Method for detecting degraded impurities in ezetimibe atorvastatin calcium tablets

Abstract

The invention discloses a method for detecting degraded impurities in ezetimibe atorvastatin calcium tablets, and belongs to the technical field of pharmaceutical analysis. The detection method comprises the following steps: mixing an acetic acid-ammonium acetate buffer solution with the concentration of 3.0-5.0 g / L and the pH value of 5.4-6.0 with acetonitrile to obtain a diluent; preparing a test sample solution by utilizing the diluent, and then determining the test sample solution by adopting a high performance liquid chromatography; chromatographic parameters are as follows: the sample introduction temperature is 2-8 DEG C; a chromatographic column takes phenylsilane bonded silica gel as a filling agent; a mobile phase A is a mixed solution of an acetic acid-ammonium acetate buffer solution and tetrahydrofuran, and a mobile phase B is a mixed solution of acetonitrile and tetrahydrofuran. The detection method disclosed by the invention can effectively control the increase of impurities in the solution, is high in specificity, high in precision and good in accuracy, and can effectively control the medicine quality of the ezetimibe atorvastatin calcium tablets.

Description

Technical Field

[0001] The present invention relates to the technical field of drug analysis, and in particular to a method for detecting degradation impurities in ezetimibe and atorvastatin calcium tablets. Background Art

[0002] The information disclosed in the background of the invention is only intended to enhance the understanding of the overall background of the invention and should not be necessarily regarded as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Ezetimibe and atorvastatin calcium tablets are compound tablets of ezetimibe and atorvastatin calcium, developed by Schering-Plough Corp. and approved by the U.S. FDA in 2008. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, and the target of ezetimibe is the sterol steroid Niemann-Pick C1-like 1 (NPC1L1). The two synergistically reduce the level of low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia. The two active ingredients of ezetimibe and atorvastatin calcium tablets have different mechanisms of action and are generally in the form of double-layer tablets, that is, the two active ingredients exist as separate entities in a single solid dosage form. The compound preparation has better efficacy and patient adaptability, and has broad market application prospects.

[0004] The structural formula of ezetimibe is shown below:

[0005]

[0006] The structural formula of atorvastatin calcium is shown below:

[0007]

[0008] The main degradation impurity produced by Ezetimibe in the forced degradation experiment is Ezetimibe impurity H, whose chemical name and structural formula are as follows:

[0009] Ezetimibe impurity H: (2R, 3R, 6S)-N, 6-bis(4-fluorophenyl)-2-(4-hydroxyphenyl)tetrahydro-2H-pyran-3-carboxamide, with the structural formula as follows:

[0010]

[0011] In the forced degradation experiment, atorvastatin calcium mainly produces the following six degradation impurities, namely atorvastatin lactone, atorvastatin lactam, diepoxy epoxide, hydroxyisopropyl epoxide, diketo epoxide and dihydroxy epoxide. Their chemical names and structural formulas refer to the import standard of ezetimibe atorvastatin calcium compound tablets (JX20230098), as follows:

[0012] Atorvastatin lactone: (4R, 6R)-6-[2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-carbamoyl-1H-pyrrol-1-yl]-ethyl]-4-hydroxytetrahydro-2H-pyran-2-one, the structural formula is as follows:

[0013]

[0014] Atorvastatin lactam: 7-[5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-phenyl-3-(phenylcarbamoyl)-2,3-dihydro-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid, with the following structural formula:

[0015]

[0016] Diepoxy epoxide: 7-(4-fluorophenyl)hexahydro-β,7-dihydroxy-1b-isopropyl-7a-phenyl-1a-phenylcarbamoyl-3H-oxiranyl[3,4]pyrrolo[2,1-b][1,3]oxazine-3-butyric acid, with the following structural formula:

[0017]

[0018] Hydroxyisopropyl epoxide: 1b-(4-fluorophenyl)hexahydro-β,7-dihydroxy-7-isopropyl-1a-phenyl-7a-phenylcarbamoyl-3H-epoxyvinyl[3,4]pyrrolo[2,1-b][1,3]oxazine-3-butyric acid, the structural formula is as follows:

[0019]

[0020] Diketo epoxide: 3-(4-fluorobenzoyl)-2-isobutyryl-N,3-diphenyloxirane-2-carboxamide, the structural formula is as follows:

[0021]

