Ezetimibe rosuvastatin calcium tablet related substance determination method

Abstract

The invention relates to the technical field of pharmaceutical analysis, in particular to a method for determining related substances of ezetimibe rosuvastatin calcium tablets, impurities of the ezetimibe rosuvastatin calcium tablets are determined by high performance liquid chromatography, a chromatographic column filler is octadecylsilane chemically bonded silica, a mobile phase A is 0.08-0.12% phosphoric acid aqueous solution, a mobile phase B is a mobile phase C, a mobile phase D is a mobile phase C, a mobile phase D is a mobile phase C, and a mobile phase D is a mobile phase C; the volume ratio of the mobile phase B acetonitrile to the mobile phase B methanol is (92-98): (8-2); the flow velocity is 0.9-1.1 ml per minute, the column temperature is 30-40 DEG C, the detection wavelength is 240-244nm, and the temperature of a sample disc is 5 DEG C; the sample injection volume is 5 microliters. According to the determination method disclosed by the invention, process impurities and degradation impurities of ezetimibe and rosuvastatin calcium can be detected by adopting the same method, and the method is high in accuracy, good in stability, strong in durability, high in detection efficiency and low in cost.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical analysis, and particularly relates to a method for determining related substances in ezetimibe rosuvastatin calcium tablets. Background Art

[0002] Ezetimibe rosuvastatin calcium film-coated tablets (English name: Ezetimibe Rosuvastatin Calcium Film-Coated Tablets) is a compound preparation of ezetimibe and rosuvastatin calcium. Ezetimibe is a potent lipid-lowering drug. After oral administration, it is rapidly absorbed and extensively conjugated into a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide), and its structure is shown as follows:

[0003]

[0004] Rosuvastatin calcium is a selective HMG-CoA reductase inhibitor. Ezetimibe rosuvastatin calcium tablets is a lipid-lowering drug with dual effects, and can be used to treat chronic diseases caused by excessive blood lipids, such as fat, cholesterol and triglycerides. Currently, it is on the market in countries such as Japan (license holder: Merck Sharp & Dohme), the Czech Republic (license holder: Sanofi), and Poland, and its structure is shown as follows:

[0005]

[0006] To ensure the quality of drugs and the safety of clinical medication, it is necessary to study the impurities in drugs. This product has not been included in any national pharmacopoeia. There are many impurities related to rosuvastatin calcium and ezetimibe. Table 1 is a statistical table of process impurities and degradation impurities in ezetimibe rosuvastatin calcium tablets. Existing reports all determine the related substances of single components, and the chromatographic conditions are complex and the methods are cumbersome. The stabilities of the two components of this product are inconsistent in the solution state, and there is no literature report on accurately attributing and controlling the impurities in the same method.

[0007] Table 1 Statistical Table of Impurities in Ezetimibe Rosuvastatin Calcium Tablets

[0008] Summary of the Invention

[0009] The purpose of the present invention is to overcome the deficiencies of the prior art and establish a method for determining related substances in ezetimibe rosuvastatin calcium tablets. This determination method can meet the separation of process impurities and degradation impurities of ezetimibe and rosuvastatin calcium, and can accurately detect the impurities of ezetimibe and rosuvastatin calcium by using the same treatment method.

[0010] The present invention provides a method for determining related substances in ezetimibe rosuvastatin calcium tablets, including:

[0011] Determine the impurities in ezetimibe and rosuvastatin calcium tablets by high performance liquid chromatography;

[0012] The chromatographic column packing material is octadecylsilyl silica gel;

[0013] Mobile phase A is an aqueous solution of 0.08% - 0.12% phosphoric acid, and mobile phase B is a mixture of acetonitrile and methanol with a volume ratio of 92 - 98:8 - 2, for gradient elution;

[0014] The flow rate is 0.9 - 1.1 ml per minute; the column temperature is 30 - 40 °C; the detection wavelength is 240 - 244 nm;

[0015] The sample tray temperature is 5 °C; the injection volume is 5 μl.

