Olmesartan medoxomil bulk drug and genotoxic impurity detection method

Abstract

The invention relates to an olmesartan medoxomil bulk drug and a method for detecting genotoxic impurities, and belongs to the technical field of medicine detection. The detection method comprises the following steps: (1) preparation of a test solution: taking a proper amount of the product, adding a blank solvent for dissolving and quantitatively diluting, filtering, and taking a subsequent filtrate for sample injection; preparing a reference substance solution: taking a proper amount of reference substances of the impurity 1, the impurity 2, the impurity 3 and the impurity 4, adding a blank solvent for dissolving, and quantitatively diluting to obtain the reference substance solution; (2) detecting by using gas chromatography under the chromatographic conditions that a detector is a hydrogen flame ionization detector and a capillary chromatographic column is CP-Volamine; the temperature of a sample inlet is 150-200 DEG C, the temperature of a detector is 215-225 DEG C, and the column temperature is programmed temperature rise. The method has the advantages of simplicity in operation, low cost, good selectivity, high accuracy and strong universality, and is suitable for research on genotoxic impurities in olmesartan medoxomil bulk drugs and key starting materials thereof.

Description

Technical Field

[0001] The invention relates to a detection method for an olmesartan medoxomil raw material drug and genotoxic impurities, belonging to the technical field of medical detection. Background Art

[0002] Olmesartan medoxomil is an angiotensin II receptor antagonist drug, mainly used to treat hypertension. The drug was jointly developed by Japan's Sankyo and the United States' Forest laboratories and was launched in the United States in 2002. Compared with similar antihypertensive drugs, it has obvious advantages such as small dosage, rapid onset, long half-life, and low adverse reaction rate.

[0003] Even trace amounts of residual genotoxic impurities can cause serious toxic side effects, so their residue limits in drugs are usually controlled at a low level (ppm level or lower). Drug regulatory authorities and pharmaceutical companies in various countries take a conservative and strict control attitude towards the research on such impurities to ensure the safety of drugs.

[0004] The names and structures of the genotoxic impurities involved in the key starting material (4-chloromethyl-5-methyl-1,3-dioxol-2-one) in the preparation of Olmesartan Medoxomil API are as follows:

[0005] Impurity 1 is an isomer of the key starting material of Olmesartan Medoxomil (4-chloromethyl-5-methyl-1,3-dioxol-2-one). It and Impurity 2 are both residual raw materials in the process of synthesizing materials, and do not have functional groups that participate in the process reaction of Olmesartan Medoxomil. Although they will not participate in the reaction, there is a potential risk of residual prototypes in the raw material product; Impurity 3 and Impurity 4 are a pair of diastereoisomers, both of which are by-products in the process of synthesizing materials, and there is also a potential risk of residual in the raw material product. Through the impurity toxicity assessment, according to the ICH M7 impurity toxicity classification principle, this impurity belongs to Class 2 impurities and needs to be controlled as a genotoxic impurity. The literature survey did not obtain toxicological data for these four impurities. According to the "Guidelines on Limits of Genotoxic Impurities" launched by EMA (European Medicines Evaluation Organization), the acceptable intake can be calculated using TTC for impurities without toxicological research data, that is, the acceptable intake of a single impurity is 1.5 µg / day. The maximum daily dose of Olmesartan Medoxomil is 40 mg / day, and the limits of the above impurities are all 37.5 ppm.

[0006] The limit of genotoxic impurities is low, and conventional detection methods may have the problem of insufficient sensitivity. At present, GC-MS or HPLC-MS are mostly used for detection in the industry, and the testing cost is relatively high. It is urgent to develop a simple, accurate, and low-cost test method for the detection of genotoxic impurities in Olmesartan Medoxomil and its key starting materials. Summary of the invention

[0007] The present invention aims at the deficiencies in the prior art and provides a method for detecting olmesartan medoxomil raw materials and genotoxic impurities. The method has the advantages of simple operation, low cost, good selectivity, high accuracy and strong universality, and can effectively study the genotoxic impurities in olmesartan medoxomil.