[0022] Dihydroxy epoxide: 4-(Fluorophenyl)-2,4-dihydroxy-2-isopropyl-N,5-diphenyl-3,6-dioxy-bicyclo[3.1.0]hexane-1-carboxamide, the structural formula is as follows:

[0023]

[0024] The method provided by the prior art for simultaneously determining the degradation impurities of ezetimibe tablets and atorvastatin calcium tablets is prone to causing an excessively rapid increase in the content of degradation impurities, thereby resulting in inaccurate test results; this is because ezetimibe and atorvastatin calcium interact with each other, ezetimibe accelerates the degradation of atorvastatin calcium, and the alkaline stabilizer required for the atorvastatin calcium layer accelerates the degradation of ezetimibe. Therefore, currently, the degradation impurities of ezetimibe tablets and atorvastatin calcium tablets are mostly detected separately, but separate detection increases the workload, prolongs the detection time and increases the detection cost.

[0025] Therefore, it is very necessary to provide a method with high accuracy and simple operation for simultaneously detecting ezetimibe degradation impurities and atorvastatin calcium degradation impurities in ezetimibe and atorvastatin calcium compound preparations. Summary of the invention

[0026] In view of this, the present invention provides a method for detecting degradation impurities in ezetimibe atorvastatin calcium tablets. The detection method of the present invention can effectively determine the degradation impurities of two active ingredients in ezetimibe atorvastatin calcium tablets, and the method has high sensitivity, good specificity, high precision, good accuracy, and the detection results are accurate and reliable.

[0027] In a first aspect, the present invention provides a method for detecting degradation impurities in ezetimibe atorvastatin calcium tablets, comprising the following steps:

[0028] Mixing acetic acid-ammonium acetate buffer solution with a concentration of 3.0 to 5.0 g / L and a pH of 5.4 to 6.0 with acetonitrile to obtain a diluent; preparing a test solution using the diluent, and then measuring the test solution by high performance liquid chromatography;

[0029] The chromatographic parameters were as follows: injection temperature was 2-8°C; the chromatographic column was filled with phenylsilane bonded silica gel; mobile phase A was a mixture of acetic acid-ammonium acetate buffer and tetrahydrofuran, and mobile phase B was a mixture of acetonitrile and tetrahydrofuran, with gradient elution.

[0030] The gradient elution procedure is as follows:

[0031] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 65～75 25～35 20 55～65 35～45 50 35～45 55～65 65 35～45 55～65 66 65～75 25～35 80 65～75 25～35

[0032] The degradation impurities are: ezetimibe impurity H of formula (I), diketo epoxide of formula (II), dihydroxy epoxide of formula (III), atorvastatin lactone of formula (IV), atorvastatin lactam of formula (V), diepoxy epoxide of formula (VI) and hydroxyisopropyl epoxide of formula (VII);

[0033]

[0034]

[0035] Preferably, the volume ratio of the acetic acid-ammonium acetate buffer to acetonitrile is (45-55):(45-55).

[0036] Furthermore, the concentration of the acetic acid-ammonium acetate buffer is 3.9 g / L, the pH value is 5.6, and the volume ratio of the acetic acid-ammonium acetate buffer to acetonitrile is 50:50.

[0037] Preferably, the volume fraction of tetrahydrofuran in the mobile phase A is 3-8%, the concentration of acetic acid-ammonium acetate buffer in the mobile phase A is 3.0-5.0 g / L, and the pH is 5.4-6.0; the volume fraction of tetrahydrofuran in the mobile phase B is 3-8%.

[0038] Furthermore, the volume fraction of tetrahydrofuran in the mobile phase A is 5%, the concentration of acetic acid-ammonium acetate buffer in the mobile phase A is 3.9 g / L, and the pH is 5.6; the volume fraction of tetrahydrofuran in the mobile phase B is 5%.

[0039] Preferably, the column temperature of the chromatographic column is 30-40° C., more preferably 35° C.; the detection wavelength is 239-249 nm, more preferably 244 nm.

[0040] Preferably, the gradient elution procedure is as follows:

[0041] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 70 30 20 60 40 50 40 60 65 40 60 66 70 30 80 70 30

[0042] The injection temperature was 5°C and the injection volume was 10 μL.

[0043] Preferably, the flow rate of the mobile phase A and the mobile phase B is 0.9-1.1 mL / min, more preferably 1.0 mL / min.

[0044] In a second aspect, the present invention provides a quality control method for ezetimibe atorvastatin calcium tablets, which is determined by the above-mentioned detection method.

