Treatment method and detection method of sample containing cyanobiphenyl halide impurities

Abstract

The invention provides a treatment method for improving response of cyanobiphenyl halide in a sample to be detected and an analysis method of cyanobiphenyl halide in sartan drugs. According to the treatment method of the sample to be detected, a trace amount of potassium acetate is introduced, so that the cyanobiphenyl halide generates an obvious mass spectrum signal peak, and complicated chemical derivation is not needed. The analysis method does not need to adopt special ion sources (APCI and APPI ion sources), and has the characteristics of simplicity in operation, low sensitivity, high specificity, high accuracy, wide linear range, good reproducibility and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of analytical chemistry, and particularly relates to a treatment method for improving the response of genotoxic cyanobiphenyl halide impurities in a sample to be tested and a detection method therefor. Technical Background

[0002] Sartan drugs generally refer to angiotensin II receptor antagonists, which are first-line drugs in the clinical field of blood pressure treatment. Common sartan drugs include valsartan, irbesartan, losartan potassium, olmesartan, etc.

[0003] Since most sartan drugs (including valsartan, irbesartan, losartan potassium, olmesartan, etc.) are synthesized from the starting material cyanobiphenyl bromide, and the starting material cyanobiphenyl bromide contains cyanobiphenyl chloride. According to the ICH M7 guideline, both cyanobiphenyl bromide and cyanobiphenyl chloride have warning structures and are classified as category 3 genotoxic substances. Based on TTC 1.5 μg / day and combined with the maximum daily dose of 320 mg / day of valsartan in valsartan, irbesartan, losartan potassium, and olmesartan, the limit values of cyanobiphenyl bromide and cyanobiphenyl chloride are calculated to be 4.7 ppm, and there is no analytical detection method for trace cyanobiphenyl halides in sartan drugs in the prior art.

[0004] The molecular structures of cyanobiphenyl bromide impurity A and cyanobiphenyl chloride impurity B are as follows:

[0005] Summary of the Invention

[0006] The first aspect of the present invention provides a treatment method for improving the response of cyanobiphenyl halides in a sample to be tested, including the following steps: dissolving the sample to be tested in a diluent to prepare a test solution; the diluent is a buffer solution containing trace potassium salts,

[0007] The cyanobiphenyl halide is a compound represented by formula (II),

[0008]

[0009] X is -Br, -I or -Cl, preferably -Br or -Cl.

[0010] In some embodiments of the present invention, the buffer solution is a mixed solution of an organic solvent and an aqueous potassium salt solution; preferably, the potassium salt is potassium acetate; the organic solvent is methanol, acetonitrile or a mixture of methanol and acetonitrile, preferably acetonitrile.

[0011] In some embodiments of the present invention, the concentration of the potassium salt aqueous solution is 0.01 - 2 mM, preferably 0.01 - 1 mM, such as 1 mM; the volume ratio of the organic solvent to the potassium salt aqueous solution is 6:4 - 8:2, such as 7:3.

[0012] In some embodiments of the present invention, the sample to be tested includes sartan drugs, sartan drug synthesis intermediates, and their derivatives or sartan drug compositions; preferably, the sartan drugs include alisartan, azilsartan, meallasartan potassium, femarasartan potassium, irbesartan, losartan, valsartan, telmisartan, candesartan cilexetil, or olmesartan medoxomil; more preferably, the sartan drug is valsartan, irbesartan, or losartan potassium.

[0013] In some embodiments of the present invention, the content of cyanobiphenyl halide in the sample to be tested is above 2.4 ppm, preferably 2.4 - 47.0 ppm; the concentration of the sample to be tested in the test solution is 3 - 200 mg / mL, preferably 5 - 100 mg / mL.

[0014] The second aspect of the present invention provides a method for analyzing cyanobiphenyl halide impurities, which is characterized by including the following steps:

[0015] (1) Prepare a test solution according to the sample treatment method described in the first aspect of the present invention;

[0016] (2) Detect and analyze the test solution in step (1) by liquid chromatography - mass spectrometry.

