Ezetimibe rosuvastatin calcium tablet isomer determination method

Abstract

The invention relates to the technical field of medicine analysis, in particular to a method for measuring ezetimibe isomer impurities in ezetimibe rosuvastatin calcium tablets, which adopts high performance liquid chromatography to measure ezetimibe isomer impurities in the ezetimibe rosuvastatin calcium tablets, and adopts a polysaccharide derivative reversed-phase coating type chiral chromatographic column as a chromatographic column. The volume ratio of the mobile phase acetonitrile to the mobile phase water is (20-55): (45-80), the detection wavelength is 248 nm, the flow velocity is 0.3-0.4 ml per minute, the column temperature is 5-15 DEG C, and the sample size is 5-20 microliters. The ezetimibe and rosuvastatin calcium tablet isomer determination method provided by the invention can meet the separation of ezetimibe and enantiomer and diastereomer impurities thereof, and eliminates the interference of rosuvastatin calcium and isomer impurities thereof in a two-component preparation; the measuring method is good in system adaptability, linearity and range and high in accuracy and durability.

Description

Technical Field

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

[0002] Ezetimibe rosuvastatin calcium tablets (English name: Ezetimibe Rosuvastatin Calcium Film-Coated Tablets) are a compound preparation of ezetimibe and rosuvastatin calcium. Ezetimibe is a potent lipid-lowering drug. After oral administration, it is rapidly absorbed and widely 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 are 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 (licensee: Merck Sharp & Dohme), the Czech Republic (licensee: Sanofi), and Poland, and its structure is shown as follows:

[0005]

[0006] In order to control the quality of drugs, it is necessary to control the contents of the isomers of rosuvastatin calcium and ezetimibe. There are many isomeric impurities and process impurities related to rosuvastatin calcium and ezetimibe. Existing reports only determine the isomers of a single component, and it is impossible to exclude the mutual interference of the isomeric impurities of the two components, and the chromatographic conditions are complex. There is no literature report on the detection method for the isomers and process impurities of ezetimibe in the ezetimibe rosuvastatin calcium two-component preparation. Tables 1 and 2 show the structures of the ezetimibe isomeric impurities and rosuvastatin calcium isomeric impurities in ezetimibe rosuvastatin calcium tablets.

[0007] Table 1 Statistical Table of Ezetimibe Isomeric Impurities

[0008]

[0009] Table 2 Statistical Table of Rosuvastatin Calcium Isomeric Impurities

[0010] Summary of the Invention

[0011] The object of the present invention is to establish a method for determining the isomers of ezetimibe rosuvastatin calcium tablets to determine the ezetimibe isomer impurities in ezetimibe rosuvastatin calcium tablets. This determination method uses a reverse-phase system, which can meet the separation of ezetimibe and its enantiomers and diastereoisomer impurities, and exclude the interference of rosuvastatin calcium and its isomer impurities in the two-component preparation, and accurately detect the isomer impurities of ezetimibe.

[0012] The present invention provides a method for determining the isomers of ezetimibe rosuvastatin calcium tablets, comprising:

[0013] Using high performance liquid chromatography to determine the ezetimibe isomer impurities in ezetimibe rosuvastatin calcium tablets;

[0014] The chromatographic column uses a polysaccharide derivative reverse-phase coated chiral chromatographic column;

[0015] The volume ratio of acetonitrile and water in the mobile phase is 20-55:45-80;

[0016] The detection wavelength is 248 nm; the flow rate is 0.3-0.4 ml per minute; the column temperature is 5-15 °C; the injection volume is 5-20 μl.

[0017] In some embodiments, two of the chromatographic columns are connected in series.

[0018] In some embodiments, the packing material of the chromatographic column is silica gel surface-coated with cellulose tris(3,5-dimethylphenylcarbamate) or cellulose tris(4-methylphenylformate); the chromatographic column is CHIRALCEL OD-RH, 150 mm × 4.6 mm, with a particle size of 5 μm or CHIRALCEL OJ-RH, 150 mm × 4.6 mm, with a particle size of 5 μm.

