Method for detecting impurities in losartan potassium

Abstract

The invention belongs to the technical field of pharmaceutical analysis, particularly relates to a method for detecting impurities in losartan potassium, and provides a convenient, efficient and accurate detection method for solving the problem of detection of impurities in losartan potassium. The content of 2-butyl-4-chloro-5-(azido methyl)-1-[(2 '-(1H-tetrazole-5-yl) biphenyl-4-yl) methyl-1H-imidazole and 4'-((5-(azido methyl)-2-butyl-4-chloro-1H-imidazole-1-yl) methyl)-[1, 1 '-biphenyl]-2-nitrile group in losartan potassium can be detected, so that the medication safety is effectively guaranteed, the quality control of losartan potassium is facilitated, and the detection sensitivity is high. The method is convenient, efficient and accurate, completely conforms to the guidance principle verified by a Chinese pharmacopoeia method in the aspects of system applicability, repeatability, specificity and accuracy, and can be used for quality control of losartan potassium.

Description

Technical Field

[0001] The invention belongs to the technical field of drug analysis, and particularly relates to a method for detecting impurities in losartan potassium. Background Art

[0002] Losartan potassium is the first clinical non-peptide angiotensin II (AngII) receptor blocker and the first sartan antihypertensive drug to be marketed. Losartan potassium was jointly developed by Merck and DuPont in the United States. Because of its advantages such as easy administration, significant antihypertensive effect and little impact on renal function, it is a safe and highly effective antihypertensive drug. Since its launch, losartan potassium still ranks first in global sartan drug sales.

[0003] 2-Butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole (hereinafter referred to as: SLS-IM-19), chemical structure: , 4'-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile (hereinafter referred to as: SLS-IM-33), the chemical structure is: , 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole and 4'-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile are potential by-products that may be produced during the synthesis of losartan potassium and may remain in losartan potassium. They are genotoxic impurities. Therefore, their content needs to be strictly controlled during the production of losartan potassium, referring to the ICH M7 toxicology threshold TTC. =1.5µg / day, while the maximum daily dose of losartan potassium in losartan potassium tablets is 150mg / day. According to the formula limit = TTC / maximum daily dose, it is calculated that the limit of 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole and 4'-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile in the raw material losartan potassium is 10ppm.

[0004] At present, there are few literature reports on the detection methods of 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole and 4'-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-nitrile. As a pharmaceutical industry, it is very necessary to strictly control the impurity content in products. The study of material impurities is helpful for the optimization of drug synthesis process and quality control. The detection methods of 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole in losartan potassium were studied. The method for testing the 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole or 4'-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile group in losartan potassium provides a good reference for evaluating the quality of losartan potassium drugs, and also provides a technical basis for optimizing the synthesis process of losartan potassium drugs. It is of great significance for determining the adverse reactions caused by 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole or 4'-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile group in losartan potassium drugs.

[0005] The invention discloses a method for detecting 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole and 4'-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-nitrile in losartan potassium by using GC-MS / MS. The method is used for detection by using the GC-MS / MS method to solve the problem of 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole and 4'-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-nitrile in losartan potassium. The present invention aims to solve the problem of detecting ((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile group, and provides a convenient, efficient and accurate detection method, which can detect the content of 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole or 4'-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile group in losartan potassium, thereby effectively ensuring the safety of drug use and facilitating the quality control of losartan potassium. Summary of the invention

[0006] The invention provides a detection method for determining impurities in losartan potassium by adopting GC-MS / MS. In order to solve the detection problem of impurities in losartan potassium, a convenient, efficient and accurate detection method is provided. The method can determine the content of 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole or 4'-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-nitrile in losartan potassium, thereby effectively ensuring the safety of drug use and facilitating the quality control of losartan potassium. The method is convenient, efficient and accurate, fully complies with the guiding principles of method verification of the Chinese Pharmacopoeia in terms of system applicability, repeatability, specificity and accuracy, and can be used for the quality control of losartan potassium.

