A method for detecting related substances of mesartan potassium intermediates by ultra-high performance liquid chromatography

Abstract

The present invention solves the problems existing in the prior art and provides an ultra-high performance liquid chromatography detection method for related substances of mesartan potassium intermediates. The method is simple to operate, has good specificity, linearity and precision, and has high sensitivity and good method durability. The method can be used for quality control of mesartan potassium intermediate compound (III) and meets existing needs.

Description

1. Technical field

[0001] The invention belongs to the technical field of drug analysis, and in particular relates to an ultra-high performance liquid chromatography method for separating and detecting substances related to an intermediate of potassium asartan. 2. Background technology

[0002] Azilsartan potassium (prodrug) and its active metabolite azilsartan are benzimidazole-7-carboxylic acid derivatives, angiotensin II (ATⅡ) receptor antagonists (ARB) antihypertensive drugs, selective for AT1 receptors. They can be used alone or in combination with other antihypertensive drugs.

[0003] The intermediate compound (III) (CAS No.: 1449029-77-9) is a key intermediate for the preparation of Asartan Potassium API, and its structural formula is as follows:

[0004]

[0005] Multiple structurally similar impurities of the intermediate compound (iii) of measartan potassium will directly participate in the reaction during the synthesis process to produce process by-product impurities corresponding to measartan potassium. Since their structures are similar to measartan potassium and their properties are similar, they are difficult to remove during the synthesis process, which may affect the quality of the final product measartan potassium.

[0006] Some impurities and compound (III) are very similar in structure, but from the perspective of polarity, some impurities have large polarity differences. Therefore, it is very necessary to establish a stable and efficient detection method for the determination of related substances of the intermediate compound (III) of mesartan potassium on the same chromatographic column to improve the quality control of the intermediate. At present, no detection method for related substances of the intermediate compound (III) of mesartan potassium has been retrieved. 3. Summary of the invention

[0007] The present invention solves the problems existing in the prior art and provides a reversed-phase UPLC determination method for efficiently determining related substances of an intermediate compound (III) of mesartan potassium. The method is simple to operate, has good specificity, linearity and precision, and has high sensitivity and good method durability. The method can be used for quality control of the intermediate compound (III) of mesartan potassium and meets existing needs.

[0008] The invention provides an ultra-high performance liquid chromatography detection method for related substances of potassium salsartan intermediates, comprising the following steps: respectively sampling a separation solution and a test solution, detecting according to ultra-high performance liquid chromatography conditions, and recording a chromatogram; the chromatographic conditions are: a chromatographic column: a chromatographic column with octadecyl bonded surface charged hybrid particle silica gel as a filler; a mobile phase: a mobile phase A is a buffer solution, a mobile phase B is an organic solvent, and gradient elution is performed according to the following table:

[0009] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 83～87 13～17 12 61～69 31～39 25 13～17 83～87 35 13～17 83～87 35.1 83～87 13～17 40 83～87 13～17 ;

[0010] Preferably, the gradient elution conditions are:

[0011] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 85 15 12 65 35 25 15 85 35 15 85 35.1 85 15 40 85 15 ;

[0012] Wherein, the related substances include impurity iii-3 and impurity via-5, and their structures are shown below:

[0013]

[0014] The related substances may further include impurities as shown below:

[0015]

[0016] The chromatographic conditions also include:

[0017] Detector: PDA detector;

[0018] Flow rate: 0.4ml / min;

[0019] Column temperature: 30-40°C, preferably 35°C;

[0020] Detection wavelength: 210nm;

[0021] Injection volume: 2μl.

[0022] The chromatographic column is preferably Waters Acquity UPLC CSH C18, 100 mm×2.1 mm, 1.7 μm.

[0023] The mobile phase A, the buffer solution is a phosphate buffer, which can be selected from one or more of ammonium dihydrogen phosphate solution, potassium dihydrogen phosphate solution, sodium dihydrogen phosphate solution, and calcium dihydrogen phosphate solution, preferably ammonium dihydrogen phosphate solution. The pH value of the ammonium dihydrogen phosphate solution is adjusted to 2.3-2.7, preferably 2.5, with an acidic reagent, and its concentration is 10-50 mmol / L, preferably 10 mmol / L. The acidic reagent is selected from one or more of glacial acetic acid, phosphoric acid, and formic acid, preferably phosphoric acid.