[0019] In some embodiments, the volume ratio of acetonitrile and water in the mobile phase is 45:55.

[0020] In some embodiments, the flow rate is 0.35 ml per minute.

[0021] In some embodiments, the column temperature is 5 °C.

[0022] In some embodiments, the injection volume is 10 μl.

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

[0024]

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

[0026] Mixed impurity stock solution: Prepared by dissolving reference substances of impurity A, impurity B, impurity C, impurity D, and impurity E in a solvent respectively;

[0027] System suitability solution: Prepared by dissolving ezetimibe reference substance and rosuvastatin calcium reference substance in a solvent, and then adding the mixed impurity stock solution and diluting with the solvent.

[0028] In some embodiments, the solvent is acetic acid: water: acetonitrile, with a volume ratio of 1:200:800.

[0029] Beneficial effects:

[0030] The present invention provides a method for determining the isomers of ezetimibe rosuvastatin calcium tablets, which can satisfy the separation of ezetimibe and its enantiomers and diastereoisomer impurities, and exclude the interference of rosuvastatin calcium and its isomer impurities in the two-component preparation. The system suitability, linearity, and range of the determination method are good, and the accuracy and durability are high. The isomer impurities of ezetimibe can be accurately detected, and the resolution can reach more than 1.5. Brief description of the drawings

[0031] 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 detection chromatogram of ezetimibe rosuvastatin calcium isomer impurities;

[0033] Figure 2 It is the detection chromatogram of the ezetimibe isomer system suitability solution under the conditions of column temperature 5°C and flow rate 0.35 ml / min;

[0034] Figure 3 It is the detection chromatogram of the ezetimibe isomer system suitability solution under the condition of column temperature 10°C;

[0035] Figure 4 It is the detection chromatogram of the ezetimibe isomer system suitability solution under the condition of column temperature 15°C;

[0036] Figure 5 It is the detection chromatogram of the ezetimibe isomer system suitability solution under the condition of flow rate 0.3 ml / min;

[0037] Figure 6 It is the detection chromatogram of the ezetimibe isomer system suitability solution under the condition of flow rate 0.4 ml / min;

[0038] Figure 7It is the detection chromatogram of ezetimibe isomer system suitability solution under the condition of an injection volume of 5 μl;

[0039] Figure 8 It is the detection chromatogram of ezetimibe isomer system suitability solution under the condition of an injection volume of 10 μl;

[0040] Figure 9 It is the detection chromatogram of ezetimibe isomer system suitability solution under the condition of an injection volume of 20 μl;

[0041] Figure 10 It is the detection chromatogram of ezetimibe isomer system suitability solution by Ultimate 3000 chromatograph;

[0042] Figure 11 It is the detection chromatogram of ezetimibe isomer system suitability solution by CHIRALCEL OJ-RH. Detailed implementation manners

[0043] To enable those skilled in the art to understand the features and effects of the present invention, the following is a general description and definition of the terms and expressions 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 for the present invention. In case of conflict, the definition in this specification shall prevail.

[0044] The theories or mechanisms described and disclosed herein, whether correct or not, shall not limit the scope of the present invention in any way, 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 (including integers and fractions) within the range.

[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 following further elaborates the present invention 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] In the following examples, conventional instruments and equipment in the art are used. For the experimental methods without specific conditions noted in the following examples, they are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. In the following examples, various raw materials are used. Unless otherwise specified, commercially available products are used, and their specifications are conventional specifications in the art. In the specification of the present invention and the following examples, unless otherwise specified, "%" represents weight percentage, "parts" represents weight parts, and the ratios represent weight.

[0049] The following further illustrates a method for determining the isomers of ezetimibe and rosuvastatin calcium tablets provided by the present application in combination with specific examples.