[0016] In some embodiments, the chromatographic column is XBrige Shield RP18, 150 mm × 4.6 mm, with a particle size of 3.5 μm.

[0017] In some embodiments, mobile phase A is an aqueous solution of 0.1% phosphoric acid; mobile phase B is a mixture of acetonitrile and methanol with a volume ratio of 95:5.

[0018] In some embodiments, the gradient elution program is as follows:

[0019] Time (min) Mobile Phase A (%) Mobile Phase B (%) 0 65 35 12 65 35 25 45 55 40 45 55 40.1 65 35 45 65 35 。

[0020] In some embodiments, the flow rate is 1 ml per minute.

[0021] In some embodiments, the column temperature is 35 °C.

[0022] In some embodiments, the detection wavelength is 242 nm.

[0023] In some embodiments, the impurities are impurities A, B, C, D, E, F, G, and their structures are as follows:

[0024]

[0025] In some embodiments, the method for determining the impurities in ezetimibe and rosuvastatin calcium tablets includes preparing a mixed impurity stock solution and a system suitability solution;

[0026] Mixed impurity stock solution: Respectively take impurity reference substances of A, B, C, D, E, F, and G and dissolve them with a solvent to prepare it;

[0027] System suitability solution: Take ezetimibe and rosuvastatin calcium tablets, disperse them with a solvent, add the above mixed impurity stock solution, and add a solvent to prepare it.

[0028] In some embodiments, the solvent is acetonitrile and water, and the volume ratio of acetonitrile to water is 80:20.

[0029] Beneficial effects:

[0030] The method for determining related substances of ezetimibe and rosuvastatin calcium tablets established in the present invention can detect the impurities of ezetimibe and rosuvastatin calcium by the same method, with high accuracy, good stability, strong durability, high detection efficiency and low cost. Brief description of the drawings

[0031] In order to more clearly illustrate the technical solutions of the present application, the drawings required for use in the embodiments will be briefly introduced below. Obviously, for those of ordinary skill in the art, other drawings can also be obtained based on these drawings without creative efforts.

[0032] Figure 1 It is the system suitability chromatogram of related substances of ezetimibe and rosuvastatin calcium tablets;

[0033] Figure 2 It is the system suitability chromatogram of related substances of ezetimibe and rosuvastatin calcium tablets at a flow rate of 0.9 ml / min;

[0034] Figure 3 It is the system suitability chromatogram of related substances of ezetimibe and rosuvastatin calcium tablets at a flow rate of 1.1 ml / min;

[0035] Figure 4 It is the system suitability chromatogram of related substances of ezetimibe and rosuvastatin calcium tablets at a column temperature of 30 °C;

[0036] Figure 5 It is the system suitability chromatogram of related substances of ezetimibe and rosuvastatin calcium tablets at a column temperature of 40 °C;

[0037] Figure 6 It is the system suitability chromatogram of related substances of ezetimibe and rosuvastatin calcium tablets with mobile phase A being 0.08% phosphoric acid aqueous solution;

[0038] Figure 7 It is the system suitability chromatogram of related substances of ezetimibe and rosuvastatin calcium tablets with mobile phase A being 0.12% phosphoric acid aqueous solution;

[0039] Figure 8 It is the system suitability chromatogram of related substances of ezetimibe and rosuvastatin calcium tablets with mobile phase B being acetonitrile - methanol (92:8, v / v);

[0040] Figure 9 It is the system suitability chromatogram of related substances of ezetimibe and rosuvastatin calcium tablets with mobile phase B being acetonitrile - methanol (98:2, v / v);

[0041] Figure 10 System suitability chromatogram of impurities in ezetimibe and rosuvastatin calcium tablets at a wavelength of 240 nm;

[0042] Figure 11 System suitability chromatogram of impurities in ezetimibe and rosuvastatin calcium tablets at a wavelength of 244 nm. Detailed implementation manners

[0043] To enable those skilled in the art to understand the features and effects of the present invention, the following provides a general description and definition of the terms and phrases mentioned in the specification and claims. Unless otherwise specified, all technical and scientific terms used herein shall have the ordinary meaning understood by those skilled in the art with respect to the present invention. In case of conflict, the definition in this specification shall prevail.