[0024] The mobile phase B, the organic solvent is selected from one or more of acetonitrile, methanol, and tetrahydrofuran, preferably acetonitrile.

[0025] The separation solution is prepared by the following process: taking an appropriate amount of each impurity reference substance, adding a solvent to dissolve and dilute, shaking well, and using the result as the impurity stock solution; taking an appropriate amount of compound (iii), adding a solvent to dissolve, then adding an appropriate amount of each impurity stock solution, diluting with a solvent and shaking well to obtain the separation solution.

[0026] The test solution is prepared by the following process: taking an appropriate amount of compound (iii), adding a solvent to dissolve it, and diluting and shaking it to obtain the solution.

[0027] The solvent is mobile phase A:mobile phase B=40-60:60-40, preferably 50:50.

[0028] The present invention further provides an ultra-high performance liquid chromatography detection method for related substances of potassium salsartan intermediates, comprising the following steps: respectively taking a separation solution and a test solution for injection, detecting according to ultra-high performance liquid chromatography conditions, and recording a chromatogram; the chromatographic conditions are: chromatographic column: Waters Acquity UPLC CSH C18, 100mm×2.1mm, 1.7μm; mobile phase: mobile phase A is ammonium dihydrogen phosphate solution, mobile phase B is acetonitrile, and gradient elution is performed according to the following table:

[0029] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 83～87 13～17 12 61～69 31～39 25 13～17 83～87 35 13～17 83～87 35.1 83～87 13～17 40 83～87 13～17 ;

[0030] Preferably, the gradient elution conditions are:

[0031] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 85 15 12 65 35 25 15 85 35 15 85 35.1 85 15 40 85 15 ;

[0032] Wherein, the related substances include impurity iii-3 and impurity via-5, and their structures are shown below:

[0033]

[0034] The related substances may further include impurities as shown below:

[0035]

[0036] The chromatographic conditions also include:

[0037] Detector: PDA detector;

[0038] Flow rate: 0.4ml / min;

[0039] Column temperature: 35°C;

[0040] Detection wavelength: 210nm;

[0041] Injection volume: 2μl.

[0042] The mobile phase A, ammonium dihydrogen phosphate solution, was adjusted to pH 2.5 with phosphoric acid, and its concentration was 20 mmol / L.

[0043] The separation solution is prepared by the following process: Impurity stock solution: (1) Take about 2 mg of each of impurity ⅶa-6 reference substance, compound (ⅵa) reference substance, impurity ⅵa-6 reference substance, compound (5a) reference substance, and impurity ⅲ-3 reference substance, place them in different 10 ml volumetric bottles, add about 2 ml of tetrahydrofuran to dissolve them, and dilute them to the scale with solvent. (2) Take about 2 mg of each of impurity ⅶa-11 reference substance, compound (ⅶa) reference substance, compound (ⅴb) reference substance, compound (ⅳ) reference substance, impurity ⅲ-1 reference substance, and impurity ⅲ-4 reference substance, place them in 10 ml volumetric bottles, add solvent to dissolve them and dilute them to the scale. (3) Take about 2 mg of impurity ⅵa-5 reference substance, place them in a 10 ml volumetric bottle, add tetrahydrofuran to dissolve them and dilute them to the scale. Separation solution: Take about 10 mg of compound (III) and place it in a 50 ml volumetric flask. Add an appropriate amount of solvent to dissolve it. Take an appropriate amount of each impurity stock solution to prepare a solution containing about 0.2 mg of the main component and 2 μg of each impurity per 1 ml.

[0044] The test solution is prepared by the following process: take about 10 mg of compound (III), put it in a 50 ml volumetric flask, add about 5 ml of tetrahydrofuran to dissolve it, dilute it to the scale with solvent, shake well and filter it to obtain the solution.

[0045] The solvent is mobile phase A:mobile phase B=50:50.

[0046] The present invention further provides an ultra-high performance liquid chromatography detection method for related substances of sartan potassium intermediates and its use in the quality control of sartan potassium.