[0045] Compared with the prior art, the present invention has achieved the following beneficial effects:

[0046] (1) The present invention has found in the previous detection research that the two active ingredients in the ezetimibe atorvastatin calcium tablets will interact with each other, ezetimibe will accelerate the degradation of atorvastatin calcium, and the alkaline stabilizer required for the atorvastatin calcium layer will accelerate the degradation of ezetimibe. The pH value of the solution prepared with a neutral diluent is weakly alkaline, and the ezetimibe impurity H increases significantly under alkaline conditions, while the atorvastatin impurity increases significantly under acidic conditions. Therefore, the present invention mixes acetic acid-ammonium acetate buffer with a concentration of 3.0-5.0 g / L and a pH of 5.4-5.8 with acetonitrile to obtain a diluent. The test solution prepared using the diluent is neutral, and the injection temperature of the present invention is 2-8°C. Therefore, the present invention can effectively control the growth of solution impurities, achieve the stability of the test solution, and achieve high repeatability and accuracy of impurity detection.

[0047] (2) The chromatographic conditions of the present invention can quickly and efficiently separate impurities and excipients in ezetimibe atorvastatin calcium tablets under the same chromatographic conditions, and the chromatographic conditions are simple and easy to operate.

[0048] (3) The HPLC method provided by the present invention can effectively separate and determine the content of ezetimibe atorvastatin calcium tablets and their degradation impurities. Through methodological verification, the detection method has strong specificity, high precision and good accuracy, and can effectively control the drug quality of ezetimibe atorvastatin calcium tablets. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] The drawings constituting part of the present invention are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their description are used to explain the present invention and do not constitute an improper limitation of the present invention. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative work.

[0050] Figure 1 This is a high performance liquid chromatogram of the blank auxiliary material in Example 1 of the present invention;

[0051] Figure 2 is a high performance liquid chromatogram of the mixed solution in Example 1 of the present invention;

[0052] Figure 3 The HPLC chromatogram of the test solution in Example 1 of the present invention is shown in FIG. DETAILED DESCRIPTION

[0053] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0054] Example 1 Selection of diluent and injection temperature

[0055] (1) Chromatographic conditions:

[0056] Chromatographic column: Phenyl bonded silica gel as filler (Synergi Polar-RP 4.6mm×250mm, 4μm);

[0057] UV detector (detection wavelength: 244 nm);

[0058] Mobile phase A: ammonium acetate solution (3.9 g / L ammonium acetate solution, pH adjusted to 5.6 with glacial acetic acid)-tetrahydrofuran (950 / 50);

[0059] Mobile phase B: acetonitrile-tetrahydrofuran (950 / 50);

[0060] Injection volume: 10 μl; column temperature: 35°C; flow rate: 1.0 ml / min;

[0061] Perform gradient elution according to Table 1:

[0062] Table 1 Gradient elution program

[0063] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 70 30 20 60 40 50 40 60 65 40 60 66 70 30 80 70 30

[0064] (2) Solution preparation:

[0065] Test solution: Take an appropriate amount of ezetimibe and atorvastatin calcium tablets, grind them into powder, take an appropriate amount of fine powder (equivalent to 10 mg of ezetimibe), accurately weigh it, put it in a 10 mL volumetric flask, add an appropriate amount of diluent, dissolve ezetimibe and atorvastatin calcium by ultrasound, cool, dilute to the scale with diluent, shake well, filter, and take the filtrate as the test solution.

[0066] The test results of different diluents and injection temperatures are shown in Table 2. The room temperature in Table 2 refers to 30°C, and the acetic acid-ammonium acetate buffer solution is prepared by adjusting 3.9 g / L ammonium acetate aqueous solution with glacial acetic acid.

[0067] Table 2 Test results of different diluents and injection temperatures

[0068]

[0069] As can be seen from Table 2, when the sample was injected at room temperature, the degradation of diketo epoxide was obvious, while the growth rate of degradation impurities slowed down when injected at 5°C, so the injection temperature of 5°C was selected in the subsequent experiments. When the diluent was acetonitrile / water (50 / 50), the pH value of the test solution was close to 8.0, which was weakly alkaline, and ezetimibe was unstable in alkalinity, and the impurity H of ezetimibe increased significantly; when the diluent was acetonitrile / acetic acid-ammonium acetate buffer (pH values ​​of 5.0, 5.6, and 6.0), the pH values ​​of the test solution were 6.3, 6.9, and 7.3, respectively. Through the comparison of relevant data, when the pH value of acetic acid-ammonium acetate buffer was 5.6, the degradation impurities in the test solution were optimal, and the diluent was finally set as acetonitrile / acetic acid-ammonium acetate buffer (pH value of 5.6) (50 / 50) for subsequent experiments.