[0044] The theories or mechanisms described and disclosed herein, whether right or wrong, shall not in any way limit the scope of the present invention, that is, the content of the present invention can be implemented without being limited by any specific theory or mechanism.

[0045] In this article, all features defined in the form of numerical ranges or percentage ranges, such as numerical values, quantities, contents, and concentrations, are only for the sake of brevity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be regarded as having covered and specifically disclosed all possible sub-ranges and individual numerical values within the range (including integers and fractions).

[0046] In this article, for the sake of concise description, all possible combinations of all technical features in each embodiment or example are not described. Therefore, as long as there is no contradiction in the combination of these technical features, the technical features in each embodiment or example can be combined arbitrarily, and all possible combinations should be considered as the scope described in this specification.

[0047] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

[0048] Conventional instrument and equipment in the art are used in the following embodiments. For the experimental methods without specific conditions indicated in the following embodiments, they are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Various raw materials are used in the following embodiments. Unless otherwise stated, commercially available products are used, and their specifications are conventional specifications in the art. In the specification of the present invention and the following embodiments, unless otherwise specified, "%" represents weight percentage, "parts" represents weight parts, and ratios represent weight.

[0049] The following further describes a method for determining related substances of ezetimibe and rosuvastatin calcium tablets provided by this application in combination with specific embodiments.

[0050] Example 1:

[0051] 1. Chromatographic conditions

[0052] Chromatographic column: XBrige Shield RP18 (150 mm × 4.6 mm, 3.5 μm);

[0053] Mobile phase A: 0.1% phosphoric acid aqueous solution, mobile phase B: acetonitrile - methanol (95:5, v / v)

[0054] Column temperature: 35°C; Detection wavelength: 242 nm;

[0055] Flow rate: 1 ml / min; Sample tray temperature: 5°C; Injection volume: 5 μl

[0056] Gradient program: As shown in Table 2.

[0057] Table 2 Gradient elution program table

[0058] Time (min) Mobile Phase A (%) Mobile Phase B (%) 0 65 35 12 65 35 25 45 55 40 45 55 40.1 65 35 45 65 35

[0059] 2. Solution preparation

[0060] Solvent: Take 800 ml of acetonitrile and 200 ml of water, mix well, and ultrasonically degas.

[0061] Mixed impurity stock solution: Accurately weigh about 20 mg of each of the impurity reference substances A, B, C, D, E, F, and G, place them in the same 100 ml volumetric flask, dissolve and dilute to the scale with the solvent by ultrasonic treatment, and shake well; accurately measure 5 ml of this solution, place it in a 50 ml volumetric flask, and dilute to the scale with the solvent, and shake well to obtain.

[0062] System suitability solution: Take 5 tablets of this product, place them in a 50 ml volumetric flask, add an appropriate amount of solvent (about 70% of the volumetric flask volume), ultrasonically disperse for 30 minutes, take out, accurately add 5 ml of the mixed impurity stock solution, and dilute to the scale with the solvent, and shake well to obtain.

[0063] 3. Results

[0064] The chromatogram for determining related substances of ezetimibe and rosuvastatin calcium tablets is as Figure 1 shown. It can be seen from Table 3 that the resolution of process impurities and degradation impurities of ezetimibe and rosuvastatin calcium is good, and the impurities of ezetimibe and rosuvastatin calcium can be detected by the same method.