[0047] The beneficial technical effects of the present invention are:

[0048] (1) The present invention can achieve the control of impurities with large polarity differences (such as impurity ⅲ-3 and impurity ⅵa-5) by the same method, avoiding long analysis and detection time or developing multiple chromatographic methods for sample detection, greatly reducing the investment in related manpower and material resources, saving costs, and improving detection efficiency.

[0049] (2) The present invention can achieve effective separation of the mesartan potassium intermediate compound (iii) from adjacent impurities, is easy to operate, has good specificity, linearity, and precision, and has high sensitivity and good method durability. It can be used for quality control of the mesartan potassium intermediate compound (iii) and meets existing needs. 4. Description of the drawings

[0050] Figure 1 The chromatogram of the test solution under condition ① in Example 1.

[0051] Figure 2 The chromatogram of the test solution under condition ② in Example 1.

[0052] Figure 3 The chromatogram of the test solution under condition ③ in Example 1.

[0053] Figure 4 The separation solution chromatogram of condition ④ in Example 1.

[0054] Figure 5 This is the chromatogram of the system suitability test in Example 2.

[0055] Figure 6 This is the linear graph of compound (iii) in Example 3.

[0056] Figure 7 It is the chromatogram of the quantitative limit in Example 4.

[0057] Figure 8 This is the detection limit chromatogram in Example 4.

[0058] Fig. 9 This is an overlapping diagram of the precision test in Example 5.

[0059] Fig.10 This is an overlapping diagram of the stability test in Example 6.

[0060] Fig.11 This is an overlapping diagram of solutions for different column temperature system suitability in Example 7.

[0061] Fig.12 This is an overlay diagram of the system suitability solutions for different mobile phase A pH values ​​in Example 7.

[0062] Fig.13 This is an overlapping diagram of the solutions for the different gradient system suitability in Example 7. 5. Specific implementation methods

[0063] Specific embodiments of the present invention are described in detail below. It should be noted that the embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0064] Instruments and reagents

[0065] Instrument: Waters UPLC H-class, PDA detector;

[0066] Solvent: mobile phase A-mobile phase B (50:50);

[0067] Detection wavelength: 210nm;

[0068] Column temperature: 35°C.

[0069] Solution preparation:

[0070] Test solution: Prepare freshly before use. Take about 10 mg of compound (III) and place it in a 100 ml volumetric flask. Add solvent to dissolve and dilute to the mark, and shake well.

[0071] Stock solution of compound (III) reference substance: Take about 11.5 mg of compound (III) reference substance (batch number: 20122101), place in a 100 ml volumetric flask, add solvent to dissolve and dilute to the scale, and shake well.

[0072] Impurity reference stock solution:

[0073] (1) Take about 10 mg of each of impurity ⅶa-6 reference substance, compound (ⅵa) reference substance, impurity ⅵa-6 reference substance, compound (5a) reference substance, and impurity ⅲ-3 reference substance, place them in different 100 ml volumetric flasks, add about 10 ml of tetrahydrofuran to dissolve, dilute to the mark with solvent, and shake well;

[0074] (2) Take about 10 mg of each of the reference substance of impurity ⅶa-11, the reference substance of compound (ⅶa), the reference substance of compound (ⅴb), the reference substance of compound (ⅳ), the reference substance of impurity ⅲ-1, and the reference substance of impurity ⅲ-4, place them in a 100 ml volumetric flask, add solvent to dissolve and dilute to the mark, and shake well;

[0075] (3) Take about 10 mg of impurity ⅵa-5 reference substance and place it in a 100 ml volumetric flask. Add tetrahydrofuran to dissolve it and dilute it to the mark. Shake well.

[0076] System suitability solution: Take about 10 mg of compound (III) and place it in a 100 ml volumetric flask. Add solvent to dissolve it. Add 1 ml of the stock solution of each impurity reference substance, dilute to the scale with solvent, and shake well.

[0077] Example 1 Selection of Chromatographic Conditions

[0078] Based on the above instruments and chromatographic conditions, continue to screen the most suitable chromatographic conditions.