[0070] Example 2 Methodology Verification

[0071] 1. Specificity test

[0072] Diluent: Adjust the pH of 3.9 g / L ammonium acetate aqueous solution to 5.6 with glacial acetic acid, and then mix with acetonitrile in a volume ratio of 50:50.

[0073] Test solution: Take an appropriate amount of fine powder (equivalent to approximately 10 mg of ezetimibe), accurately weigh it, place it in a 10 mL volumetric flask, add an appropriate amount of diluent, sonicate to dissolve ezetimibe and atorvastatin calcium, cool, dilute to the scale with diluent, shake well, filter, and take the filtrate as the test solution.

[0074] Control solution: Accurately measure 1 mL of the test solution, place it in a 50 mL volumetric flask, dilute it to the mark with diluent, shake well, accurately measure 5 mL, place it in a 50 mL volumetric flask, dilute it to the mark with diluent, shake well, as the control solution.

[0075] Sensitivity solution: Accurately measure 2 mL of the control solution, place it in a 10 mL volumetric flask, dilute to the scale with diluent, shake well, and use it as the sensitivity solution.

[0076] System suitability solution: Take an appropriate amount of fine powder, ezetimibe impurity H, atorvastatin lactam, atorvastatin lactone, diepoxy epoxide, hydroxyisopropyl epoxide, dihydroxy epoxide and diketo epoxide, dissolve and dilute with diluent to make a mixed solution containing approximately 1 mg of ezetimibe, 2 mg of atorvastatin and 2 μg of each impurity per 1 mL, shake well and use as the system suitability solution.

[0077] Mixed solution: Take an appropriate amount of fine powder of the preparation (equivalent to approximately 10 mg of ezetimibe), accurately weigh it, place it in a 10 mL volumetric flask, add an appropriate amount of diluent, shake it ultrasonically to dissolve it, accurately add 0.5 mL of each impurity stock solution, dilute it to the scale with diluent, shake well, take an appropriate amount of solution, filter it, and take the filtrate as the mixed solution.

[0078] Blank excipient solution: Take about 375 mg of blank excipient in the prescription ratio, accurately weigh it, put it in a 10 mL volumetric flask, add an appropriate amount of diluent, sonicate and dilute to the scale, shake well, filter, and take the filtrate as the blank excipient solution.

[0079] Accurately measure 10 μl of each of the above solutions, inject into liquid chromatograph, and record the chromatogram.

[0080] Table 3 Results of peak location test on degradation impurities in Ezetimibe Atorvastatin Calcium Tablets

[0081]

[0082] The test results show that the impurity peaks are well separated and the solvents and excipients do not interfere with the determination of impurities.

[0083] 2. Sensitivity test

[0084] Take appropriate amounts of ezetimibe impurity H, atorvastatin lactam, atorvastatin lactone, diepoxy epoxide, hydroxyisopropyl epoxide, dihydroxy epoxide and diketo epoxide, and set the S / N (signal-to-noise ratio) ≈ 10 as the quantification limit, and the S / N (signal-to-noise ratio) ≈ 3 as the detection limit.

[0085] Table 4 Results of quantitative limit and detection limit test for degradation impurities in Ezetimibe and Atorvastatin Calcium Tablets

[0086]

[0087]

[0088] The test results show that the limits of each impurity / limit of quantitation are greater than 3, and the detection sensitivity of this method is good.

[0089] 3. Linearity test

[0090] Take appropriate amounts of ezetimibe, ezetimibe impurity H, atorvastatin calcium, atorvastatin lactam, atorvastatin lactone, diepoxy epoxide, hydroxyisopropyl epoxide, dihydroxy epoxide and diketo epoxide, dissolve in solvent and dilute to 0.04%, 0.08%, 0.16%, 0.2%, 0.4%, 1.2% linear concentration solutions. Accurately measure 10 μl of each of the solvent and the above solutions, inject into the liquid chromatograph, record the chromatogram, and perform linear regression of the peak area with the concentration.

[0091] Table 5 Linearity test results of degradation impurities in Ezetimibe Atorvastatin Calcium Tablets

[0092]

[0093]

[0094] The test results show that the correlation coefficient of each impurity in the concentration range of 0.4μg / ml to 12μg / ml is r≥0.99, the ratio of intercept to 100% response value is ≤25%, and the linear relationship is good.