[0065] Table 3 Related substances table of ezetimibe and rosuvastatin calcium tablets

[0066] Name Retention Time / min Resolution 9.655 Rosuvastatin 11.569 5.68 Impurity A 12.485 2.24 Impurity B 16.242 9.45 Impurity C 17.055 2.31 Impurity D 17.678 1.90 Impurity E 19.945 8.02 20.537 2.89 21.006 2.54 Ezetimibe 22.352 9.42 Impurity F 24.901 10.02 Impurity G 26.367 6.70 27.024 3.08

[0067] Example 2:

[0068] 1. The flow rate is 0.9 ml / min, and other conditions are the same as those in Example 1.

[0069] 2. Results

[0070] The chromatogram of related substances determination of ezetimibe and rosuvastatin calcium tablets is shown in Figure 2, and its related substances and resolution are shown in Table 4. It can be concluded that the resolution of process impurities and degradation impurities of ezetimibe and rosuvastatin calcium is good, and the impurities of ezetimibe and rosuvastatin calcium can be detected by the same method.

[0071] Table 4 Related substances of ezetimibe and rosuvastatin calcium tablets with a flow rate of 0.9 ml / min

[0072] Name Retention Time / min Resolution 9.799 Rosuvastatin 11.752 5.70 Impurity A 12.671 2.23 Impurity B 16.427 9.44 Impurity C 17.212 2.26 Impurity D 17.820 1.87 Impurity E 20.106 7.80 Ezetimibe 22.466 9.39 Impurity F 25.014 1.11 Impurity G 26.472 6.52 27.111 3.13

[0073] Example 3:

[0074] 1. The flow rate is 1.1 ml / min, and other conditions are the same as those in Example 1.

[0075] 2. Results

[0076] The chromatogram of related substances determination of ezetimibe and rosuvastatin calcium tablets is shown in Figure 3, and its related substances and resolution are shown in Table 5. It can be concluded that the resolution of process impurities and degradation impurities of ezetimibe and rosuvastatin calcium is good, and the impurities of ezetimibe and rosuvastatin calcium can be detected by the same method.

[0077] Table 5 Related substances of ezetimibe and rosuvastatin calcium tablets with a flow rate of 1.1 ml / min

[0078] Name Retention Time / min Resolution Rosuvastatin 10.661 Impurity A 11.518 1.63 Impurity B 15.140 6.48 Impurity C 15.767 1.24 Impurity D 16.686 1.93 Impurity E 18.846 5.07 19.807 1.92 Ezetimibe 21.244 3.07 Impurity F 23.545 7.37 Impurity G 25.205 5.53 28.439 9.04 32.327 1.08

[0079] Example 4:

[0080] 1. The column temperature is 30 °C, and other conditions are the same as those in Example 1.

[0081] 2. Results

[0082] The chromatogram of related substances determination of ezetimibe and rosuvastatin calcium tablets is shown in Figure 4, and its related substances and resolution are shown in Table 6. It can be concluded that the resolution of process impurities and degradation impurities of ezetimibe and rosuvastatin calcium is good, and the impurities of ezetimibe and rosuvastatin calcium can be detected by the same method.

[0083] Table 6 Related substances of ezetimibe and rosuvastatin calcium tablets with a column temperature of 30 °C

[0084] Name Retention Time / min Resolution Rosuvastatin 16.698 Impurity A 17.553 2.69 18.965 4.95 Impurity B 19.955 3.88 Impurity C 20.422 1.99 Impurity D 20.918 2.20 22.096 5.40 Impurity E 22.520 6.83 23.095 2.36 Ezetimibe 24.488 5.04 Impurity F 26.578 10.62 26.941 1.80 Impurity G 27.893 4.57 28.512 2.74

[0085] Example 5:

[0086] 1. The column temperature was 40°C, and other conditions were the same as those in Example 1.

[0087] 2. Results

[0088] The chromatogram of related substances determination of ezetimibe and rosuvastatin calcium tablets is shown in Figure 5, and the related substances and their resolution are shown in Table 7. It can be concluded that the resolution of process impurities and degradation impurities of ezetimibe and rosuvastatin calcium is good, and the impurities of ezetimibe and rosuvastatin calcium can be detected by the same method.