[0017] In some embodiments of the present invention, the mass spectrometry detector for liquid chromatography - mass spectrometry includes a single - stage quadrupole mass spectrometry detector; the ion source of the mass spectrometry detector for liquid chromatography - mass spectrometry is ESI(+).

[0018] In some embodiments of the present invention, the analysis method of the present invention includes the following steps:

[0019] (1) Weigh the sample to be tested and prepare a test solution using a buffer solution containing trace potassium acetate as a diluent;

[0020] (2) Use a reverse - phase chromatographic column, with the mobile phase being an aqueous potassium acetate solution and an organic solvent, for gradient elution. The concentration of the aqueous potassium acetate solution is 0.01 - 2 mM, and the organic solvent is acetonitrile and / or methanol;

[0021] (3) Set the flow rate of the mobile phase to 0.2 - 2.0 mL / min, and control the column temperature at 20 - 50 °C;

[0022] (4) Use a mass spectrometry detector, set the positive - ion SIM scanning mode, and the SIM ion current is [M + K] of the target impurity +Peak;

[0023] (5) Inject the test sample solution from step (1), record the mass spectrometry ion current spectrum, and perform detection and analysis.

[0024] In some embodiments of the present invention, the concentration of the potassium acetate aqueous solution is 0.01 - 1 mM, preferably 0.05 - 1 mM, such as 1 mM; the organic solvent is acetonitrile.

[0025] In some embodiments of the present invention, the mobile phase flow rate is 0.2 - 1.0 mL / min, preferably 0.5 - 1.0 mL / min, such as 1.0 mL / min.

[0026] In some embodiments of the present invention, the column temperature is 30 - 50 °C, preferably 35 - 45 °C, such as 40 °C.

[0027] Another aspect of the present invention provides the use of a sample treatment method according to the first aspect of the present invention or an analysis method according to the second aspect of the present invention in the impurity control of sartan drugs;

[0028] Preferably, the impurity control of the sartan drugs includes detecting the content of cyanobiphenyl halide impurities in any step of the synthesis process; for example, detecting the content of the impurities in the raw materials or products, and adjusting the process route according to the impurity content to ensure that the content of the impurities in the intermediate or final product meets the release standard;

[0029] More preferably, when using cyanobiphenyl bromide as a raw material to prepare sartan drugs, the analysis method of the present invention is used for impurity control.

[0030] Another aspect of the present invention provides the use of a sample treatment method according to the first aspect of the present invention or an analysis method according to the second aspect of the present invention in the drug quality control of sartan drugs;

[0031] Preferably, the drug quality control of the sartan drugs includes detecting the cyanobiphenyl halide impurities in the raw materials or products to determine whether the product quality meets the standard;

[0032] More preferably, the standard includes the standard in the ICH M7 guideline.

[0033] The sample treatment method developed by the present invention, by introducing a trace amount of potassium acetate, enables the cyanobiphenyl halide impurities that could not be directly protonated on the ESI ion source to produce obvious mass spectrometry signal peaks, without the need for complex chemical derivatization. The analysis method of the present invention does not require the use of special ion sources (APCI and APPI ion sources), and has the characteristics of simple operation, low sensitivity, strong specificity, high accuracy, wide linear range, and good reproducibility. Description of the Drawings

[0034] Appendix Figure 1 : Mass spectrometry bar chart of impurity A solution obtained according to Example 1 of the present invention.

[0035] Appendix Figure 2 : SIM ion current chromatogram of the mixed solution obtained according to Example 2 of the present invention (upper figure: impurity A; lower figure: impurity B).

[0036] Appendix Figure 3 : SIM ion current chromatogram of the 5-fold concentration standard solution obtained according to Example 3 of the present invention (upper figure: impurity A; lower figure: impurity B).

[0037] Appendix Figure 4 : SIM ion current chromatogram of the blank solution obtained according to Example 4 of the present invention (upper figure: impurity A; lower figure: impurity B).

[0038] Appendix Figure 5 : Mass spectrometry bar chart of the standard solution obtained according to Example 4 of the present invention (upper figure: impurity A; lower figure: impurity B).