[0050] Example 1: Method for determining the isomers of ezetimibe and rosuvastatin calcium tablets

[0051] 1. Chromatographic conditions

[0052] Chromatograph: Agilent 1260 Infinity II high performance liquid chromatograph;

[0053] Chromatographic column: Daicel CHIRALCEL OD-RH, 150 mm × 4.6 mm, 5 μm, two in series;

[0054] Mobile phase: water-acetonitrile (55:45) as the mobile phase; Flow rate: 0.35 ml / min;

[0055] Column temperature: 5°C; Detection wavelength: 248 nm; Injection volume: 10 μl.

[0056] 2. Solution preparation

[0057] Solvent: acetic acid-water-acetonitrile (1:200:800, v / v)

[0058] Mixed impurity stock solution: Accurately weigh about 10 mg of each of the reference substances of impurity A, impurity B, impurity C, impurity D, and impurity E, place them in a 50 ml volumetric flask, add the solvent and dissolve them by ultrasonic treatment and dilute to the mark, and shake well; Accurately measure 5 ml of this solution, place it in a 50 ml volumetric flask, and dilute to the mark with the solvent, and shake well to obtain.

[0059] System suitability solution: Accurately weigh about 20 mg of ezetimibe reference substance and 20 mg of rosuvastatin calcium reference substance, place them in a 50 ml volumetric flask, add an appropriate amount of solvent and dissolve them by ultrasonic treatment, then accurately measure 5 ml of the impurity stock solution, dilute to the mark with the solvent, and shake well as the system suitability solution.

[0060] 3. Results

[0061] The chromatogram for detecting ezetimibe isomer impurities is as Figure 1As shown in the figure and Table 3, by the determination method of the present invention, ezetimibe and its enantiomers and diastereoisomer impurities can be well separated, and the interference of rosuvastatin calcium and its isomer impurities in the two-component preparation can be excluded.

[0062] Table 3 Ezetimibe Rosuvastatin Calcium Isomer Impurities

[0063]

[0064] Example 2: Durability (Selection of Column Temperature)

[0065] 1. Chromatographic Conditions

[0066] For the selection of column temperature, the present invention respectively conducts tests at column temperatures of 5°C, 10°C, and 15°C, and other chromatographic conditions are the same as those in Example 1.

[0067] 2. Solution Preparation

[0068] Mixed Impurity Stock Solution 2: Accurately weigh about 10 mg of each of the reference substances of Impurity A, Impurity B, Impurity C, Impurity D, Impurity E, and Impurity F, place them in a 50-ml volumetric flask, dissolve them by ultrasonic wave with a solvent and dilute to the scale, and shake well; accurately measure 5 ml of this solution, place it in a 50-ml volumetric flask, and dilute to the scale with a solvent, and shake well to obtain.

[0069] System Suitability Solution 2: Accurately weigh about 20 mg of ezetimibe reference substance and about 20 mg of rosuvastatin calcium reference substance, place them in a 50-ml volumetric flask, dissolve them by ultrasonic wave with an appropriate amount of solvent, then accurately measure 5 ml of the impurity stock solution, dilute to the scale with a solvent, and shake well to obtain System Suitability Solution 2.

[0070] 3. Results

[0071] Perform high-performance liquid chromatography analysis on the prepared system suitability solution under the above conditions, record the chromatogram, and the results are as Figure 2 、 Figure 3 、 Figure 4 shown. Under the condition that other conditions are the same and only the column temperature is different, the resolution is shown in Table 4. The result is that the resolution of each substance can reach more than 1.5. It is preferred to use 5°C as the column temperature, and it can be concluded that the system adaptability of this test method is good.