[0089] Table 7 Related substances of ezetimibe and rosuvastatin calcium tablets at column temperature of 40°C

[0090] Name Retention Time / min Resolution Rosuvastatin 10.249 Impurity A 11.013 2.14 13.105 5.20 Impurity B 14.619 3.45 Impurity C 15.533 2.09 Impurity D 16.365 2.09 18.336 5.70 Impurity E 18.981 6.81 Ezetimibe 21.817 5.13 22.873 3.77 Impurity F 24.685 6.68 25.145 1.88 Impurity G 26.359 5.05

[0091] Example 6:

[0092] 1. Mobile phase A was 0.08% phosphoric acid aqueous solution, and other conditions were the same as those in Example 1.

[0093] 2. Results

[0094] The chromatogram of related substances determination of ezetimibe and rosuvastatin calcium tablets is shown in Figure 6, and the related substances and their resolution are shown in Table 8. It can be concluded that the resolution of process impurities and degradation impurities of ezetimibe and rosuvastatin calcium is good, and the impurities of ezetimibe and rosuvastatin calcium can be detected by the same method.

[0095] Table 8 Related substances of ezetimibe and rosuvastatin calcium tablets with mobile phase A being 0.08% phosphoric acid aqueous solution

[0096]

[0097]

[0098] Example 7:

[0099] 1. Mobile phase A was 0.12% phosphoric acid aqueous solution, and other conditions were the same as those in Example 1.

[0100] 2. Results

[0101] The chromatogram of related substances determination of ezetimibe and rosuvastatin calcium tablets is shown in Figure 7, and the related substances and their resolution are shown in Table 9. It can be concluded that the resolution of process impurities and degradation impurities of ezetimibe and rosuvastatin calcium is good, and the impurities of ezetimibe and rosuvastatin calcium can be detected by the same method.

[0102] Table 9 Related Substances Table of Ezetimibe and Rosuvastatin Calcium Tablets with Mobile Phase A as 0.12% Aqueous Phosphoric Acid Solution

[0103] Name Retention Time / min Resolution 9.747 Rosuvastatin 11.666 5.36 Impurity A 12.599 2.35 14.411 4.50 Impurity B 16.352 5.31 Impurity C 17.169 2.44 Impurity D 17.778 1.98 Impurity E 20.027 8.16 20.608 2.20 21.074 1.57 Ezetimibe 22.422 5.01 23.334 4.16 Impurity F 24.963 7.61 Impurity G 26.429 7.14 26.831 1.77

[0104] Example 8:

[0105] 1. Mobile phase B is acetonitrile - methanol (92:8, v / v), and other conditions are the same as those in Example 1.

[0106] 2. Results

[0107] The chromatogram of related substances of ezetimibe and rosuvastatin calcium tablets is shown in Figure 8, and its related substances and resolution are shown in Table 10. It can be concluded that the resolution of process impurities and degradation impurities of ezetimibe and rosuvastatin calcium is good, and the impurities of ezetimibe and rosuvastatin calcium can be detected by the same method.

[0108] Table 10 Related Substances Table of Ezetimibe and Rosuvastatin Calcium Tablets with Mobile Phase B as Acetonitrile - Methanol (92:8, v / v)

[0109]

[0110]

[0111] Example 9:

[0112] 1. Mobile phase B is acetonitrile - methanol (98:2, v / v), and other conditions are the same as those in Example 1.

[0113] 2. Results

[0114] The chromatogram of related substances of ezetimibe and rosuvastatin calcium tablets is shown in Figure 9, and its related substances and resolution are shown in Table 11. It can be concluded that the resolution of process impurities and degradation impurities of ezetimibe and rosuvastatin calcium is good, and the impurities of ezetimibe and rosuvastatin calcium can be detected by the same method.