[0039] Appendix Figure 6 : SIM ion current chromatogram of the standard solution obtained according to Example 4 of the present invention (upper figure: impurity A; lower figure: impurity B). Detailed implementation manners

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0041] Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

[0042] The terms "comprising", "including", "having", "containing" or "involving" and their other variant forms herein are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0043] The term "liquid chromatography - mass spectrometry", "LC-MS" or "LCMS" refers to liquid chromatography - mass spectrometry, which is an analytical chemistry technique that combines the physical separation ability of liquid chromatography (or HPLC) with the mass analysis ability of mass spectrometry (MS).

[0044] The term "HPLC" includes high performance liquid chromatography, and a device or method in which a liquid is used as the mobile phase, a high pressure infusion system is adopted, a single solvent with different polarities or a mixed solvent, buffer solution, etc. with different ratios are pumped into a chromatographic column filled with a stationary phase, and after the components in the column are separated, they enter a detector for detection, thereby realizing the analysis of the sample.

[0045] The term "mass spectrometry" or "MS" refers to an analytical technique for identifying compounds by their mass. The basic principle of mass spectrometry is to ionize the components in a sample in an ion source to generate charged ions with different mass-to-charge ratios. Under the action of an accelerating electric field, an ion beam is formed and enters a mass analyzer. In the mass analyzer, the electric and magnetic fields are used to cause opposite velocity dispersions, and they are focused separately to obtain a mass spectrum, thereby determining their mass. MS techniques generally include (1) ionizing a compound to form a charged compound; and (2) detecting the molecular weight of the charged compound and calculating the mass-to-charge ratio. A compound can be ionized and detected by any suitable method.

[0046] The term "ESI" refers to an electrospray ionization source. The term "ESI(+)" refers to the ESI positive ion scan mode.

[0047] The term "APCI" refers to an atmospheric pressure chemical ionization source.

[0048] The term "APPI" refers to an atmospheric pressure photoionization source.

[0049] The term "detection limit" refers to the lowest concentration or lowest amount of the analyte component that can be detected by an analytical method under specified experimental conditions.

[0050] The term "quantitation limit" refers to the lowest concentration or lowest amount of the analyte component in a sample that can be quantitatively determined by an analytical method. The lower the quantitation limit, the higher the sensitivity.

[0051] The term "external standard method" refers to a method of quantitative analysis by comparing the response signals of a reference substance of the analyte component and the analyte component in the sample. For specific details of the external standard method, reference can be made to General Chapter 0512, Volume IV of the Chinese Pharmacopoeia 2020 Edition.

[0052] The term "sartan drugs" refers to angiotensin II receptor antagonists, including but not limited to alisartan, azilsartan, meallasartan potassium, fevalsartan potassium, irbesartan, losartan, valsartan, telmisartan, candesartan cilexetil or olmesartan medoxomil.

[0053] The term "sartan drug composition" refers to a composition containing sartan drugs, such as sacubitril valsartan sodium tablets, amlodipine and losartan potassium tablets, etc.

[0054] The term "drug quality control" includes corresponding organizational structures, document systems, as well as sampling, inspection, etc., to ensure that necessary inspections are completed on materials or products before release and to confirm that their quality meets the requirements.

[0055] The term "materials" refers to raw materials, excipients, packaging materials, etc.

[0056] The term "products" includes intermediate products, products to be packaged and finished products of drugs.

[0057] The terms "intermediate product", "intermediate", or "synthetic intermediate" refer to a product that has completed some processing steps and still requires further processing to become a product ready for packaging.

[0058] Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between a liquid and a solid, the percentage is volume / weight percentage; when the present invention relates to the percentage between a solid and a liquid, the percentage is weight / volume percentage; and the rest are weight / weight percentages.

[0059] In the present invention, all the numbers disclosed herein are approximate values, whether or not words such as "about" or "approximately" are used. Based on the disclosed numbers, the numerical value of each number may have a difference of less than ±10% or a reasonable difference considered by those skilled in the art, such as a difference of ±1%, ±2%, ±3%, ±4%, or ±5%.