[0008] The technical solution of the present invention to solve the above technical problems is as follows: a method for detecting Olmesartan Medoxomil API and genotoxic impurities, the detection method is: (1) Preparation of solution: Preparation of test solution: Take an appropriate amount of the product, add blank solvent to dissolve and quantitatively dilute, filter, and take the filtrate for sampling; Preparation of reference solution: Take appropriate amount of reference substances of impurity 1, impurity 2, impurity 3 and impurity 4, add blank solvent to dissolve and quantitatively dilute to obtain reference solution; The impurity 1 is 4-chloro-4-methyl-5-enyl-1,3-dioxol-2-one, the impurity 2 is 4,5-dimethyl-1,3-dioxol-2-one, the impurity 3 is (4R,5R)-4,5-dichloro-4,5-dimethyl-1,3-dioxol-2-one, and the impurity 4 is (4S,5R)-4,5-dichloro-4,5-dimethyl-1,3-dioxol-2-one; (2) Detection by gas chromatography, the chromatographic conditions are: The detector was a hydrogen flame ionization detector, and the capillary column was CP-Volamine; The injection port temperature was 150-200°C, the detector temperature was 215-225°C, the column temperature was programmed, and the carrier gas was nitrogen.

[0009] Further, the blank solvent is any one of dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, chloroform, methanol, ethanol, isopropanol, a combination of chloroform-methanol, a combination of chloroform-ethanol, a combination of chloroform-isopropanol, a combination of dichloromethane-methanol, a combination of dichloromethane-ethanol, a combination of dichloromethane-isopropanol, a combination of dichloromethane-chloroform-methanol, a combination of dichloromethane-chloroform-ethanol, and a combination of dichloromethane-chloroform-isopropanol.

[0010] Preferably, the blank solvent is a combination of dichloromethane and isopropanol, and the volume ratio of dichloromethane to isopropanol is 9:1, 8:2, 6:4, 1:1, 3:7, 2:8 or 7:3.

[0011] Preferably, the specifications of the CP-Volamine chromatographic column are: 30m×0.32mm×5μm.

[0012] Furthermore, the injection method is headspace injection or direct injection.

[0013] Furthermore, the flow rate in step (2) is 0.5 mL / min to 4.0 mL / min.

[0014] Preferably, the flow rate in step (2) is 1.0 mL / min.

[0015] Further, the programmed temperature rising process is: 1) The starting temperature is 40°C and the maintenance time is 5-6 minutes; 2) The heating rate is 10°C per minute to 100°C; 3) The heating rate is 30°C per minute, the temperature is raised to 200°C, and the maintenance time is 10-20 minutes.

[0016] Preferably, the programmed temperature rising process is: 1) The starting temperature is 40°C and the maintenance time is 5 minutes; 2) The heating rate is 10°C per minute to 100°C; 3) The heating rate is 30°C per minute, the temperature is raised to 200°C, and the maintenance time is 20 minutes.

[0017] Preferably, the injection port temperature is 150°C and the detector temperature is 220°C.

[0018] The beneficial effects of the present invention are: 1. The present invention creatively uses gas chromatography to study the genotoxic impurities in Olmesartan Medoxomil API and its key starting materials.

[0019] 2. The present invention adopts a method of mixing two solvents to solve the problem of poor solubility of Olmesartan Medoxomil and effectively improve the concentration of the test solution.

[0020] 3. The present invention can effectively separate the genotoxic impurity from other impurities completely by baseline, and even if there are trace amounts of impurities remaining, the separation requirements can be met, and it can also provide a technical basis for the separation of other genotoxic impurities.

[0021] 4. The present invention uses conventional detectors to effectively monitor genotoxic impurities, avoiding the use of expensive mass spectrometer detectors, solving the problem of "low limit and poor sensitivity" of genotoxic impurities while significantly reducing testing costs and expanding the universality of the method.