[0115] Table 11 Related Substances Table of Ezetimibe and Rosuvastatin Calcium Tablets with Mobile Phase B as Acetonitrile - Methanol (98:2, v / v)

[0116] Name Retention Time / min Resolution 9.472 Rosuvastatin 11.320 5.37 Impurity A 12.207 2.30 13.987 3.17 Impurity B 15.938 3.62 Impurity C 16.831 2.54 Impurity D 17.422 1.84 Impurity E 19.790 8.36 20.373 2.24 20.833 1.62 Ezetimibe 22.195 5.18 23.121 4.16 Impurity F 24.782 7.63 Impurity G 26.240 7.05 26.608 1.70

[0117] Example 10:

[0118] 1. The wavelength is 240 nm, and other conditions are the same as those in Example 1.

[0119] 2. Results

[0120] The chromatogram for the determination of related substances of ezetimibe and rosuvastatin calcium tablets is shown in Figure 10, and the related substances and their resolution are shown in Table 12. It can be concluded that the resolution of process impurities and degradation impurities of ezetimibe and rosuvastatin calcium is good, and the impurities of ezetimibe and rosuvastatin calcium can be detected by the same method.

[0121] Table 12 Related Substances of Ezetimibe and Rosuvastatin Calcium Tablets at a Wavelength of 240 nm

[0122] Name Retention Time / min Resolution 9.678 Rosuvastatin 11.586 5.69 Impurity A 12.502 2.28 Impurity B 16.268 9.66 Impurity C 17.080 2.39 Impurity D 17.699 1.95 Impurity E 19.962 8.04 21.012 3.76 Ezetimibe 22.374 5.24 Impurity F 24.922 1.18 Impurity G 26.389 7.02

[0123] Example 11:

[0124] 1. The wavelength is 244 nm, and other conditions are the same as those in Example 1.

[0125] 2. Results

[0126] The chromatogram for the determination of related substances of ezetimibe and rosuvastatin calcium tablets is shown in Figure 11, and the related substances and their resolution are shown in Table 13. It can be concluded that the resolution of process impurities and degradation impurities of ezetimibe and rosuvastatin calcium is good, and the impurities of ezetimibe and rosuvastatin calcium can be detected by the same method.

[0127] Table 13 Related Substances of Ezetimibe and Rosuvastatin Calcium Tablets at a Wavelength of 240 nm

[0128] Name Retention Time / min Resolution 9.682 Rosuvastatin 11.586 5.65 Impurity A 12.504 2.30 Impurity B 16.269 9.66 Impurity C 17.077 2.38 Impurity D 17.699 1.98 Impurity E 19.962 8.07 21.025 3.86 Ezetimibe 22.374 5.27 Impurity F 24.922 1.18 Impurity G 26.389 6.99 42.516 2.01

[0129] Comparative Example 1:

[0130] 1. Other conditions are the same as those in Example 1, and the stability of the test sample at room temperature and 5 °C is tested.

[0131] 2. Results

[0132] The sample stability, that is, the change of each impurity content with time, is shown in Table 14. It can be seen from Table 14 that at room temperature, after 18 h, impurities E and F are unstable; while at 5 °C, all impurities are still stable after 72 h. Therefore, setting the sample tray at 5 °C of the present invention can improve the stability of the sample solution and can more effectively inhibit the degradation of impurities E and F.

[0133] Table 14 Comparison Table of the Stability of Spiked Test Samples at Room Temperature and 5 °C (Area Normalization Method)

[0134]

[0135] Comparative Example 2:

[0136] 1. The solvent is acetate - acetonitrile (20:80, v / v) with a pH of 4.5, and other conditions are the same as those in Example 1.