[0060] For the numerical ranges in the present invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each intermediate value within any stated value or stated range and each smaller range between any other stated value or intermediate value within the stated range are also included in the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0061] In various embodiments of the present application, the magnitude of the sequence numbers of the above processes does not mean the order of execution. Some or all of the steps may be executed in parallel or sequentially. The order of execution of each process should be determined by its function and internal logic, and should not constitute any limitation to the implementation process of the embodiments of the present application.

[0062] For those not specifying specific experimental steps or conditions in the embodiments herein, the operations or conditions of the conventional experimental steps described in the literature in this field can be followed. For those reagents or instruments without indicating the manufacturer, they are all conventional reagent products that can be obtained through commercial purchase.

[0063] The technical solutions of the present invention will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the scope of protection of the present invention.

[0064] Example 1: Method Development - Selecting an Adduct Ion for Trace Analysis

[0065] 1. Solution Preparation

[0066] Diluent: Acetonitrile

[0067] Blank solution: Diluent

[0068] Impurity A solution: Weigh about 20 mg of Impurity A reference standard, accurately weigh, place in a 10 mL volumetric flask, dissolve with acetonitrile and dilute to the mark, mix well. (Concentration of Impurity A: 2 mg / mL)

[0069] 2. Detection conditions

[0070] Table 1 Detection conditions of Example 1

[0071]

[0072]

[0073] 3. Detection

[0074] Under the above conditions, perform LC-MS analysis on the Impurity A solution, record the mass spectrum bar chart of the Impurity A solution, see Appendix Figure 1 . The results show that under acidic low pH conditions, there is almost no hydrogenation signal peak for this compound. But there are two obvious [M + 18] + signal peaks. After analysis, it is considered that they may be [M + NH4 + peaks. At this time, the concentration of Impurity A is relatively high and the signal response is limited.

[0075] Example 2: Method development - Exploration of potassium ion addition response signal

[0076] 1. Solution preparation

[0077] Refer to the preparation method of Example 1 to prepare an impurity mixed solution with the concentrations of both Impurity A and Impurity B being 2000 ng / mL.

[0078] 2. Detection conditions

[0079] Table 2 Detection conditions of Example 2

[0080]

[0081]

[0082] 3. Detection

[0083] Under the above conditions, perform LC-MS analysis on the impurity mixed solution, record the SIM ion chromatogram of the impurity mixed solution, see Appendix Figure 2 . The results show that under these conditions, both Impurity A and Impurity B have obvious [M + 39] + signal peaks, but the detection sensitivity is limited.

[0084] Example 3: Add a small amount of potassium acetate to enhance the mass spectrometry response signal of potassium ion addition

[0085] 1. Solution Preparation

[0086] Diluent: Acetonitrile: 1 mM Potassium Acetate Aqueous Solution = 7:3 (V / V)

[0087] Standard Stock Solution: Weigh 4.7 mg of Standard Substances of Impurity A and Impurity B, accurately weigh and transfer them into a 10 mL volumetric flask, dissolve with acetonitrile and dilute to the mark, mix well; accurately pipette 50 μL into a 10 mL volumetric flask, dilute to the mark with acetonitrile, and mix well. (Concentrations of Impurity A and Impurity B: 2350 ng / mL)

[0088] 5 - fold Concentration Standard Solution (500%STD): Accurately pipette 500 μL of the standard stock solution into a 10 mL volumetric flask, dilute to the mark with the diluent, and mix well thoroughly. (Concentration of Impurity A: 117.5 ng / mL, Concentration of Impurity B: 117.5 ng / mL)

[0089] 2. Detection Conditions

[0090] Table 3 Detection Conditions of Example 3

[0091]

[0092]

[0093] 3. Detection

[0094] Under the above conditions, perform LC - MS analysis on the 5 - fold concentration standard solution, record the SIM ion current chromatogram of the 5 - fold concentration standard solution, see Appendix Figure 3 .

[0095] The results show that after injecting the 5 - fold concentration standard solution treated with trace potassium acetate, under the above conditions, Impurity A and Impurity B have very obvious potassium - ion addition mass spectrometry signals, and there is room for further optimization of the chromatographic conditions.