[0022] 5. The present invention adopts gas chromatography, which does not require complicated pretreatment, has low cost, strong universality, high precision, and good separation. It can be smoothly transferred to the quality control laboratory of a pharmaceutical company to carry out quality control of olmesartan medoxomil, thereby ensuring its safety, effectiveness, and quality controllability. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is the blank solution chromatogram in Example 1; Figure 2 It is the chromatogram of the test solution in Example 1; Figure 3 It is the chromatogram of the reference substance solution in Example 1; Figure 4 The chromatogram of the spiked test solution in Example 1; Figure 5 It is the chromatogram of test solution 1 in Example 2; Figure 6 This is the chromatogram of test solution 2 in Example 2; Figure 7 It is the chromatogram of test solution 3 in Example 2; Figure 8 It is the chromatogram of test solution 4 in Example 2; Fig. 9 It is the chromatogram of test solution 5 in Example 2; Fig.10 The chromatogram of the spiked test solution in Example 2; Fig.11 This is the chromatogram of the spiked test solution (injection port 150°C) in Example 3; Fig.12 This is the chromatogram of the spiked test solution (injection port 180°C) in Example 3; Fig.13 This is the chromatogram of the spiked test solution (injection port 200°C) in Example 3; Fig.14 This is the chromatogram of the test solution (injection port 200°C) in Example 3; Fig.15 The chromatogram of the test solution in Example 4; Fig.16 The chromatogram of the spiked test solution in Example 4; Fig.17 It is the material solution chromatogram in Example 6; Fig.18 This is the chromatogram of the spiked test solution in Comparative Example 1; Fig.19 It is the chromatogram of blank solution in Comparative Example 2; Fig. 20 This is the chromatogram of the spiked test solution in Comparative Example 4. DETAILED DESCRIPTION

[0024] In order to make the above-mentioned purpose, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below. In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without violating the connotation of the present invention, so the present invention is not limited by the specific embodiments disclosed below.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0026] A method for detecting olmesartan medoxomil API and genotoxic impurities, the detection method comprising: (1) Preparation of solution: Preparation of test solution: Take an appropriate amount of the product, dissolve it in blank solvent and quantitatively dilute it to make a solution containing about 100 mg per 1 mL, filter it, and take the filtrate for sampling; Preparation of reference solution: Take appropriate amount of reference substances of impurity 1, impurity 2, impurity 3 and impurity 4, dissolve them in blank solvent and quantitatively release them to make reference solution containing about 4 μg of each impurity per 1 mL; The impurity 1 is 4-chloro-4-methyl-5-enyl-1,3-dioxol-2-one, the impurity 2 is 4,5-dimethyl-1,3-dioxol-2-one, the impurity 3 is (4R,5R)-4,5-dichloro-4,5-dimethyl-1,3-dioxol-2-one, and the impurity 4 is (4S,5R)-4,5-dichloro-4,5-dimethyl-1,3-dioxol-2-one; (2) Detection by gas chromatography, the chromatographic conditions are: The detector was a hydrogen flame ionization detector, and the capillary column was CP-Volamine; The injection port temperature was 150-200°C, the detector temperature was 215-225°C, the column temperature was programmed, and the carrier gas was nitrogen.

[0027] Further, the blank solvent is any one of dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, chloroform, methanol, ethanol, isopropanol, a combination of chloroform-methanol, a combination of chloroform-ethanol, a combination of chloroform-isopropanol, a combination of dichloromethane-methanol, a combination of dichloromethane-ethanol, a combination of dichloromethane-isopropanol, a combination of dichloromethane-chloroform-methanol, a combination of dichloromethane-chloroform-ethanol, and a combination of dichloromethane-chloroform-isopropanol.

[0028] Preferably, the blank solvent is a combination of dichloromethane and isopropanol, and the volume ratio of dichloromethane to isopropanol is 9:1, 8:2, 6:4, 1:1, 3:7, 2:8 or 7:3.

[0029] More preferably, the mass ratio of dichloromethane to isopropanol is 7:3.

[0030] Preferably, the specification of the CP-Volamine chromatographic column is 30m×0.32mm×5μm.

[0031] Furthermore, the injection method is headspace injection or direct injection.

[0032] Preferably, the injection method is direct injection.

[0033] Furthermore, the flow rate in step (2) is 0.5 mL / min to 4.0 mL / min.

[0034] Preferably, the flow rate in step (2) is 1.0 mL / min.

[0035] Further, the programmed temperature rising process is: 1) The starting temperature is 40°C and the maintenance time is 5-6 minutes; 2) The heating rate is 10°C per minute to 100°C; 3) The heating rate is 30°C per minute, the temperature is raised to 200°C, and the maintenance time is 10-20 minutes.

[0036] Preferably, the programmed temperature rising process is: 1) The starting temperature is 40°C and the maintenance time is 5 minutes; 2) The heating rate is 10°C per minute to 100°C; 3) The heating rate is 30°C per minute, the temperature is raised to 200°C, and the maintenance time is 20 minutes.

[0037] Preferably, the injection port temperature is 150°C and the detector temperature is 220°C.