[0079] ①Chromatographic column: octadecylsilane bonded silica gel (Waters Acquity UPLC BEH C18, 100 mm × 2.1 mm, 2.5 μm); mobile phase: mobile phase A is 10 mmol / L ammonium dihydrogen phosphate solution (pH adjusted to 3.0 with phosphoric acid); mobile phase B is acetonitrile; gradient elution is performed according to the following table:

[0080] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 85 15 20 15 85 25 15 85 25.1 85 15 30 85 15 ;

[0081] Flow rate: 0.8ml / min;

[0082] Column temperature: 35°C;

[0083] Test solution ①: Weigh about 10 mg of compound (iii) and place it in a 100 ml volumetric flask. Add solvent [acetonitrile-water-phosphoric acid (60:40:0.1)] to dissolve and dilute to the scale. Shake well and filter.

[0084] Accurately measure 5 μl of the mixed solution, inject it into the liquid chromatograph, and record the chromatogram.

[0085] Results: The retention time of the main peak in the test solution was 6.141 minutes, the peak height was 1262227, the number of theoretical plates was 41698, the tailing factor was 2.06, and the main peak had severe tailing. Figure 1 .

[0086] ② Mobile phase A is 10mmol / L diammonium hydrogen phosphate solution (adjust the pH value to 7.0 with phosphoric acid); perform gradient elution according to the following table:

[0087] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 85 15 15 15 85 20 15 85 20.1 85 15 25 85 15 ;

[0088] Flow rate: 0.4ml / min;

[0089] The rest of the conditions are the same as condition ①.

[0090] Test solution ②: Weigh about 10 mg of compound (iii) and place it in a 50 ml volumetric flask. Add solvent [acetonitrile-10 mmol / L diammonium hydrogen phosphate solution (adjust pH to 7.0 with phosphoric acid) (50:50)] to dissolve and dilute to the scale. Shake well and filter.

[0091] Accurately measure 2 μl of the mixed solution, inject it into the liquid chromatograph, and record the chromatogram.

[0092] Results: The baseline drifted down seriously, and the impurities after the main peak were not separated from the main peak; the peak shape of the impurities at 2 to 3 minutes was poor. Figure 2 .

[0093] ③Chromatographic column: Octadecyl bonded surface charged hybrid particle silica gel (Waters Acquity UPLC CSHC18, 100mm×2.1mm.1.7μm)

[0094] Mobile phase A is 20mmol / L ammonium dihydrogen phosphate solution (pH adjusted to 3.0 with phosphoric acid), and gradient elution is performed according to the following table:

[0095] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 85 15 20 15 85 30 15 85 30.1 85 15 35 85 15 ;

[0096] The rest of the conditions are the same as condition ②.

[0097] Test solution ③: Weigh about 10 mg of compound (iii) and place it in a 50 ml volumetric flask. Add about 5 ml of tetrahydrofuran to dissolve it. Dilute to the mark with solvent [10 mmol / L diammonium hydrogen phosphate solution-acetonitrile (30:70)], shake well, and filter.

[0098] Accurately measure 2 μl of the mixed solution, inject it into the liquid chromatograph, and record the chromatogram.

[0099] Result: The main peak overlaps with the adjacent known impurity peak, see Figure 3 .

[0100] ④ Mobile phase A: 20mmol / L ammonium dihydrogen phosphate solution (adjust the pH to 2.5 with phosphoric acid), perform gradient elution according to the following table:

[0101] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 85 15 12 65 35 25 15 85 35 15 85 35.1 85 15 40 85 15 ;

[0102] The rest of the conditions are the same as condition ③.

[0103] Impurity stock solution: (1) Take about 2 mg of each of impurity viia-6 reference substance, compound (via) reference substance, impurity via-6 reference substance, compound (5a) reference substance, and impurity iii-3 reference substance, place them in different 10 ml volumetric flasks, add about 2 ml of tetrahydrofuran to dissolve them, and dilute to the scale with solvent.

[0104] (2) Take about 2 mg each of the impurity ⅶa-11 reference substance, compound (ⅶa) reference substance, compound (ⅴb) reference substance, compound (ⅳ) reference substance, impurity ⅲ-1 reference substance, and impurity ⅲ-4 reference substance, place them in a 10 ml volumetric flask, add solvent to dissolve and dilute to the scale.

[0105] (3) Take about 2 mg of impurity ⅵa-5 reference substance, place it in a 10 ml volumetric flask, add tetrahydrofuran to dissolve it and dilute to the scale.