[0095] 4. Stability test

[0096] Take an appropriate amount of fine powder of this product (equivalent to approximately 10 mg of ezetimibe), accurately weigh it, place it in a 10 ml volumetric flask, add an appropriate amount of solvent, sonicate to dissolve ezetimibe and atorvastatin calcium, cool, dilute to the scale with solvent, shake well, filter, and take the filtrate as the test solution.

[0097] Accurately measure 1 ml of the test solution, place it in a 50 ml volumetric flask, dilute it to the mark with solvent, shake well, accurately measure 5 ml, place it in a 50 ml volumetric flask, dilute it to the mark with solvent, shake well, as the control solution.

[0098] Place the test solution and the control solution under low temperature conditions for 24 hours. Accurately measure 10 μl at 0 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours, inject into the liquid chromatograph, and record the chromatogram.

[0099] Table 6 Stability test results of degradation impurities in Ezetimibe Atorvastatin Calcium Tablets - test solution

[0100]

[0101] The test results show that when the test solution is placed under low temperature conditions for 24 hours, the impurities have a slight growth trend, and the extreme differences are all less than 0.05%. The test solution is basically stable when placed under low temperature conditions for 24 hours.

[0102] Table 7 Stability test results of degradation impurities in Ezetimibe Atorvastatin Calcium Tablets - Control solution

[0103]

[0104]

[0105] The test results show that when the control solution was placed under low temperature conditions for 24 hours, the response value recoveries of ezetimibe and atorvastatin were both within the range of 98% to 101%, and there was no obvious degradation trend, and they were basically stable.

[0106] 5. Accuracy test

[0107] Impurity stock solution 1: Take about 1 mg of ezetimibe impurity H, accurately weigh it, place it in the same 25 ml volumetric flask, dissolve it with solvent and dilute it to the scale, shake well, and obtain it.

[0108] Impurity stock solution 2: Take about 1 mg each of atorvastatin lactone and atorvastatin lactam, weigh accurately, place in the same 25 ml volumetric flask, dissolve and dilute to the scale with solvent, shake well, and obtain.

[0109] Impurity stock solution 3: Take about 1 mg of diketo epoxide, weigh accurately, place in the same 25 ml volumetric flask, dissolve and dilute to the scale with solvent, shake well, and obtain.

[0110] Impurity stock solution 4: Take about 1 mg each of diepoxy epoxide and hydroxyisopropyl epoxide, accurately weigh, place in the same 25 ml volumetric flask, dissolve and dilute to the scale with solvent, shake well, and obtain.

[0111] Impurity stock solution 5: Take about 2 mg of dihydroxy epoxide, weigh accurately, place in a 50 ml volumetric flask, dissolve and dilute to the scale with solvent, shake well, and obtain.

[0112] Impurity stock solution 6: Take about 4 mg of ezetimibe impurity H, accurately weigh it, place it in the same 100 ml volumetric flask, dissolve it with solvent and dilute it to the scale, shake well, and obtain.

[0113] Impurity stock solution 7: Take about 4 mg of diketo epoxide, weigh accurately, place in the same 100 ml volumetric flask, dissolve and dilute to the scale with solvent, shake well, and obtain.

[0114] Impurity stock solution 8: Take about 4 mg of dihydroxy epoxide, weigh accurately, place in a 100 ml volumetric flask, dissolve and dilute to the scale with solvent, shake well, and obtain.

[0115] Impurity stock solution 9: Take about 2 mg each of atorvastatin lactone, atorvastatin lactam, diepoxy epoxide and hydroxyisopropyl epoxide, accurately weigh, place in a 50 ml volumetric flask, dissolve and dilute to the scale with solvent, shake well, and obtain.

[0116] Take an appropriate amount of fine powder of the preparation (10mg / 20mg) (equivalent to approximately 20mg of ezetimibe), accurately weigh it, place it in a 20ml volumetric bottle, add an appropriate amount of solvent to dissolve ezetimibe and atorvastatin calcium, accurately add the volume of each impurity reference substance stock solution as shown in the figure below, dilute to the scale with solvent, shake well, filter, and you are done. Prepare three copies in the same way. The accuracy of the study on degradation impurities of ezetimibe and atorvastatin calcium tablets is shown in Tables 8 to 12.

