{degradation product} , and the chromatographic peak area A _control of BHA (butylated hydroxyanisole) in the reference solution;

D: calculation: obtain the content of 6-oxosimvastatin in the test solution according to formula (1);

In the formula, A _{degradation product} is the peak area of 6-oxosimvastatin; A _control is the main peak area of BHA (butylated hydroxyanisole) in the reference solution; C _control is the BHA (butylated hydroxyanisole) in the reference solution. ether) concentration; W is _the weighing sample size of the test sample; W is the _average tablet weight; n is the _dilution ratio of the test solution; 2.64 is the relative response factor of 6-oxosimvastatin; Specification of simvastatin in test solution.

A further improvement of the technical solution of the present invention is that, in the steps A and B, the solvent is a 0.025mol/L citric acid solution, and 50% sodium hydroxide solution is used to adjust the pH of the citric acid solution to 4.0, and then prepare a solution with a volume ratio of 80:20 with acetonitrile.

A further improvement of the technical solution of the present invention is that, in the step A, the concentration of simvastatin contained in the test solution is 1.5-2.5 mg/ml.

A further improvement of the technical solution of the present invention is that, in the step B, the concentration of BHA (butylated hydroxyanisole) contained in the reference solution is 4.0-4.4 μg/ml.

A further improvement of the technical solution of the present invention is that the concentration of simvastatin contained in the test solution is 2 mg/ml.

A further improvement of the technical solution of the present invention is that the concentration of BHA (butylated hydroxyanisole) contained in the reference solution is 4.2 μg/ml.

A further improvement of the technical solution of the present invention is that, in the step A, ultrasonic treatment at room temperature is carried out for 30 min.

A further improvement of the technical solution of the present invention is that the chromatographic column used in the high-performance liquid chromatography method is Phenomenex Luna Phenyl-Hexyl, and the specifications are 150 mm×4.6 mm, 3 μm.

Compared with the prior art, the beneficial effects of the present utility model are:

The detection method of the invention has strong specificity and high sensitivity, 6-oxosimvastatin can achieve good separation from other components in the sample, and has a good linear relationship with its peak area in the range of 0.02 μg/ml to 8 μg/ml (r=0.99998, n=6), the limit of detection was 0.87ng, and the limit of quantification was 2.17ng; the recovery rate of 6-oxosimvastatin at each concentration was between 80% and 115%, and the average recovery rate was 98.27%. The RSD was 4% and the recovery rate was good; the method was simple, accurate and reproducible, and could be used for the quality control of 6-oxosimvastatin in ezetimibe simvastatin tablets.

Description of drawings

FIG. 1 is a chromatogram of a system suitability solution in an example of the present invention.

detailed description

Below in conjunction with embodiment, the present invention is described in further detail:

A method for detecting the content of 6-oxosimvastatin in ezetimibe simvastatin tablets adopts high performance liquid chromatography to detect, and the adopted chromatographic column is Phenomenex Luna Phenyl-Hexyl, the size is 150mm×4.6mm, 3μm. The detection conditions are as follows:

Stationary phase: The stationary phase is octadecylsilane bonded silica gel;

The detection wavelength is 290nm;

Mobile phase A: sodium dihydrogen phosphate solution with a concentration of 0.025mol/L, the sodium dihydrogen phosphate solution is adjusted to pH 4.0 with 10% phosphoric acid solution, and then mixed with acetonitrile to prepare a solution with a volume ratio of 80:20;

Mobile phase B: acetonitrile;

Elution mode: gradient elution;

The procedure for the elution gradient is:

0min, the volume fraction of mobile phase A is 100%, and the volume fraction of mobile phase B is 0;

27.00min, the volume fraction of mobile phase A is 46%, and the volume fraction of mobile phase B is 54%;

27.01min, the volume fraction of mobile phase A is 100%, and the volume fraction of mobile phase B is 0;

37.00min, the volume fraction of mobile phase A is 100%, and the volume fraction of mobile phase B is 0;

The flow rate is 1.5ml/min;

The injection volume is 100 μl;

The column temperature was 30°C.