[0007] To achieve the above object, the present invention provides the following technical solutions: A method for testing impurities in losartan potassium, wherein the impurity structural formula is , where R is CN or Any one of the above, the detection method comprises the following steps: (1) Prepare solutions including blank solution, sensitivity solution, reference solution and test solution.

[0008] (2) Determination method: LC-MS / MS was used to determine the content of impurities in losartan potassium. After the system was stable, blank solution, sensitivity solution, reference solution and test solution were added respectively, and the chromatogram was recorded. The chromatographic conditions are as follows: Chromatographic column: octadecylsilane bonded silica gel as filler, injection volume: 1-10µl, column temperature: 25±5℃, flow rate: 0.4±0.1ml / min, formic acid solution or ammonium formate solution as mobile phase A, acetonitrile as mobile phase B, gradient elution; The mass spectrometry conditions were as follows: drying gas temperature: 320°C, drying gas flow rate: 8 L / min, nebulizing gas pressure: 40 psi, sheath gas temperature: 350°C, sheath gas flow rate: 10 L / min, capillary voltage: 3500 V, polarity: positive, scanning mode: MRM, EMV: 200 V, switching time setting of the switch valve: 0.0 min: to Waste; 5.0 min: to MS; 12.0 min: to Waste.

[0009] A method for testing impurities in losartan potassium, wherein the impurity is 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole, and the detection method comprises the following steps: (1) Prepare solutions including blank solution, sensitivity solution, reference solution and test solution.

[0010] (2) Determination method: LC-MS / MS was used to determine the content of 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole in losartan potassium. After the system was stable, blank solution, sensitivity solution, reference solution and test solution were added respectively, and the chromatogram was recorded. The chromatographic conditions are as follows: Chromatographic column: octadecylsilane bonded silica gel as filler, injection volume: 1µl, column temperature: 25℃, flow rate: 0.4ml / min, formic acid: water volume ratio of 1:1000 as mobile phase A, acetonitrile as mobile phase B, gradient elution; The mass spectrometry conditions were as follows: drying gas temperature: 320 °C, drying gas flow rate: 8 L / min, nebulizer gas pressure: 40 psi, sheath gas temperature: 350 °C, sheath gas flow rate: 10 L / min, capillary voltage: 3500 V, polarity: positive, scan mode: MRM, EMV: 200 V, switching time setting of the switch valve: 0.0 min: to Waste; 5.0 min: to MS; 12.0 min: to Waste, .

[0011] Further, the blank solution: methanol; the reference solution: take an appropriate amount of 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole reference solution and place it in a volumetric bottle, add the blank solution to dilute to the scale, and shake well; the sensitivity solution: take an appropriate amount of the reference solution, place it in a volumetric bottle, add the blank solution to dilute to the scale, and shake well; the test solution: take an appropriate amount of the test sample, place it in a volumetric bottle, add the blank solution to dilute to the scale, and shake well; the chromatographic column is Agilent Eclipse plus C18 RRHD 3.0×150mm, 1.8 μm or a chromatographic column with equivalent performance; the gradient elution is as follows: .

[0012] A method for testing impurities in losartan potassium, wherein the impurity is 4'-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-nitrile, and the detection method comprises the following steps: (1) Prepare solutions including blank solution, sensitivity solution, reference solution and test solution.

[0013] (2) Determination method: LC-MS / MS was used to determine the content of 4'-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile in losartan potassium. After the system was stable, blank solution, sensitivity solution, reference solution and test solution were added respectively, and the chromatogram was recorded. The chromatographic conditions are as follows: Chromatographic column: octadecylsilane bonded silica gel as filler, injection volume: 5µl, column temperature: 25℃, flow rate: 0.4ml / min, 10mM ammonium formate solution as mobile phase A, acetonitrile as mobile phase B, gradient elution; The mass spectrometry conditions were as follows: drying gas temperature: 320 °C, drying gas flow rate: 8 L / min, nebulizer gas pressure: 40 psi, sheath gas temperature: 350 °C, sheath gas flow rate: 10 L / min, capillary voltage: 3500 V, polarity: positive, scan mode: MRM, EMV: 200 V, switching time setting of the switch valve: 0.0 min: to Waste; 5.0 min: to MS; 12.0 min: to Waste, .