[0038] Testing Procedure: Accurately measure the reference solution and the test solution in step (1), inject directly, and record the chromatogram. Calculate the impurity content according to the external standard method, the calculation formula is: Impurity content (%) = A 供 ×c 对 / A 对 / c 供 ×100%; Where: A 供 : Peak area of ​​the test product pA*min; A 对 : Reference peak area pA*min; c 供 : Test sample concentration μg / mL; c 对 : Concentration of reference substance μg / mL.

[0039] 1. Detection Example Example 1 (1) Solution preparation: Blank solvent: Dichloromethane and isopropanol were mixed in a volume ratio of 7:3 to obtain a blank solvent.

[0040] Preparation of test solution: Take an appropriate amount of the product (Olmesartan Medoxomil to be tested), dissolve it in blank solvent and quantitatively dilute it to make a solution containing about 100 mg per 1 mL, filter it, and take the filtrate for sampling.

[0041] Preparation of reference solution: Take appropriate amount of reference substances of impurity 1, impurity 2, impurity 3 and impurity 4, dissolve them in blank solvent and quantitatively dilute them to make solutions containing approximately 4 μg of each substance per 1 ml.

[0042] Spiked test solution: Take an appropriate amount of this product, dissolve it in the reference solution and quantitatively dilute it to make a solution containing about 100 mg of olmesartan medoxomil and about 4 μg of each genotoxic impurity per 1 mL, filter it and take the filtrate for sampling.

[0043] (2) Use gas chromatograph for detection. The gas chromatographic conditions are: The chromatographic column was a capillary column for the analysis of amine compounds (CP-Volamine, 30m×0.32mm, 5μm); the injection port temperature was 150°C; the detector was a hydrogen flame ionization detector at 220°C. The carrier gas was nitrogen at a flow rate of 1.0mL / min.

[0044] The program temperature rise process is: 1) The starting temperature is 40°C and the maintenance time is 5 minutes; 2) The heating rate is 10°C per minute to 100°C; 3) The heating rate is 30°C per minute, the temperature is raised to 200°C, and the maintenance time is 20 minutes.

[0045] (3) Conclusion: The specific detection spectrum is as follows Figure 1-Figure 4 As shown, from Figure 1-Figure 4 It can be seen that the separation between genotoxic impurities meets the requirements and these four impurities were not detected in the test solution.

[0046] Example 2 (1) Solution preparation: Blank solvent 1: N,N-dimethylformamide.

[0047] Preparation of test solution 1: Take an appropriate amount of the product (olmesartan medoxomil to be tested), dissolve it in blank solvent 1 and quantitatively dilute it to make a solution containing about 100 mg per 1 mL, filter it, and take the filtrate for sampling.

[0048] Blank solvent 2: dimethyl sulfoxide.

[0049] Preparation of test solution 2: Take an appropriate amount of the product (olmesartan medoxomil to be tested), dissolve it in blank solvent 2 and quantitatively dilute it to make a solution containing about 100 mg per 1 mL, filter it, and take the filtrate for sampling.

[0050] Blank solvent 3: n-heptane.

[0051] Preparation of test solution 3: Take an appropriate amount of the product (olmesartan medoxomil to be tested), dissolve it in blank solvent 3 and quantitatively dilute it to make a solution containing about 100 mg per 1 mL, filter it, and take the filtrate for sampling.

[0052] Blank solvent 4: Dichloromethane, chloroform and isopropanol were mixed in a volume ratio of 7:7:3 to obtain blank solvent 4.

[0053] Preparation of test solution 4: Take an appropriate amount of the product (olmesartan medoxomil to be tested), dissolve it in blank solvent 4 and quantitatively dilute it to make a solution containing about 100 mg per 1 mL, filter it, and take the filtrate for sampling.

[0054] Blank solvent 5: Ethanol and dichloromethane were mixed in a volume ratio of 1:1 to obtain blank solvent 5.

[0055] Preparation of test solution 5: Take an appropriate amount of the product (olmesartan medoxomil to be tested), dissolve it in blank solvent 5 and quantitatively dilute it to make a solution containing about 100 mg per 1 mL, filter it, and take the filtrate for sampling.

[0056] Preparation of reference solution: Take appropriate amount of reference substances of impurity 1, impurity 2, impurity 3 and impurity 4, dissolve them in blank solvent 5 and quantitatively dilute them to make solutions containing approximately 4 μg of each substance per 1 mL.