Include the following steps:

A: Preparation of the test solution: Weigh the ezetimibe simvastatin tablets as the test sample to _be ground into a powder and place it in a measuring bottle of n _dilute ml, add the solvent and then ultrasonically treat it at room temperature for 30min. Add solvent to volume to the mark to prepare a test solution containing simvastatin with a concentration of 1.5 to 2.5 mg/ml, preferably 2 mg/ml, for use; wherein, the solvent is a 0.025 mol/L citric acid solution , using 50% sodium hydroxide solution to adjust the pH value of the citric acid solution to 4.0, and then prepare a solution with a volume ratio of 80:20 with acetonitrile;

B: Preparation of reference solution: Weigh BHA (butylated hydroxyanisole), dissolve it in acetonitrile, and then use solvent to prepare a reference solution containing BHA (butylated hydroxyanisole) with a concentration of 4.0-4.4 μg/ml , preferably 4.2 μg/ml, for use; wherein, the solvent is a 0.025mol/L citric acid solution, and 50% sodium hydroxide solution is used to adjust the pH of the citric acid solution to 4.0, and then prepared with acetonitrile to a volume ratio of 80:20 solution;

C: measure: respectively measure the need testing solution and the reference solution and inject it into a high-performance liquid chromatograph to measure, to obtain the chromatographic peak area of ezetimibe and the chromatographic peak area of 6-oxosimvastatin in the test solution. Chromatographic peak area A _{degradation product} , and the chromatographic peak area A _control of BHA (butylated hydroxyanisole) in the reference solution;

D: calculation: according to the formula in the formula (1), the content of 6-oxosimvastatin in the test solution is obtained;

In the formula, A _{degradation product} is the peak area of 6-oxosimvastatin; A _control is the main peak area of BHA (butylated hydroxyanisole) reference solution; C _control is BHA (butylated hydroxyanisole) reference solution W is the weighing sample size of the test sample; W is _{the average} tablet weight; n is the _dilution ratio of the test solution; 2.64 is the relative response factor of 6-oxosimvastatin; the marked amount is the test sample Specifications of simvastatin in solution. The labeled amount is the specification of the sample. If each tablet contains ezetimibe 10 mg, simvastatin 20 mg, and simvastatin labeled amount is 20 mg, if each tablet contains ezetimibe 10 mg, simvastatin 40 mg, simvastatin The labeled amount is 40mg.

According to the guiding principles of the Chinese Pharmacopoeia, the indicated content of 6-oxosimvastatin=the content of 6-oxosimvastatin×average tablet weight/the indicated amount of simvastatin. Because 6-oxosimvastatin is a degradation product of simvastatin. Therefore, the formula is converted to the content of 6-oxosimvastatin based on the labeled amount of simvastatin, and the calculation method is to more objectively reflect the degradation impurity 6-oxosimvastatin of simvastatin.

It should be noted that the percentage in the formula (1) is the mass percentage of the degraded impurity 6-oxosimvastatin and the simvastatin in the test sample.

Among them, the principle of this formula (1) is to use the external standard method with a correction factor to measure, the concentration of 6-oxosimvastatin/6-oxosimvastatin peak area=BHA (butylated hydroxyanisole) Concentration/(peak area of BHA (butyl hydroxyanisole) x 2.64), ie concentration of 6-oxosimvastatin = C _control x A _{degradation product} /(A _control x 2.64).

Example

1 Instruments and reagents

1.1 Instruments: high performance liquid chromatograph (Agilent, model: 1260), electronic analytical balance (Mettler-Toledo, model: XS105).

1.2 Reagents: ezetimibe simvastatin tablets (self-made, batch numbers: 130801, 130802, 130803); BHA (butylated hydroxyanisole) (source: USP, content: 99.8%); anhydrous sodium dihydrogen phosphate (Analysis pure, Sinopharm Group Chemical Reagent Co., Ltd.); phosphoric acid (analytical grade, Sinopharm Group Chemical Reagent Co., Ltd.); acetonitrile (chromatographic grade, CNW).

2 detection steps

2.1 Chromatographic conditions: Column: Phenomenex Luna Phenyl-Hexyl column (150×4.6mm, 3μm); Mobile phase A: 0.025mol/L sodium dihydrogen phosphate solution (adjust pH to 4.0 with 10% phosphoric acid solution)-acetonitrile ( 80:20); mobile phase B: acetonitrile; flow rate is 1.5ml/min; detection wavelength is 290nm; injection volume is 100μl; column temperature is 30°C; gradient elution procedure is shown in Table 1:

Table 1

time (minutes)	Mobile phase (A%)	Mobile phase (B%)
0	100	0
27.00	46	54
27.01	100	0
37.00	100	0

2.2 Preparation of solution:

2.2.1 Preparation of the test solution

Take about 20 self-made ezetimibe simvastatin tablets, grind them uniformly, accurately weigh the ground powder (equivalent to 20 mg of simvastatin), put it in a 10ml measuring bottle, add an appropriate amount of solvent, and sonicate at room temperature for 30 minutes. Add solvent to volume to the mark, shake well.