[0096] Example 4: Determination of Detection Conditions or Parameters

[0097] 1. Solution Preparation

[0098] Diluent: Acetonitrile: 1 mM Potassium Acetate Aqueous Solution = 7:3 (V / V)

[0099] Blank Solution: Diluent

[0100] Standard Solution: Accurately pipette 100 μL of the standard stock solution into a 10 mL volumetric flask, dilute to the mark with the diluent, and mix well thoroughly. (Concentrations of Impurity A and Impurity B: 23.5 ng / mL)

[0101] 2. Detection Conditions

[0102] Instrument and Conditions:

[0103] High performance liquid chromatograph equipped with a single-stage quadrupole mass detector: Agilent 1260 infinity, quadrupole mass spectrometer

[0104] Chromatographic column: Agilent Zorbax SB C8 4.6mm×150, 3.5μm

[0105] Mobile phase A: 1 mM aqueous potassium acetate solution.

[0106] Mobile phase B: acetonitrile

[0107] Gradient is as follows: from 0 - 12 min, the proportion of the organic phase changes from 45% to 65%, at 12.1 min the proportion of the organic phase changes to 95%, from 12.1 - 15 min, the proportion of the organic phase remains 95%, and at 15.1 min the proportion of the organic phase returns to 45%

[0108] Flow rate: 1.0 mL / min

[0109] Injection volume: 20 μL

[0110] Mass spectrometry parameter settings:

[0111] Table 4 Mass spectrometry parameter settings for Example 4

[0112]

[0113] 3. Detection

[0114] Under the above conditions, LC-MS analysis was performed on the blank solution and the standard solution, and the SIM ion current chromatogram of the blank solution was recorded, see Appendix Figure 4 . The mass spectrometry bar chart and SIM ion current chromatogram of the standard solution were recorded, and thus the mass spectrometry bar charts of impurity A and impurity B were obtained, see Appendix Figure 5 ; the SIM ion current chromatogram of the standard solution, see Appendix Figure 6 .

[0115] Example 5: Detection method for impurity A and impurity B

[0116] 1. Solution preparation

[0117] Diluent: acetonitrile : 1 mM aqueous potassium acetate solution = 7:3 (V / V)

[0118] Weigh 5 mg of the test sample of sartan, accurately weigh it into a 2 mL injection vial, add 1.0 mL of diluent and dissolve it by ultrasonic treatment to obtain the test sample solution. (Concentration of the test sample: 5 mg / mL)

[0119] 2. Detection

[0120] Under the conditions of Example 4, the test solution was analyzed by LC-MS, and the contents of impurity A and impurity B were quantitatively calculated by the external standard method based on the peak area.

[0121] Example 6: Method Validation

[0122] 1. Solution Preparation

[0123] Diluent: Acetonitrile: 1 mM potassium acetate aqueous solution = 7:3 (V / V)

[0124] Blank solution: Diluent

[0125] Referring to the solution preparation method in Example 4, a system suitability stock solution with an impurity A concentration of 2.945 μg / mL and an impurity B concentration of 2.785 μg / mL, and a system suitability standard solution with an impurity A concentration of 29.45 ng / mL and an impurity B concentration of 27.85 ng / mL were prepared.

[0126] 2. Specificity

[0127] Under the conditions of Example 4, the blank solution and the system suitability standard solution were analyzed by LC-MS, and the retention times of the target peaks were recorded. The test results are shown in Table 5.

[0128] Table 5 Specificity Test Results

[0129]

[0130] The results showed that the blank solution had no interference in the detection of impurity A and impurity B.

[0131] 3. Repeatability

[0132] Under the conditions of Example 4, the system suitability standard solution was analyzed by LC-MS 6 times, and the peak areas of the main peaks were recorded. The test results are shown in Table 6.

[0133] Table 6 Repeatability Test Results

[0134]

[0135]

[0136] The results showed that the RSD of the main peak area of impurity A was 2.2%, and the RSD of the main peak area of impurity B was 1.7%, indicating good repeatability.