[0117] Table 8 Accuracy test results of degradation impurities in Ezetimibe Atorvastatin Calcium Tablets-1

[0118]

[0119] Accurately measure 1 ml of each of impurity stock solution 1, impurity stock solution 2, impurity stock solution 3, impurity stock solution 4, and impurity stock solution 5, place them in the same 20 ml volumetric flask, dilute to the mark with solvent, shake well, and use them as reference solution 1; accurately measure 1 ml of each of impurity stock solution 6, impurity stock solution 7, impurity stock solution 8, and impurity stock solution 9, place them in the same 20 ml volumetric flask, dilute to the mark with solvent, shake well, and use them as reference solution 2. Determine in the same way and record the chromatogram. Calculate the measured amount (μg) by peak area according to the external standard method. The ratio of the measured amount to the input amount is the recovery rate (%).

[0120] Table 9 Accuracy test results of degradation impurities in Ezetimibe Atorvastatin Calcium Tablets-2

[0121]

[0122]

[0123] Table 10 Accuracy test results of degradation impurities in Ezetimibe Atorvastatin Calcium Tablets-3

[0124]

[0125] Table 11 Accuracy test results of degradation impurities in Ezetimibe Atorvastatin Calcium Tablets-4

[0126]

[0127]

[0128] Table 12 Accuracy test results of degradation impurities in Ezetimibe Atorvastatin Calcium Tablets-5

[0129]

[0130] Note: The input amount in Tables 9 to 12 is the sum of the sample content and the actual added amount.

[0131] The test results show that the average recovery rate of each impurity determined by the established method is in the range of 90% to 108%, with good recovery rate and high accuracy.

[0132] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for detecting degradation impurities in ezetimibe atorvastatin calcium tablets, characterized in that: The steps include: Mixing acetic acid-ammonium acetate buffer solution with a concentration of 3.0 to 5.0 g / L and a pH of 5.4 to 6.0 with acetonitrile to obtain a diluent; preparing a test solution using the diluent, and then measuring the test solution by high performance liquid chromatography; The chromatographic parameters are as follows: injection temperature is 2-8°C; the chromatographic column is filled with phenylsilane bonded silica gel; mobile phase A is a mixture of acetic acid-ammonium acetate buffer and tetrahydrofuran, and mobile phase B is a mixture of acetonitrile and tetrahydrofuran, with gradient elution; The gradient elution procedure is as follows: The degradation impurities are: ezetimibe impurity H of formula (I), diketo epoxide of formula (II), dihydroxy epoxide of formula (III), atorvastatin lactone of formula (IV), atorvastatin lactam of formula (V), diepoxy epoxide of formula (VI) and hydroxyisopropyl epoxide of formula (VII); 2. The detection method according to claim 1, characterized in that The volume ratio of the acetic acid-ammonium acetate buffer to acetonitrile is (45-55):(45-55).

3. The detection method according to claim 2, characterized in that The concentration of the acetic acid-ammonium acetate buffer solution is 3.9 g / L, the pH value is 5.6, and the volume ratio of the acetic acid-ammonium acetate buffer solution to acetonitrile is 50:

50.

4. The detection method according to claim 1, characterized in that The volume fraction of tetrahydrofuran in the mobile phase A is 3-8%, the concentration of acetic acid-ammonium acetate buffer in the mobile phase A is 3.0-5.0 g / L, and the pH is 5.4-6.0; the volume fraction of tetrahydrofuran in the mobile phase B is 3-8%.

5. The detection method according to claim 4, characterized in that: The volume fraction of tetrahydrofuran in the mobile phase A is 5%, the concentration of acetic acid-ammonium acetate buffer in the mobile phase A is 3.9 g / L, and the pH is 5.6; the volume fraction of tetrahydrofuran in the mobile phase B is 5%.

6. The detection method according to claim 1, characterized in that The column temperature of the chromatographic column is 30-40°C; the detection wavelength is 239-249 nm.

7. The detection method according to claim 6, characterized in that The column temperature of the chromatographic column was 35°C; the detection wavelength was 244 nm.

8. The detection method according to claim 1, characterized in that The gradient elution procedure is as follows: The injection temperature was 5°C and the injection volume was 10 μL.

9. The detection method according to claim 1, characterized in that: The flow rates of the mobile phase A and the mobile phase B are 0.9-1.1 mL / min.

10. A quality control method for ezetimibe atorvastatin calcium tablets, characterized in that: The determination is carried out using the detection method described in any one of claims 1 to 9.

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