2.2.2 Preparation of reference solution

Precisely weigh about 21mg of BHA (butylated hydroxyanisole) reference substance to a 50ml volumetric flask, add acetonitrile to dissolve, and make up to the mark. Since BHA (butylated hydroxyanisole) is almost insoluble in water, it is easily soluble in acetonitrile. Dissolving in acetonitrile first, and then diluting with solvent to its corresponding concentration can effectively improve the problem of poor solubility. After shaking, take a 1ml to 100ml volumetric flask, add solvent to dilute to the mark, and shake well.

2.2.3 Negative excipient solution

Precisely weigh about 180 mg of blank excipients without ezetimibe and simvastatin to a 10 ml volumetric flask, add an appropriate amount of solvent, sonicate for 30 min, add solvent to volume to the mark, and shake well.

2.2.4 Preparation of 6-oxosimvastatin stock solution

Accurately weigh about 21mg of 6-oxosimvastatin reference substance, put it in a 50ml volumetric flask, add solvent to dissolve and dilute to the mark, shake well, transfer 1ml to 10ml volumetric flask, add solvent to dilute to volume, shake well, As a 6-oxosimvastatin stock solution.

2.2.5 Preparation of solvent

0.025mol/L citric acid solution (take 4.8g of anhydrous citric acid, add 900ml of water to dissolve, adjust the pH value to 4.0 with 50% sodium hydroxide solution, add water to 1000ml)-acetonitrile (80:20).

3. Test results

3.1 System Applicability Experiment

Take the test solution as the system suitability solution, according to the chromatographic conditions under "2.1", inject the sample for analysis, and record the chromatogram. The retention time of ezetimibe was 19.223min, the retention time of BHA (butylated hydroxyanisole) was 17.848min, and the retention time of 6-oxosimvastatin was 16.203min (see Figure 1). The measurement has no interference, meets the system suitability requirements, and has a good peak shape, which meets the requirements of the Chinese Pharmacopoeia.

3.2 Detection limit and quantification limit

Precisely weigh about 10 mg of 6-oxosimvastatin reference substance and BHA (butylated hydroxyanisole) reference substance respectively, dilute step by step, inject samples according to the chromatographic conditions under "2.1", and record the chromatogram. When the signal-to-noise ratio S/N=10, the limit of quantification of 6-oxosimvastatin is 2.17ng, and the limit of quantification of BHA (butylated hydroxyanisole) is 8.20ng, when the signal-to-noise ratio S/N=3 , the detection limit of 6-oxosimvastatin was 0.87ng, and the detection limit of BHA (butylated hydroxyanisole) was 3.28ng.

3.3 Recovery experiment

Precisely weigh about 200 mg of self-made ezetimibe simvastatin tablets and grind them into a uniform powder, put them in a 10 ml volumetric flask, and precisely pipette 6-oxosimvastatin according to 50%, 100%, and 150% of the concentration of 6-oxosimvastatin. Add 0.5ml, 1ml and 1.5ml of simvastatin stock solution into the volumetric flask, add appropriate amount of solvent, ultrasonicate for 30min at room temperature, add solvent to volume to the mark, shake well, and prepare 3 copies of each concentration in parallel.

Precisely measure 100 μl of the above solution and the reference solution and inject them into a high performance liquid chromatograph. According to the chromatographic conditions under “2.1”, inject and analyze, and record the chromatogram. The results are shown in Table 2 below:

Table 2

It can be seen from Table 2 that the recovery rate of 6-oxosimvastatin at each concentration is between 80% and 115%, the average recovery rate is 98.27%, the RSD is 4%, and the recovery rate is good.