[0014] Further, the blank solution: methanol; the reference solution: take an appropriate amount of 4'-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-nitrile reference and place it in a volumetric bottle, add the blank solution to dilute to the scale, and shake well; the sensitivity solution: take an appropriate amount of the reference solution, place it in a volumetric bottle, add the blank solution to dilute to the scale, and shake well; the test solution: take an appropriate amount of the test sample, place it in a volumetric bottle, add the blank solution to dilute to the scale, and shake well; the chromatographic column is Agilent Eclipse plus C18 RRHD 3.0×150mm, 1.8 μm or a chromatographic column with equivalent performance; the gradient elution is as follows: .

[0015] The invention discloses a method for detecting impurities in losartan potassium. In order to solve the problem of detecting impurities in losartan potassium, a convenient, efficient and accurate detection method is provided. The method can detect the content of 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole or 4'-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-nitrile in losartan potassium, thereby effectively ensuring the safety of drug use. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1This is the blank solution spectrum of SLS-IM-19 in losartan potassium Figure 2 The SLS-IM-19 sensitivity solution spectrum in losartan potassium Figure 3 Spectrum of SLS-IM-19 reference solution in losartan potassium Figure 4 Spectrum of SLS-IM-19 test solution in losartan potassium Implementation

[0017] The present invention is further illustrated by the following examples, but are not intended to limit the present invention.

[0018] Example 1: Determination of 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole in losartan potassium Prepare the solution: Diluent: methanol; Blank solution: diluent; Reference substance stock solution: Take about 25 mg of SLS-IM-19 reference substance, accurately weigh it, place it in a 100 ml volumetric flask, add diluent to dissolve and dilute to the mark, shake well; accurately measure 100 µl of the above solution, place it in a 50 ml volumetric flask, add diluent to dilute to the mark, shake well; (concentration: 500 ng / ml) Reference solution: Accurately measure 500µl of reference stock solution, place in a 25ml volumetric flask, add diluent to dilute to scale and shake well. (Concentration: SLS-IM-19 10ng / ml) Sensitivity solution: Accurately measure 2.0 ml of the reference solution, place it in a 10 ml volumetric bottle, add diluent to dilute to the mark, and shake well. (Concentration: SLS-IM-19 2 ng / ml) Test solution: Take about 25 mg of the test sample, weigh accurately, place in a 25 ml volumetric flask, add diluent to dissolve and dilute to scale, shake well. (Concentration: Losartan potassium 1 mg / ml) Chromatographic conditions: Instruments: Ultra-high performance liquid chromatograph, triple quadrupole mass spectrometer equipped with ESI, electronic analytical balance.

[0019] Chromatographic column: a column filled with octadecylsilane bonded silica gel (e.g. Agilent Eclipse plus C18 RRHD 3.0×150mm, 1.8 μm or a column with equivalent performance) Injection volume: 1µl Column temperature: 25°C Flow rate: 0.4ml / min Mobile phase A: Formic acid: Water = 1:1000 (V / V) Mobile phase B: acetonitrile

[0020]

[0021] Switching time setting of on / off valve: 0.0min: to Waste; 5.0min: to MS; 12.0min: to Waste.

[0022]

[0023] Note: (1) * represents the quantitative ion.

[0024] (2) The switching time of the mass spectrometer switch valve can be appropriately adjusted according to the actual situation of the instrument in order to ensure the response of the SLS-IM-19 signal.

[0025] step After the system is stable, inject 1 injection of blank solution (2 to 3 injections if necessary), 1 injection of sensitivity solution, 6 injections of reference solution, 1 injection of blank solution, and 1 injection of test solution, and record the spectrum.

[0026] Require The S / N value of SLS-IM-19 in the sensitivity solution should be no less than 10; the RSD of the SLS-IM-19 peak area for the reference solution should not be greater than 10.0%.

[0027] calculate Result (ppm) = (R U / R S )×(C S / C U ) Where: R U : The peak area of ​​SLS-IM-19 in the spectrum of the test solution; R S : 6 is the average peak area of ​​SLS-IM-19 in the reference solution spectrum; C S : Concentration of SLS-IM-19 in reference solution (ng / ml); C U : Concentration of test solution (mg / ml).