[0137] 4. Linearity

[0138] 4.1 Preparation of Linear Solutions

[0139] Referring to the solution preparation method of Example 4, prepare a series of linear solutions of Impurity A and Impurity B corresponding to the concentrations of the test substance at 2.4 ppm, 4.7 ppm, 7.1 ppm, 9.4 ppm, 23.5 ppm, and 47.0 ppm, and sequentially number them as L1, L2, L3, L4, L5, and L6.

[0140] 4.2 Determination of Linear Solutions

[0141] Under the conditions of Example 4, perform LC-MS analysis on the series of linear solutions. Taking the peak area as the ordinate and the concentration as the abscissa, perform linear regression to obtain the linear equation. The test results are shown in Table 7.

[0142] Table 7 Results of Linear Test

[0143] Injection sequence Peak area of impurity A Peak area of impurity B L1 714.5 1156.15 L2 1330.21997 2336.35 L3 1907.1825 3451.98 L4 2563.8335 4585.42 L5 6326.11328 11394.10 L6 12374.40 22370.00 Slope 41776.6975 80151.1161 Y-intercept 101.6291 108.3052 <![CDATA[R 2 > 0.9999 0.9999

[0144] The results show that for Impurity A and Impurity B in the range of 2.4 ppm - 47.0 ppm, the linear relationship is good, and the regression coefficient t(R 2 ) ≥ 0.995 (n = 6).

[0145] 5. Accuracy

[0146] 5.1 Solution Preparation

[0147] Referring to the test substance solution preparation method of Example 5, prepare a losartan potassium test solution with a losartan potassium concentration of 5.216 mg / mL and a valsartan test solution with a valsartan concentration of 6.534 mg / mL.

[0148] Weigh 5.449 mg of losartan potassium test substance, accurately weigh it into a 2 mL injection vial, and add 1.0 mL of the system suitability standard solution of Impurity A and Impurity B respectively, and dissolve it by ultrasonic wave to obtain a losartan potassium recovery solution with a losartan potassium concentration of 5.449 mg / mL. Similarly, prepare a valsartan recovery solution with a valsartan concentration of 5.437 mg / mL.

[0149] 5.2 Determination of Recovery Solution

[0150] Under the conditions of Example 4, perform LC-MS analysis on the above solutions and record the peak area of the main peak.

[0151] In the repeatability test, the average peak area of Impurity A in 6 injections for system suitability is 1308, and the average peak area of Impurity B is 2327. Calculation formula: Recovery rate = (peak area of Impurity A and Impurity B in the recovery solution - peak area of Impurity A and Impurity B in the test substance solution) / average peak area of Impurity A and Impurity B in 6 injections for system suitability × 100%. The test results are shown in Table 8.

[0152] Table 8 Results of Recovery Test

[0153]

[0154] The results showed that with or without the sartan test sample, the recovery rates of impurity A were 90.0%-104.7%, and the recovery rates of impurity B were 96.3%-99.2%, which proved that sartan had no effect on the determination of the contents of impurity A and impurity B and met the verification requirements.

[0155] 6. Quantification limit

[0156] Take an appropriate amount of the system suitability stock solution, dilute it step by step, and perform LC-MS analysis under the conditions of Example 4. When the signal-to-noise ratio is at least 10, it is the lowest quantification limit concentration. The determination results are shown in Table 9.

[0157] Table 9 Results of the quantification limit test

[0158]

[0159] The results showed that the quantification limits of impurity A and impurity B were less than 2.4 ppm, far less than the limit concentration of 4.7 ppm. The concentration of the test sample (5 mg / mL) was appropriate, which could fully meet the requirements for controlling the contents of impurity A and impurity B in the drug.

[0160] Example 7: Detection of the test sample

[0161] Prepare different types of test sample solutions according to Example 5 and perform LC-MS analysis under the conditions of Example 5. Quantitatively calculate the contents of impurity A and impurity B in different test sample solutions by the external standard method based on the peak area. The determination results are shown in Table 10.

[0162] Table 10 Results of the detection of the test sample

[0163]

[0164]

[0165] The results showed that the analysis method of the present invention had good sensitivity and a wide linear range, which was conducive to effectively controlling the quality of potential genotoxic impurities A and B in the drug production quality management of sartan drugs.