[0137] 2. Results

[0138] In the examples, water and acetonitrile were used as the components of the mobile phase. Considering the dissolution characteristics of rosuvastatin and ezetimibe, the solvent was determined to be water-acetonitrile (20:80, v / v). However, considering that impurity E is prone to ring-opening to form rosuvastatin under alkaline conditions, and the solvent water-acetonitrile (20:80, v / v) selected in the present invention is slightly alkaline, so in Comparative Example 2, an acidic solvent acetate-acetonitrile (20:80, v / v) with a pH of 4.5 was selected as the solvent. The content of impurity E will increase under acidic conditions. The detection comparison results of the solvent in the examples and the solvent in Comparative Example 2 are shown in Table 15. The results of detecting impurity E with the solvent water-acetonitrile (20:80, v / v) in the examples are consistent with those in the comparative examples, that is, it is proved that the solvent of the present application will not cover up the actual detection results of impurity E, and impurity E can be detected more effectively.

[0139] Table 15 Comparison table of different solvents

[0140] Solvent Response of Impurity E Reference Substance Impurity E in Test Sample Detected Amount of Spiked Test Sample Recovery Rate % Example 200042225 0.05％ 1.63％ 101％ Comparative Example 2 202360271 0.05％ 1.64％ 106％

[0141] Although the present invention has been disclosed above with preferred embodiments, it is not intended to limit the present invention. Anyone familiar with this technology can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention should be defined by the claims.

Claims

1. A method for determining related substances in ezetimibe and rosuvastatin calcium tablets, characterized in that, Comprising: Determining impurities in ezetimibe and rosuvastatin calcium tablets by high performance liquid chromatography; The chromatographic column filler is octadecylsilyl silica gel; Mobile phase A is an aqueous solution of 0.08% - 0.12% phosphoric acid, and mobile phase B is a mixture of acetonitrile and methanol with a volume ratio of 92 - 98:8 - 2, for gradient elution; The flow rate is 0.9 - 1.1 ml per minute; the column temperature is 30 - 40 °C; the detection wavelength is 240 - 244 nm; The sample tray temperature is 5 °C; the injection volume is 5 μl.

2. The method for determining related substances of ezetimibe and rosuvastatin calcium tablets according to claim 1, wherein The chromatographic column is XBrige Shield RP18, 150 mm × 4.6 mm, with a particle size of 3.5 μm.

3. The method for determining related substances of ezetimibe and rosuvastatin calcium tablets according to claim 1, characterized in that, The mobile phase A is an aqueous solution of 0.1% phosphoric acid; the mobile phase B is a mixture of acetonitrile and methanol with a volume ratio of 95:

5.

4. The method for determining related substances of ezetimibe and rosuvastatin calcium tablets according to claim 1, wherein The program of the gradient elution is as follows: 。 5. The method for determining related substances of ezetimibe and rosuvastatin calcium tablets according to claim 1, wherein The flow rate is 1 ml per minute.

6. The method for determining related substances of ezetimibe and rosuvastatin calcium tablets according to claim 1, wherein The column temperature is 35 °C.

7. The method for determining related substances of ezetimibe and rosuvastatin calcium tablets according to claim 1, characterized in that, The detection wavelength is 242 nm.

8. The method for determining related substances of ezetimibe and rosuvastatin calcium tablets according to claim 1, characterized in that, The impurities are impurity A, B, C, D, E, F, G, and the structures are as follows:

9. The method for determining related substances of ezetimibe and rosuvastatin calcium tablets according to claim 1, characterized in that, The method for determining impurities in ezetimibe and rosuvastatin calcium tablets includes preparing a mixed impurity stock solution and a system suitability solution; Mixed impurity stock solution: Prepared by dissolving impurity reference substances A, B, C, D, E, F, and G in a solvent respectively; System suitability solution: Prepared by dispersing ezetimibe and rosuvastatin calcium tablets in a solvent, adding the mixed impurity stock solution, and then adding a solvent.

10. The method for determining related substances of ezetimibe and rosuvastatin calcium tablets according to claim 9, characterized in that, The solvent is acetonitrile and water, with a volume ratio of acetonitrile to water of 80:20.

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