[0072] Table 4 Ezetimibe Isomer Impurity Column Temperature Durability Resolution Statistical Table

[0073] Impurity Name Column Temperature 5°C Column Temperature 10°C Column Temperature 15°C Impurity A - - - Impurity B 2.67 2.73 2.82 Impurity C 1.97 2.00 2.08 Ezetimibe 2.00 1.98 1.75 Impurity D 3.56 3.55 3.54 Impurity E 2.62 2.61 2.17

[0074] Example 3: Durability (Selection of Flow Rate)

[0075] 1. Chromatographic Conditions

[0076] For the selection of the flow rate, the present invention respectively carried out tests at 0.3 ml / min, 0.35 ml / min, and 0.4 ml / min, and other chromatographic conditions were the same as those in Example 1.

[0077] 2. Solution preparation

[0078] The preparation methods of the mixed impurity stock solution and the system suitability solution were the same as those in Example 2.

[0079] 3. Results

[0080] The prepared system suitability solution was subjected to high performance liquid chromatography analysis under the above conditions, and the chromatogram was recorded. The results were as Figure 2 , Figure 5 , Figure 6 shown. Under the condition that other conditions were the same and only the flow rate was different, the resolution was shown in Table 5. It can be concluded that the system adaptability of this test method was good, and the resolution could reach more than 1.5. Considering the running time and resolution comprehensively, 0.35 ml / min was preferably selected as the flow rate.

[0081] Table 5 Statistical table of the resolution durability of ezetimibe isomer impurities at different flow rates

[0082] Impurity Name Flow Rate 0.35 ml / min Flow Rate 0.3 ml / min Flow Rate 0.4 ml / min Impurity A - - - Impurity B 2.67 2.70 2.56 Impurity C 1.97 1.90 1.78 Ezetimibe 2.00 2.06 1.98 Impurity D 3.56 3.65 3.48 Impurity E 2.62 2.74 2.56

[0083] Example 4: Durability (selection of injection volume)

[0084] 1. Chromatographic conditions

[0085] For the selection of the injection volume, the present invention respectively carried out tests with injection volumes of 5 μl, 10 μl, and 20 μl using a Dionex Ultimate 3000 high performance liquid chromatograph, and other chromatographic conditions were the same as those in Example 1.

[0086] 2. Solution preparation

[0087] The preparation methods of the mixed impurity stock solution and the system suitability solution were the same as those in Example 2.

[0088] 3. Results

[0089] The prepared system suitability solution was subjected to high performance liquid chromatography analysis under the above conditions, and the chromatogram was recorded. The results were as Figure 7 , Figure 8 , Figure 9 shown. Under the condition that other conditions were the same and only the injection volume was different, the resolution was shown in Table 6. It can be concluded that the system adaptability of this test method was good, and the resolution could reach more than 1.5. 10 μl was preferably selected as the injection volume.

[0090] Table 6 Statistical table of the resolution durability of ezetimibe isomer impurities at different injection volumes

[0091]

[0092]

[0093] Example 5: (Selection of Chromatograph)

[0094] 1. Chromatographic Conditions

[0095] The test was carried out using a Dionex Ultimate 3000 high performance liquid chromatograph, and other chromatographic conditions were the same as those in Example 1.

[0096] 2. Solution Preparation

[0097] The preparation methods of the mixed impurity stock solution and the system suitability solution were the same as those in Example 2.

[0098] 3. Results

[0099] The prepared system suitability solution was subjected to high performance liquid chromatography analysis under the above conditions, and the chromatogram was recorded. The results are shown in Figure 10 Table 7 shows the comparison of the resolution with that of the Agilent 1260 Infinity II chromatograph at a flow rate of 0.35 ml / min in Example 3. It can be concluded that the system suitability of this test method is good.