3.4 Linear relationship test

Make 6-oxosimvastatin and BHA (butyl hydroxyanisole) into 0.02μg, 2μg, 3.2μg, 4μg, 6μg and 8μg per 1ml respectively, accurately measure 100μl and inject into the liquid chromatograph, press "2.1" ” under the chromatographic conditions, injection analysis, and record the chromatogram. Taking the concentration of the control solution as the abscissa and the peak area as the ordinate, carry out linear regression processing to obtain the linear equation of 6-oxosimvastatin as Y=181315.2686x-1994.1185 (r=0.99998), BHA (butylated hydroxyanisole) ether) linear equation is Y=68729.2743x-2226.7692 (r=0.9999). The results show that 6-oxosimvastatin and BHA (butylated hydroxyanisole) have a good linear relationship within 0.02-8μg/ml, respectively. The relative response factor (RRF) = 6-oxo is calculated according to the slope of the linear correlation of known impurities. The slope of simvastatin/slope of BHA (butylated hydroxyanisole) yielded a calculated relative response factor of 2.64 for 6-oxosimvastatin.

3.5 Precision test

Take 4 μg/ml of 6-oxosimvastatin and BHA (butylated hydroxyanisole) under the linear relationship of concentration to inject 6 times, and the results are shown in Table 3 below:

table 3

3.6 Repeatability test

Take ezetimibe simvastatin tablets (batch number: 130801) to prepare 6 parts of the test solution according to the method under "2.2.1", prepare the control solution according to the method under "2.2.2", and according to "2.1" Under the chromatographic conditions for injection analysis. The results are shown in Table 4, and the results show that 6-oxosimvastatin has good repeatability.

Table 4

name	1	2	3	4	5	6	average value
6-oxosimvastatin content (%)	0.005	0.005	0.005	0.005	0.005	0.005	0.005

3.7 Solution stability

Take an appropriate amount of this product powder (equivalent to 10mg of ezetimibe) under the item of repeatability, put it in a 10ml volumetric flask, add an appropriate amount of solvent, and ultrasonically at room temperature for 30min, the ultrasonic can promote the effective dissolution of the main components and impurities, and the recovery rate is improved. , add solvent to volume to the mark, shake well, filter, take 100 μl of the continuous filtrate, inject it into the liquid chromatograph at 0h, 2h, 4h, 8h, 12h, 24h respectively, record the chromatogram, the results are shown in Table 5:

table 5

3.8 Determination of samples

Take 3 batches of ezetimibe and simvastatin tablets (batch numbers: T1636, 130801, 130802, 130803), prepare the test solution according to the method under "2.2.1" and prepare the control according to the method under "2.2.2" The product solution was injected and analyzed according to the chromatographic conditions under "2.1". The results are shown in Table 6 below:

Table 6

batch number	Amount of 6-oxosimvastatin (%)
130801	0.005%
130802	0.004%
130803	0.005%

It can be seen from the above table that the method is simple and accurate, and can effectively detect the content of 6-oxosimvastatin in ezetimibe simvastatin tablets.

As can be seen from the above detection results, the above method can not only quantitatively measure the content of 6-oxosimvastatin that exists in it, but also can completely separate 6-oxosimvastatin and each impurity, and the peak shape is good, which meets the requirements of the Chinese Pharmacopoeia. It can effectively control the quality of the ezetimibe simvastatin tablet API, with strong specificity, high resolution, high sensitivity and good accuracy.

Since the mobile phase system of "sodium dihydrogen phosphate solution: acetonitrile" is likely to cause thermal effects during the mixing process, resulting in baseline drift, poor peak reproducibility and other factors, this method adopts "(sodium dihydrogen phosphate solution-acetonitrile): The mobile phase system of "acetonitrile" can effectively improve the problem of baseline drift.

For the preparation of the sample, the ultrasonic extraction method can promote the effective dissolution of the main components and impurities, and the recovery rate is improved.

BHA (butylated hydroxyanisole) is almost insoluble in water and easily soluble in acetonitrile. The first step of this method is to dissolve in acetonitrile, and then dilute to its corresponding concentration with a solvent, which can effectively improve the problem of poor solubility.

Although the present invention has been described by using the above-mentioned preferred embodiments, it is not intended to limit the protection scope of the present invention. Any person skilled in the art can make various changes relative to the above-mentioned embodiments without departing from the spirit and scope of the present invention. and modifications still belong to the scope of protection of the present invention.