Claims

1. A method for improving the response of cyanobiphenyl halide in a sample to be tested, characterized in that: The following steps are involved: The sample to be tested is dissolved in a diluent to prepare a test solution; the diluent is a buffer solution containing a trace amount of potassium salt. The cyanobiphenyl halide impurity is a compound represented by formula (II), X is -Br, -I or -Cl, preferably -Br or -Cl.

2. The sample processing method according to claim 1, characterized in that: The buffer solution is a mixed solution of an organic solvent and a potassium salt aqueous solution; preferably, the potassium salt is potassium acetate; the organic solvent is methanol, acetonitrile or a mixed solution of methanol and acetonitrile, preferably acetonitrile.

3. The sample processing method according to claim 2, characterized in that: The concentration of the potassium salt aqueous solution is 0.01-2 mM, preferably 0.01-1 mM; the volume ratio of the organic solvent to the potassium salt aqueous solution is 6:4-8:

2.

4. The sample processing method according to any one of claims 1 to 3, characterized in that: The samples to be tested include sartan drugs, sartan drug synthetic intermediates and derivatives thereof or sartan drug compositions; preferably, the sartan drugs include allisartan, azilsartan, mesartan potassium, fimasartan potassium, irbesartan, losartan, valsartan, telmisartan, candesartan cilexetil or olmesartan medoxomil; more preferably, the sartan drugs are valsartan, irbesartan or losartan potassium.

5. The sample processing method according to any one of claims 1 to 4, characterized in that: The content of cyanobiphenyl halide in the sample to be tested is above 2.4 ppm, preferably 2.4-47.0 ppm; the concentration of the sample to be tested in the test solution is 3-200 mg / mL, preferably 5-100 mg / mL.

6. A method for analyzing cyanobiphenyl halide impurities, characterized in that: The following steps are involved: (1) preparing a sample solution according to the sample processing method according to any one of claims 1 to 5; (2) Detecting and analyzing the test solution in step (1) using liquid chromatography-mass spectrometry.

7. The analysis method according to claim 6, characterized in that The mass spectrometer detector for liquid chromatography-mass spectrometry includes a single-stage quadrupole mass spectrometer detector; the ion source of the mass spectrometer detector for liquid chromatography-mass spectrometry is ESI (+).

8. The analysis method according to any one of claims 6 to 7, characterized in that The following steps are involved: (1) Weigh the sample to be tested and prepare the test solution using a buffer solution containing a trace amount of potassium acetate as a diluent; (2) using a reverse phase chromatography column, with a mobile phase of potassium acetate aqueous solution and an organic solvent, for gradient elution, wherein the concentration of the potassium acetate aqueous solution is 0.01-2 mM, and the organic solvent is acetonitrile and / or methanol; (3) Set the mobile phase flow rate to 0.2-2.0 mL / min and control the column temperature at 20-50 °C; (4) Use a mass spectrometer detector and set the positive ion SIM scanning mode. The SIM ion current is [M+K] of the target impurity. + peak; (5) taking the test solution prepared in step (1), injecting the sample, recording the mass spectrometry ion flow spectrum, and performing detection and analysis; Wherein, the concentration of the potassium acetate aqueous solution is preferably 0.01-1 mM, more preferably 0.05-1 mM; and / or The organic solvent is preferably acetonitrile; and / or The mobile phase flow rate is preferably 0.2-1.0 mL / min, more preferably 0.5-1.0 mL / min; and / or The column temperature is preferably 30-50°C, more preferably 35-45°C.

9. Use of the sample processing method according to any one of claims 1 to 5 or the analytical method according to any one of claims 6 to 8 in the impurity control of sartan drugs; preferably, the impurity control of sartan drugs includes detecting the content of cyanobiphenyl halide impurities at any step in the synthesis process; more preferably, when cyanobiphenyl bromide is used as a raw material to prepare sartan drugs, the analytical method of the present invention is used for impurity control.

10. Use of the sample processing method according to any one of claims 1 to 5 or the analysis method according to any one of claims 6 to 8 in drug quality control of sartan drugs.

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