[0100] Table 7 Statistical Table of Resolution of Ezetimibe Isomer Impurities Chromatograph Durability

[0101] Impurity Name Agilent 1260 Infinity II Dionex Ultimate 3000 Impurity A - - Impurity B 2.67 1.94 Impurity C 1.97 1.20 Ezetimibe 2.00 1.97 Impurity D 3.56 3.17 Impurity E 2.62 2.65

[0102] Example 6: (Selection of Chromatographic Column)

[0103] 1. Chromatographic Conditions

[0104] Daicel CHIRALCEL OJ-RH, 150 mm × 4.6 mm, 5 μm, two chromatographs in series, with water - acetonitrile (50:50) as the mobile phase, and other chromatographic conditions were the same as those in Example 1.

[0105] 2. Solution Preparation

[0106] The preparation methods of the mixed impurity stock solution and the system suitability solution were the same as those in Example 2.

[0107] 3. Results

[0108] The prepared system suitability solution was subjected to high performance liquid chromatography analysis under the above conditions, and the chromatogram was recorded. The results are shown in Figure 11 Table 8 shows the comparison of the resolution with that of CHIRALCEL OD-RH at a flow rate of 0.35 ml / min in Example 3. It can be concluded that the system suitability of this test method is good.

[0109] Table 8 Statistical Table of Separation Degree of Ezetimibe Isomer Impurities by Chromatograph Durability

[0110] Impurity Name CHIRALCEL OD-RH CHIRALCEL OJ-RH Impurity A - - Impurity B 2.67 2.27 Impurity C 1.97 2.92 Ezetimibe 2.00 1.80 Impurity D 3.56 1.23 Impurity E 2.62 2.56

[0111] Experimental Example 1: Linearity and Range

[0112] 1. Chromatographic Conditions

[0113] Chromatograph: Agilent 1260 Infinity II High Performance Liquid Chromatograph;

[0114] Chromatographic column: Daicel CHIRALCEL OD-RH chiral chromatographic column (150 mm × 4.6 mm, 5 μm), two chromatographic columns in series;

[0115] Mobile phase: Mobile phase ratio water: acetonitrile (55:45);

[0116] Column temperature 5°C; Flow rate 0.35 ml / min; Detection wavelength: 248 nm; Injection volume 10 μl.

[0117] 2. Solution Preparation

[0118] Linear stock solution 1: Weigh accurately about 20 mg of each reference substance of ezetimibe, impurity A, impurity B, impurity C, impurity D, and impurity E, place them in a 50 ml volumetric flask, dissolve and dilute to the mark with solvent by ultrasonic treatment, and shake well; accurately pipette 1 ml of this solution into a 100 ml volumetric flask, dilute to the mark with solvent, and shake well to obtain.

[0119] Linear solution 1: Accurately pipette 1.5 ml of linear stock solution 1 into a 50 ml volumetric flask, dilute to the mark with solvent, and shake well as linear solution 1.

[0120] Linear solution 2: Accurately pipette 5 ml of linear stock solution 1 into a 50 ml volumetric flask, dilute to the mark with solvent, and shake well as linear solution 2.

[0121] Linear solution 3: Accurately pipette 10 ml of linear stock solution 1 into a 50 ml volumetric flask, dilute to the mark with solvent, and shake well as linear solution 3.

[0122] Perform high performance liquid chromatography analysis on the prepared linear solutions under the above conditions, record the test data, and the results are shown in Table 9. The linear range correlation coefficients of ezetimibe and its isomer impurities are all greater than 0.998, and the linearity is good within this range.

[0123] Table 9 Statistical Table of Ezetimibe Isomer Linearity Results

[0124]

[0125]

[0126] Experimental Example 2: Accuracy

[0127] 1. Chromatographic conditions

[0128] Chromatograph: Agilent 1260 Infinity II high performance liquid chromatograph;

[0129] Chromatographic column: Daicel CHIRALCEL OD-RH chiral chromatographic column (150 mm × 4.6 mm, 5 μm), two chromatographic columns in series;

[0130] Mobile phase: Mobile phase ratio water: acetonitrile (55:45);

[0131] Column temperature 5°C; Flow rate 0.35 ml / min; Detection wavelength: 248 nm; Injection volume 10 μl.