[0028] Result judgment

[0029] Example 2: System Applicability System suitability is achieved by measuring the S / N value of SLS-IM-19 in the sensitivity solution and the RSD of the peak area of ​​SLS-IM-19 in the 6-pronged reference solution. The S / N value of SLS-IM-19 in the sensitivity solution is required to be ≥10; the RSD of the peak area of ​​SLS-IM-19 in the 6-pronged reference solution should not be greater than 10.0%. In order to confirm the system suitability during the sequence operation, during the validation process, 1 prong is measured for the reference solution every approximately 8 hours and at the end of the sequence. It is required that the RSD of the peak area of ​​SLS-IM-19 in the 6-pronged reference solution should not be greater than 10.0%; if it exceeds this range, an evaluation investigation should be conducted.

[0030]

[0031] Example 3: Specificity The specificity of the method is achieved by determining whether the blank solution has no interference with the detection and the separation degree between SLS-IM-19 and adjacent peaks in the selective solution. It is required that the blank solution should have no interference with the detection and the separation degree between SLS-IM-19 and adjacent peaks in the selective solution should be no less than 1.5.

[0032]

[0033] Example 4: Precision Repeatability: Repeatability is achieved by testing the RSD of the measurement results of 6 test solutions (spiked). It is required that the RSD of the SLS-IM-19 measurement results in the 6 test solutions (spiked) should not be greater than 10.0%.

[0034]

[0035] Example 5: Limit of Detection and Limit of Quantitation The limit of quantitation and the limit of detection are achieved by measuring the ratio of the detection response signal to the noise. The signal-to-noise ratio (S / N) of the limit of quantitation should be no less than 10:1, and the signal-to-noise ratio (S / N) of the limit of detection should be no less than 3:1. At the limit of quantitation concentration level, six limit of quantitation solutions were repeatedly examined, and the RSD of the peak area per unit concentration of SLS-IM-19 in the spectra obtained from the six LOQ solutions should be no greater than 20.0%. LOQ SLS-IM-19 should be no more than 3ppm, S / N ≥ 10, S / N of SLS-IM-19 in LOD solution ≥ 3, and LOD < LOQ.

[0036]

[0037]

[0038] Example 6: Linearity and Range In the concentration range of LOQ to 150%, take 6 concentration points and draw a curve with concentration as the horizontal axis and peak area as the vertical axis. It is required that the curve should be linear in the concentration range of LOQ to 150%, the square of the linear correlation coefficient R (R2) of the curve should be no less than 0.99, and the absolute value of the y-axis intercept should be within 25% of the 100% concentration response value.

[0039]

[0040] Example 7: Accuracy Accuracy is achieved through the recovery rate between the actual concentration and theoretical concentration of the measured component and the total RSD of the recovery rate (n=9). It is required that when the accuracy solution with LOQ concentration, 100% limit concentration and 150% limit concentration is added, the recovery rate of SLS-IM-19 should be between 70.0% and 130.0%, and the total RSD of the recovery rate (n=9) should not be greater than 20.0%.

[0041]

[0042] Example 8: Durability The reference solution, test solution and selective solution were placed at room temperature for a period of time and then injected, and the change pattern of the test results over time was investigated, so as to provide a reference for the placement time of the reference solution and the test solution during the test.

[0043] Requirements: Compared with 0hr, the recovery rate of SLS-IM-19 should be between 80.0% and 120.0% when the reference solution is placed at room temperature for a period of time, and there is no obvious trend of change. The reference solution is stable during the room temperature investigation period; If SLS-IM-19 is detected in the test solution at 0 hr, and the test solution is placed at room temperature for a period of time, the change value of the test result is within 20% of the limit, and there is no obvious change trend, then the test solution is stable during the room temperature investigation; if SLS-IM-19 is not detected in the test solution at 0 hr, and the test solution is placed at room temperature for a period of time, and SLS-IM-19 is still not detected, then the test solution is stable during the room temperature investigation; When the selective solution is left at room temperature for a period of time, the recovery rate of SLS-IM-19 should be between 80.0% and 120.0%, and there should be no obvious trend of change, indicating that the selective solution is stable during the room temperature investigation.