Claims (10)

1. A method for detecting the content of 6-oxosimvastatin in ezetimibe simvastatin tablets is characterized in that the detection is carried out by using high performance liquid chromatography.
2. A method for detecting 6-oxosimvastatin content in ezetimibe simvastatin tablets according to claim 1, is characterized in that, the detection condition of described high performance liquid chromatography is as follows:

   Stationary phase: The stationary phase is octadecylsilane bonded silica gel;

   The detection wavelength is 290nm;

   Mobile phase A: sodium dihydrogen phosphate solution with a concentration of 0.025mol/L, the sodium dihydrogen phosphate solution is adjusted to pH 4.0 with 10% phosphoric acid solution, and then mixed with acetonitrile to prepare a solution with a volume ratio of 80:20;

   Mobile phase B: acetonitrile;

   Elution mode: gradient elution;

   The procedure for the elution gradient is:

   0min, the volume fraction of mobile phase A is 100%, and the volume fraction of mobile phase B is 0;

   27.00min, the volume fraction of mobile phase A is 46%, and the volume fraction of mobile phase B is 54%;

   27.01min, the volume fraction of mobile phase A is 100%, and the volume fraction of mobile phase B is 0;

   37.00min, the volume fraction of mobile phase A is 100%, and the volume fraction of mobile phase B is 0;

   The flow rate is 1.5ml/min;

   The injection volume is 100 μl;

   The column temperature was 30°C.
3. A method for detecting 6-oxosimvastatin content in ezetimibe simvastatin tablets according to claim 2, is characterized in that comprising the following steps:

   A: Preparation of the test solution: Weigh the ezetimibe simvastatin tablets as the test sample to _be ground into a powder and place it in a _dilute ml volumetric flask, add the solvent after ultrasonic treatment at room temperature and add The solvent is adjusted to the scale to prepare the test solution, which is ready for use;

   B: preparation of reference substance solution: take by weighing butylated hydroxyanisole, dissolve it in acetonitrile and then dilute it with solvent to prepare a reference substance solution with a concentration of C _contrast , for use;

   C: measure: respectively measure the need testing solution and the reference solution and inject it into a high-performance liquid chromatograph to measure, to obtain the chromatographic peak area of ezetimibe and the chromatographic peak area of 6-oxosimvastatin in the test solution. Chromatographic peak area A _{degradation product} , and the chromatographic peak area A _control of butylated hydroxyanisole in the reference solution;

   D: calculation: obtain the content of 6-oxosimvastatin in the test solution according to formula (1);

   

   In the formula, A _{degradation product} is the peak area of 6-oxosimvastatin; A is the main peak area of butylated hydroxyanisole in the _reference solution; C is the _{concentration} of butylated hydroxyanisole in the reference solution; W _For is the weighing sample size of the test product; W is the _average tablet weight; n is the _dilution ratio of the test solution; 2.64 is the relative response factor of 6-oxosimvastatin; the marked amount is the simvastatin in the test solution Specifications for statins.
4. A method for detecting the content of 6-oxosimvastatin in ezetimibe simvastatin tablets according to claim 3, wherein, in the step A and the step B, the solvent is 0.025 mol/L citric acid solution, use 50% sodium hydroxide solution to adjust the pH value of the citric acid solution to 4.0, and then prepare a solution with a volume ratio of 80:20 with acetonitrile.
5. A method for detecting the content of 6-oxosimvastatin in ezetimibe simvastatin tablets according to claim 3 or 4, wherein in the step A, the test solution contains The concentration of simvastatin is 1.5 to 2.5 mg/ml.
6. A method for detecting the content of 6-oxosimvastatin in ezetimibe simvastatin tablets according to claim 3 or 4, characterized in that, in the step B, the reference substance solution contains dimethoxine The concentration of hydroxyanisole is 4.0-4.4 μg/ml.
7. A method for detecting the content of 6-oxosimvastatin in ezetimibe simvastatin tablets according to claim 5, wherein the concentration of simvastatin contained in the test solution is 2mg/ ml.
8. A kind of method for detecting 6-oxosimvastatin content in ezetimibe simvastatin tablet according to claim 6, is characterized in that, the concentration that contains butylated hydroxyanisole in described reference substance solution is 4.2 μg/ml.
9. A method for detecting the content of 6-oxosimvastatin in ezetimibe simvastatin tablets according to claim 3, characterized in that, in the step A, ultrasonic treatment at room temperature is performed for 30 min.
10. A method for detecting the content of 6-oxosimvastatin in ezetimibe simvastatin tablets according to any one of claims 1 to 9, wherein the chromatographic column used in the high performance liquid chromatography It is Phenomenex Luna Phenyl-Hexyl, the size is 150mm×4.6mm, 3μm.

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