[0057] Spiked test solution: Take an appropriate amount of this product, dissolve it in the reference solution and quantitatively dilute it to make a solution containing about 100 mg of olmesartan medoxomil and about 4 μg of each genotoxic impurity per 1 mL, filter it and take the filtrate for sampling.

[0058] (2) Use gas chromatograph for detection. The gas chromatographic conditions are: The chromatographic column was a capillary column for the analysis of amine compounds (CP-Volamine, 30m×0.32mm, 5μm); the injection port temperature was 200°C; the detector was a hydrogen flame ionization detector at 220°C. The carrier gas was nitrogen at a flow rate of 1.0mL / min.

[0059] The program temperature rise process is: 1) The starting temperature is 40°C and the maintenance time is 5 minutes; 2) The heating rate is 10°C per minute to 100°C; 3) The heating rate is 30°C per minute, the temperature is raised to 200°C, and the maintenance time is 20 minutes.

[0060] (3) Conclusion: The specific detection spectrum is as follows Figure 5-Figure 10 As shown, from Figure 5-Figure 10 It can be seen that the separation between genotoxic impurities meets the requirements and these four impurities were not detected in the test solution.

[0061] Example 3 (1) Solution preparation: Blank solvent: Chloroform and isopropanol were mixed in a volume ratio of 7:3 to obtain a blank solvent.

[0062] Preparation of test solution: Take an appropriate amount of the product (Olmesartan Medoxomil to be tested), dissolve it in blank solvent and quantitatively dilute it to make a solution containing about 100 mg per 1 mL, filter it, and take the filtrate for sampling.

[0063] Preparation of reference solution: Take appropriate amount of reference stock solution of impurity 1, impurity 2, impurity 3 and impurity 4, dissolve them in blank solvent and quantitatively dilute them to make solutions containing approximately 4 μg of each in 1 mL.

[0064] Spiked test solution: Take an appropriate amount of this product, dissolve it in the reference solution and quantitatively dilute it to make a solution containing about 100 mg of olmesartan medoxomil and about 4 μg of each genotoxic impurity per 1 mL, filter it and take the filtrate for sampling.

[0065] (2) Use gas chromatograph for detection. The gas chromatographic conditions are: The chromatographic column was a capillary column for the analysis of amine compounds (CP-Volamine, 30m×0.32mm, 5μm); the injection port temperatures were 150℃, 180℃, and 200℃, respectively; the detector was a hydrogen flame ionization detector at 220℃. The carrier gas was nitrogen at a flow rate of 1mL / min.

[0066] The program temperature rise process is: 1) The starting temperature is 40°C and the maintenance time is 5 minutes; 2) The heating rate is 10°C per minute to 100°C; 3) The heating rate is 30°C per minute, the temperature is raised to 200°C, and the maintenance time is 20 minutes.

[0067] (3) Conclusion: The specific detection spectrum is as follows Figure 11-Figure 14 As shown, from Figure 11-Figure 14 It can be seen that the separation between genotoxic impurities meets the requirements and these four impurities were not detected in the test solution.

[0068] Example 4 (1) Solution preparation: Blank solvent: Ethanol and dichloromethane were mixed in a volume ratio of 1:1 to obtain a blank solvent.

[0069] Preparation of test solution: Take an appropriate amount of the product (Olmesartan Medoxomil to be tested), dissolve it in blank solvent and quantitatively dilute it to make a solution containing about 100 mg per 1 mL, filter it, and take the filtrate for sampling.

[0070] Preparation of reference solution: Take appropriate amount of reference substances of impurity 1, impurity 2, impurity 3 and impurity 4, dissolve them in blank solvent and quantitatively dilute them to make solutions containing approximately 4 μg of each substance per 1 mL.

[0071] Spiked test solution: Take an appropriate amount of this product, dissolve it in the reference solution and quantitatively dilute it to make a solution containing about 100 mg of olmesartan medoxomil and about 4 μg of each genotoxic impurity per 1 mL, filter it and take the filtrate for sampling.

[0072] (2) Use gas chromatograph for detection. The gas chromatographic conditions are: The chromatographic column was a capillary column for the analysis of amine compounds (CP-Volamine, 30m×0.32mm, 5μm); the injection port temperature was 200°C; the detector was a hydrogen flame ionization detector at 220°C. The carrier gas was nitrogen at a flow rate of 1.0mL / min.