[0044]

[0045]

[0046]

[0047] Example 9: Determination of 4'-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-nitrile in losartan potassium Diluent: methanol; Blank solution: diluent; Reference substance stock solution: Take about 25 mg of SLS-IM-33 reference substance, accurately weigh it, place it in a 100 ml volumetric flask, add diluent to dissolve and dilute to the mark, shake well; accurately measure 100 µl of the above solution, place it in a 50 ml volumetric flask, add diluent to dilute to the mark, shake well; (concentration: 500 ng / ml) Reference substance solution: Accurately measure 1.0 ml of reference substance stock solution, place in a 10 ml volumetric flask, add diluent to dilute to scale and shake well. (Concentration: SLS-IM-33 50 ng / ml) Sensitivity solution: Accurately measure 2.0 ml of the reference solution, place it in a 10 ml volumetric bottle, add diluent to dilute to the mark, and shake well. (Concentration: SLS-IM-33 10 ng / ml) Test solution: Take about 50 mg of the test sample, weigh accurately, place in a 10 ml volumetric flask, add diluent to dissolve and dilute to the scale, shake well. (Concentration: Losartan potassium 5 mg / ml) Chromatographic conditions Instruments: Ultra-high performance liquid chromatograph, triple quadrupole mass spectrometer equipped with ESI, electronic analytical balance.

[0048] Chromatographic column: a column filled with octadecylsilane bonded silica gel (e.g. Agilent Eclipse plus C18 RRHD 3.0×150mm, 1.8 μm or a column with equivalent performance) Injection volume: 5µl Column temperature: 25°C Flow rate: 0.4ml / min Mobile phase A: 10 mM ammonium formate solution Mobile phase B: acetonitrile

[0049]

[0050] Switching time settings of the on-off valve: 0.0min: to Waste; 7min: to MS; 10min: to Waste.

[0051]

[0052] Note: (1) * represents the quantitative ion.

[0053] (2) The switching time of the mass spectrometer switch valve can be appropriately adjusted according to the actual situation of the instrument in order to ensure the response of the SLS-IM-33 signal.

[0054] step After the system is stable, inject 1 injection of blank solution (2 to 3 injections if necessary), 1 injection of sensitivity solution, 6 injections of reference solution, 1 injection of blank solution, and 1 injection of test solution, and record the spectrum.

[0055] Require The S / N value of SLS-IM-33 in the sensitivity solution should be no less than 10; the RSD of the SLS-IM-33 peak area for the reference solution should not be greater than 10.0%.

[0056] calculate Result (ppm) = (R U / R S )×(C S / C U ) Where: R U : The peak area of ​​SLS-IM-33 in the spectrum of the test solution; R S : 6 is the average peak area of ​​SLS-IM-33 in the reference solution spectrum; C S : Concentration of SLS-IM-33 in reference solution (ng / ml); C U : Concentration of test solution (mg / ml).

[0057] limit

[0058]

Claims

1. A method for detecting impurities in losartan potassium, characterized in that, The structural formula of the impurity is , where R is CN or any one of them, and the detection method includes the following steps: (1) Prepare solutions, and prepare blank solution, sensitivity solution, reference solution and test solution respectively; (2) Detection method: Use LC-MS / MS to determine the content of impurities in losartan potassium. After the system is stable, inject blank solution, sensitivity solution, reference solution and test solution respectively, and record the chromatogram; The chromatographic conditions are as follows: Chromatographic column: A chromatographic column filled with octadecylsilyl-bonded silica gel, injection volume: 1 - 10 μl, column temperature: 25 ± 5 °C, flow rate: 0.4 ± 0.1 ml / min. Use formic acid solution or ammonium formate solution as mobile phase A, and acetonitrile as mobile phase B, and adopt gradient elution; The mass spectrometry conditions are as follows: Drying gas temperature: 320 °C, drying gas flow rate: 8 L / min, nebulizing gas pressure: 40 psi, sheath gas temperature: 350 °C, sheath gas flow rate: 10 L / min, capillary voltage: 3500 V, polarity: positive, scanning mode: MRM, EMV: 200 V, switching time setting of switching valve: 0.0 min: to Waste; 5.0 min: to MS; 12.0 min: to Waste.