[0106] Impurity localization solution: Take an appropriate amount of each impurity stock solution and dilute it with solvent to make a solution containing approximately 2 μg of each impurity per 1 ml.

[0107] Separation solution: Take about 10 mg of compound (III) and place it in a 50 ml volumetric flask. Add an appropriate amount of solvent to dissolve it. Take an appropriate amount of each impurity stock solution to prepare a solution containing about 0.2 mg of the main component and 2 μg of each impurity per 1 ml.

[0108] Take 2 μl of separation solution and each impurity location solution, inject into the liquid chromatograph, and record the chromatogram. Results: The separation between the main peak and the adjacent impurities is not less than 1.5, and the minimum separation between other impurities is 5.55, which is good. The specific results are shown in Table 1 and Figure 4 .

[0109] Table 1 Separation test results

[0110]

[0111] Example 2 System suitability test

[0112] Take 2 μl of the system suitability solution, inject it into the liquid chromatograph, and record the chromatogram. The results show that impurity ⅲ-1, impurity ⅶa-11, compound (ⅲ) and impurity ⅲ-4 appear in sequence, and the separation degree between impurity ⅶa-11 and the main peak is 2.04, which meets the requirements. Figure 5 .

[0113] Example 3 Linearity Test

[0114] Quantitation limit solution: Accurately measure 0.03 ml of compound (iii) and each impurity reference stock solution, place them in the same 100 ml volumetric flask, dilute to the mark with solvent, and shake well.

[0115] Linear solutions: Take about 11.5 mg of the reference substance of compound (iii) (batch number: 20122101), accurately weigh it, place it in a 100 ml volumetric flask, add solvent to dissolve and dilute it to make solutions containing about 0.1 μg / ml, 1 μg / ml, 10 μg / ml, 50 μg / ml of compound (iii), respectively, as linear solutions 1 to 4. Take about 13.5 mg of the reference substance of compound (iii) (batch number: 20122101), accurately weigh it, place it in a 100 ml volumetric flask, add solvent to dissolve and dilute it to the mark, shake well, and make linear solution 5.

[0116] Accurately measure 2 μl of each of the linear 1 to linear 5 solutions and the quantitative limit solution, inject them into the liquid chromatograph, and record the chromatogram. Plot a curve of peak area versus concentration, and calculate the regression equation, correlation coefficient, and intercept using the least squares method. The results are shown in Table 2 and Figure 6 The results showed that the peak area of ​​compound (iii) showed a good linear relationship with the concentration in the concentration range of 0.031 to 120.951 μg / ml.

[0117] Table 2 Results of linearity test of related substances of compound (iii)

[0118] Concentration range (μg / ml) Regression equation Correlation coefficient intercept 0.031～120.951 y=26434x+14365 0.9996 0.54％

[0119] Example 4 Quantitative Limit and Detection Limit Test

[0120] Take appropriate amount of each impurity reference substance stock solution and compound (iii) reference substance stock solution, dilute them step by step with solvent to different concentrations, accurately measure 2 μl of each, inject them into liquid chromatograph, record the chromatogram, until the measured main peak response value is not less than 10 times and 3 times higher than the noise signal, which is the quantitative limit and detection limit of each impurity and compound (iii). The results are shown in Table 3 and Figure 7 , Figure 8 .

[0121] Table 3 Quantitation limit and detection limit results

[0122]

[0123] Example 5 Precision Test

[0124] Prepare freshly before use. Prepare 6 test sample solutions in parallel. Accurately measure 2μl, inject into liquid chromatograph, and record the chromatogram. Calculate the relative standard deviation of the amount of impurity ⅲ-1, impurity ⅲ-4, other largest single impurities and total impurities by peak area normalization method. The results show that the precision test results of compound (ⅲ) related substances are good. The results are shown in Table 4. Fig. 9 .