[0073] The program temperature rise process is: 1) The starting temperature is 40°C and the maintenance time is 5 minutes; 2) The heating rate is 10°C per minute, the temperature is raised to 200°C, and the maintenance time is 15 minutes.

[0074] (3) Conclusion: The specific detection spectrum is as follows Figure 15-16 As shown, from Figure 15-16 It can be seen that the separation between genotoxic impurities meets the requirements and these four impurities were not detected in the test solution.

[0075] 2. Method Verification Example Example 5 The method of Example 1 was verified, and the verification results are shown in Table 1 below. It can be seen from Table 1 that all verifications of the method can meet the standard requirements, indicating that the method can meet the detection requirements for genotoxic impurities in Olmesartan Medoxomil and its starting materials.

[0076] Table 1 Method validation results

[0077] 3. Detection of key starting materials (4-chloromethyl-5-methyl-1,3-dioxol-2-one) Example 6 (1) Solution preparation: Blank solvent: dichloromethane.

[0078] Preparation of material solution: Take an appropriate amount of 4-chloromethyl-5-methyl-1,3-dioxol-2-one, dissolve it in blank solvent and quantitatively dilute it to make a solution containing about 200 mg per 1 mL.

[0079] (2) Gas chromatography conditions: Chromatographic column: a capillary column for the analysis of amine compounds (CP-Volamine, 30m×0.32mm, 5μm); the injection port temperature was 200°C; the detector was a hydrogen flame ionization detector at a temperature of 220°C. The carrier gas was nitrogen.

[0080] The program temperature rise process is: 1) The starting temperature is 40°C and the maintenance time is 5 minutes; 2) The heating rate is 10°C per minute to 100°C; 3) The heating rate is 30°C per minute, the temperature is raised to 200°C, and the maintenance time is 20 minutes.

[0081] (3) Conclusion: Under this chromatographic condition, the separation of genotoxic impurities from surrounding impurities in key starting materials meets the requirements. Therefore, this method can also be used to detect genotoxic impurities in key starting materials (see Figure 2). Fig.17 ).

[0082] Comparative Example 1 The same spiked test solution as in Example 1 was used for gas chromatography detection.

[0083] (1) Gas chromatography conditions: The chromatographic column was a capillary column of dimethylpolysiloxane (30m×0.32mm, 0.25μm); the starting temperature was 40°C, maintained for 5 minutes, then increased to 300°C at a rate of 15°C per minute and maintained for 10 minutes; the injection port temperature was 300°C; the detector was a hydrogen flame ionization detector at 320°C; the injection volume was 1μL; and the concentration of the mixed solution was 10mg / mL.

[0084] (2) Conclusion: This method uses conventional gas chromatography, and the separation degree between the genotoxic impurity peak and the surrounding peaks does not meet the requirements, and cannot meet the detection requirements of genotoxic impurities in Olmesartan Medoxomil (see Figure Fig.18 ).

[0085] Comparative Example 2 (1) Solution preparation: Blank solvent: N-methylpyrrolidone.

[0086] Preparation of test solution: Take an appropriate amount of the product, add blank solvent to dissolve and quantitatively dilute to make a solution containing about 100 mg per 1 mL, filter, and take the filtrate for sampling.

[0087] (2) Gas chromatography conditions: The chromatographic column was a capillary column for the analysis of amine compounds (CP-Volamine, 30m×0.32mm, 5μm); the injection port temperature was 200°C; the detector was a hydrogen flame ionization detector at 220°C. The carrier gas was nitrogen at a flow rate of 1.0mL / min.

[0088] The program temperature rise process is: 1) The starting temperature is 40°C and the maintenance time is 5 minutes; 2) The heating rate is 10°C per minute to 100°C; 3) The heating rate is 30°C per minute, the temperature is raised to 200°C, and the maintenance time is 20 minutes.

[0089] (3) Conclusion: The specific detection spectrum is as follows Fig.19 As shown, from Fig.19 Compared with the spiked test solution tested under the same chromatographic conditions ( Fig.10 ) comparison results show that the blank solvent interferes with the detection of impurities.

[0090] Comparative Example 3 (1) Solution preparation: Blank solvent: Acetonitrile and aniline were mixed evenly in a volume ratio of 9:1 to obtain a blank solvent.