2. A method for detecting impurities in losartan potassium, characterized in that, the impurity is 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole, and the detection method includes the following steps: (1) Prepare solutions, and prepare blank solution, sensitivity solution, reference solution and test solution respectively; (2) Detection method: Use LC-MS / MS to determine the content of 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-1H-imidazole in losartan potassium. After the system is stable, inject blank solution, sensitivity solution, reference solution and test solution respectively, and record the chromatogram; The chromatographic conditions are as follows: Chromatographic column: A chromatographic column filled with octadecylsilyl-bonded silica gel, injection volume: 1 μl, column temperature: 25 °C, flow rate: 0.4 ml / min. Use formic acid: water with a volume ratio of 1:1000 as mobile phase A, and acetonitrile as mobile phase B, and adopt gradient elution; The mass spectrometry conditions are as follows: Drying gas temperature: 320 °C, drying gas flow rate: 8 L / min, nebulizing gas pressure: 40 psi, sheath gas temperature: 350 °C, sheath gas flow rate: 10 L / min, capillary voltage: 3500 V, polarity: positive, scanning mode: MRM, EMV: 200 V, switching time setting of switching valve: 0.0 min: to Waste; 5.0 min: to MS; 12.0 min: to Waste, 。 3. The detection method according to claim 2, characterized in that, the blank solution: methanol; The reference solution: Take an appropriate amount of the reference substance of 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1H-imidazole and place it in a volumetric flask. Add the blank solution to dilute to the scale and shake well; The sensitivity solution: Take an appropriate amount of the reference solution, place it in a volumetric flask, add the blank solution to dilute to the scale and shake well; The test solution: Take an appropriate amount of the test substance, place it in a volumetric flask, add the blank solution to dilute to the scale and shake well; The chromatographic column is an Agilent Eclipse plus C18 RRHD 3.0×150 mm, 1.8 μm or a chromatographic column with equivalent performance; The gradient elution is as follows: 。 4. A method for detecting impurities in losartan potassium, characterized in that, the impurity is 4'-(((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile, and the detection method includes the following steps: (1) Prepare solutions, and prepare a blank solution, a sensitivity solution, a reference solution and a test solution respectively; (2) Determination method: Use LC-MS / MS to determine the content of 4'-(((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile in losartan potassium. After the system is stable, inject the blank solution, the sensitivity solution, the reference solution and the test solution respectively, and record the chromatogram; The chromatographic conditions are as follows: Chromatographic column: A chromatographic column filled with octadecylsilane chemically bonded silica gel, injection volume: 5 μl, column temperature: 25 °C, flow rate: 0.4 ml / min, using 10 mM ammonium formate solution as mobile phase A and acetonitrile as mobile phase B, and gradient elution is used; The mass spectrometry conditions are as follows: drying gas temperature: 320 °C, drying gas flow rate: 8 L / min, nebulizing gas pressure: 40 psi, sheath gas temperature: 350 °C, sheath gas flow rate: 10 L / min, capillary voltage: 3500 V, polarity: positive, scanning mode: MRM, EMV: 200 V, switching time setting of the switching valve: 0.0 min: to Waste; 5.0 min: to MS; 12.0 min: to Waste, 。 5. According to the detection method described in claim 4, characterized in that, the blank solution: methanol; The reference solution: Take an appropriate amount of the reference substance of 4'-(((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile and place it in a volumetric flask. Add the blank solution to dilute to the scale and shake well; The sensitivity solution: Take an appropriate amount of the reference solution, place it in a volumetric flask, add the blank solution to dilute to the scale and shake well; The test solution: Take an appropriate amount of the test substance, place it in a volumetric flask, add the blank solution to dilute to the scale and shake well; The chromatographic column is an Agilent Eclipse plus C18 RRHD 3.0×150 mm, 1.8 μm or a chromatographic column with equivalent performance; The gradient elution is as follows: 。

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