[0125] Table 4 Results of precision test of related substances of compound (III)

[0126] Serial number 1 2 3 4 5 6 result <![CDATA[Impurity iii-1 (%)]]> 0.82 0.82 0.82 0.82 0.82 0.82 RSD is 0 <![CDATA[Impurity iii-4 (%)]]> 0.24 0.22 0.23 0.22 0.22 0.22 RSD is 3.72% Other largest single impurities (%) 0.15 0.15 0.15 0.15 0.15 0.15 RSD is 0 Total impurities (%) <![CDATA[1.60]]> 1.59 1.59 1.58 1.59 1.61 RSD 0.65%

[0127] Example 6 Solution stability test

[0128] Take the test solution 1 under the precision test item of Example 5, place it at room temperature under natural light, accurately measure 2μl at 0, 2, and 4 hours, inject it into the liquid chromatograph, record the chromatogram, calculate and analyze the changes in the amount of impurity iii-1, impurity iii-4, other largest single impurities and total impurities. The results show that the test solution is unstable within 2 hours under room temperature and natural light, and needs to be freshly prepared before use. The results are shown in Table 5. Fig.10 .

[0129] Table 5 Results of stability test of the test solution of compound (iii) related substances

[0130] Time (hours) 0 2 4 result Impurity iii-1(%) 0.82 0.83 0.84 The rate of change is 2.44% Impurity iii-4(%) 0.24 0.24 0.24 Rate of change: 0 Other largest single impurities (%) 0.15 0.19 0.26 The rate of change in 2 hours was 26.67% Total impurities (%) 1.60 1.67 1.75 The rate of change is 9.38% Whether new impurities are generated - none none No new impurities generated within 4 hours

[0131] Example 7 Durability Test

[0132] Based on the established chromatographic conditions, different column temperatures, different pH values ​​of mobile phase A, and different gradients were used to determine the relevant substances according to Table 6. 2 μl of the system suitability solution was injected into the liquid chromatograph and the chromatogram was recorded. The results are shown in Tables 6, 7, Fig.11 , Fig.12 , Fig.13As shown, the column temperature was in the range of 30-40°C, the pH value of mobile phase A was in the range of 2.3-2.7, and the gradient was in the range of gradient 1 to gradient 3. The system applicability met the requirements, the detection amounts of impurity iii-4, impurity iii-1, other largest single impurities and total impurities were basically consistent, and the method had good durability.

[0133] Table 6 Durability of the method for testing related substances of compound (iii)

[0134]

[0135] Gradient 1

[0136]

[0137] Gradient 2

[0138]

[0139] Gradient 3

[0140]

[0141] Table 7 Results of the test system suitability and durability of the solution for compound (iii) related substances

[0142]

[0143] Note: * are the same chromatogram.

Claims

1. An ultra-high performance liquid chromatography detection method for related substances of Asartan potassium intermediates, comprising the following steps: Separation solution and test solution were sampled and tested according to ultra-high performance liquid chromatography conditions, and the chromatogram was recorded; the chromatographic conditions were as follows: chromatographic column: Waters Acquity UPLC CSH C18, 100 mm × 2.1 mm, 1.7 μm; Mobile phase: Mobile phase A is phosphate buffer, with pH adjusted to 2.3-2.7 with acidic reagent, and its concentration is 10-50mmol / L; mobile phase B is acetonitrile, and gradient elution is performed according to the following table: ； The structures of the related substances are shown below:

2. The ultra-high performance liquid chromatography detection method of the related substances of the potassium salsartan intermediate according to claim 1, characterized in that: The chromatographic conditions also include: Detector: PDA detector; Flow rate: 0.4ml / min; Column temperature: 30-40°C; Detection wavelength: 210nm; Injection volume: 2μl.

3. The ultra-high performance liquid chromatography detection method of the related substances of the potassium salsartan intermediate according to claim 1, characterized in that: The mobile phase A is selected from one or more of ammonium dihydrogen phosphate solution, potassium dihydrogen phosphate solution, sodium dihydrogen phosphate solution, and calcium dihydrogen phosphate solution.

4. The ultra-high performance liquid chromatography detection method of the related substances of the potassium salsartan intermediate according to claim 1, characterized in that: The acidic agent is selected from one or more of glacial acetic acid, phosphoric acid and formic acid.

5. The ultra-high performance liquid chromatography detection method of the related substances of the potassium salsartan intermediate according to claim 1, characterized in that: The gradient elution conditions are: 。 6. Use of the ultra-high performance liquid chromatography detection method of related substances of the sartan potassium intermediate according to claim 1 in the quality control of sartan potassium.

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