[0132] 2. Solution preparation

[0133] Mixed impurity stock solution 1: Weigh approximately 10 mg each of reference substances of impurity A, impurity B, impurity C, impurity D, impurity E, and impurity F, accurately weigh, place in a 50 ml volumetric flask, add solvent, sonicate to dissolve, and dilute to the mark, shake well; Pipette 5 ml of this solution accurately, place in a 50 ml volumetric flask, dilute to the mark with solvent, and shake well to obtain.

[0134] Accuracy solution 1: Pipette 5 ml of impurity stock solution 1 accurately, place in a 50 ml volumetric flask, dilute to the mark with solvent, and shake well as accuracy solution 1.

[0135] Accuracy solution 2: Pipette 10 ml of impurity stock solution 1 accurately, place in a 50 ml volumetric flask, dilute to the mark with solvent, and shake well as accuracy solution 2.

[0136] Accuracy solution 3: Pipette 15 ml of impurity stock solution 1 accurately, place in a 50 ml volumetric flask, dilute to the mark with solvent, and shake well as accuracy solution 3.

[0137] Perform high performance liquid chromatographic analysis on the prepared accuracy solutions under the above conditions, record the test data, and the results are shown in Table 10. It can be obtained that the accuracy and recovery rate of ezetimibe and its isomeric impurities are high.

[0138] Table 10 Statistical table of ezetimibe isomer accuracy results

[0139]

[0140] Although the present invention has been disclosed above in preferred embodiments, it is not intended to limit the present invention. Anyone skilled in this technology can make various modifications and alterations 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 the isomers of ezetimibe and rosuvastatin calcium tablets, characterized in that, Comprising: Determining the ezetimibe isomer impurities in ezetimibe and rosuvastatin calcium tablets by high performance liquid chromatography; The chromatographic column used is a polysaccharide derivative reversed-phase coated chiral chromatographic column; The volume ratio of acetonitrile and water in the mobile phase is 20 - 55:45 - 80; The detection wavelength is 248 nm; the flow rate is 0.3 - 0.4 ml per minute; the column temperature is 5 - 15 °C; the injection volume is 5 - 20 μl.

2. The method for determining the isomers of ezetimibe and rosuvastatin calcium tablets according to claim 1, wherein, Two of the said chromatographic columns are connected in series.

3. The method for determining the isomers of ezetimibe and rosuvastatin calcium tablets according to claim 1, wherein The packing material of the said chromatographic column is silica gel surface-coated with cellulose tris(3,5-dimethylphenylcarbamate) or cellulose tris(4-methylphenylformate); the said chromatographic column is CHIRALCEL OD-RH, 150 mm × 4.6 mm, particle size 5 μm or CHIRALCEL OJ-RH, 150 mm × 4.6 mm, particle size 5 μm.

4. The method for determining the isomers of ezetimibe and rosuvastatin calcium tablets according to claim 1, wherein The volume ratio of acetonitrile and water in the said mobile phase is 45:

55.

5. The method for determining the isomers of ezetimibe and rosuvastatin calcium tablets according to claim 1, wherein The said flow rate is 0.35 ml per minute.

6. The method for determining the ezetimibe rosuvastatin calcium tablet isomers according to claim 1, wherein The said column temperature is 5 °C.

7. A method for determining the isomers of ezetimibe and rosuvastatin calcium tablets according to claim 1, characterized in that, The said injection volume is 10 μl.

8. The method for determining the isomers of ezetimibe and rosuvastatin calcium tablets according to claim 1, wherein The said ezetimibe isomer impurities are impurities A, B, C, D, E, and the structures are as follows:

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

10. The method for determining the isomers of ezetimibe and rosuvastatin calcium tablets according to claim 9, wherein The said solvent is acetic acid: water: acetonitrile, with a volume ratio of 1:200:800.

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