[0091] Preparation of test solution: Take an appropriate amount of the product, dissolve it in blank solvent and quantitatively dilute it to make a solution containing about 10 mg per 1 mL.

[0092] (2) Gas chromatography conditions: The chromatographic column was a capillary column for the analysis of amine compounds (CP-Volamine, 30m×0.32mm, 5μm); the injection port temperature was 150°C; the detector was a hydrogen flame ionization detector at 220°C. The carrier gas was nitrogen at a flow rate of 1.0mL / min.

[0093] The program temperature rise process is: 1) The starting temperature is 40°C and the maintenance time is 5 minutes; 2) The heating rate is 10°C per minute to 100°C; 3) The heating rate is 30°C per minute, the temperature is raised to 200°C, and the maintenance time is 20 minutes.

[0094] (3) Conclusion: When the sample was dissolved using the solvents in the literature, the sample concentration under these conditions could not meet the requirements for impurity detection sensitivity.

[0095] Comparative Example 4 The same spiked test solution as in Example 4 was used for gas chromatography detection.

[0096] (1) Use gas chromatograph for detection. The gas chromatographic conditions are: The chromatographic column was a capillary column for the analysis of amine compounds (CP-Volamine, 30m×0.32mm, 5μm); the injection port temperature was 200°C; the detector was a hydrogen flame ionization detector at 220°C. The carrier gas was nitrogen at a flow rate of 2.0mL / min.

[0097] The program temperature rise process is: 1) The starting temperature is 40°C and the maintenance time is 5 minutes; 2) The heating rate is 10°C per minute, the temperature is raised to 200°C, and the maintenance time is 15 minutes.

[0098] (2) Conclusion: The specific detection spectrum is as follows Fig. 20 As shown, from Fig. 20 It can be seen that the separation degree between the genotoxic impurity peak and the surrounding peaks does not meet the requirements and cannot meet the detection needs of genotoxic impurities in Olmesartan Medoxomil.

[0099] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0100] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for detecting Olmesartan Medoxomil API and genotoxic impurities, characterized in that: The detection method is: (1) Preparation of solution: Preparation of test solution: Take an appropriate amount of the product, add blank solvent to dissolve and quantitatively dilute, filter, and take the filtrate for sampling; Preparation of reference solution: Take appropriate amount of reference substances of impurity 1, impurity 2, impurity 3 and impurity 4, add blank solvent to dissolve and quantitatively dilute to obtain reference solution; The impurity 1 is 4-chloro-4-methyl-5-enyl-1,3-dioxol-2-one, the impurity 2 is 4,5-dimethyl-1,3-dioxol-2-one, the impurity 3 is (4R,5R)-4,5-dichloro-4,5-dimethyl-1,3-dioxol-2-one, and the impurity 4 is (4S,5R)-4,5-dichloro-4,5-dimethyl-1,3-dioxol-2-one; (2) Detection by gas chromatography, the chromatographic conditions are: The detector was a hydrogen flame ionization detector, and the capillary column was CP-Volamine; The injection port temperature was 150-200°C, the detector temperature was 215-225°C, the column temperature was programmed, and the carrier gas was nitrogen.

2. A method for detecting olmesartan medoxomil API and genotoxic impurities according to claim 1, characterized in that: The blank solvent is any one of dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, chloroform, methanol, ethanol, isopropanol, a combination of chloroform-methanol, a combination of chloroform-ethanol, a combination of chloroform-isopropanol, a combination of dichloromethane-methanol, a combination of dichloromethane-ethanol, a combination of dichloromethane-isopropanol, a combination of dichloromethane-chloroform-methanol, a combination of dichloromethane-chloroform-ethanol, and a combination of dichloromethane-chloroform-isopropanol.

3. A method for detecting olmesartan medoxomil bulk drug and genotoxic impurities according to claim 2, characterized in that: The blank solvent is a combination of dichloromethane and isopropanol, and the volume ratio of the dichloromethane to isopropanol is 9:1, 8:2, 6:4, 1:1, 3:7, 2:8 or 7:

3.

4. A method for detecting olmesartan medoxomil API and genotoxic impurities according to claim 1, characterized in that: The specifications of the CP-Volamine chromatographic column are 30m×0.32mm×5μm.

5. A method for detecting olmesartan medoxomil API and genotoxic impurities according to claim 1, characterized in that: The injection method is headspace injection or direct injection.

6. A method for detecting olmesartan medoxomil API and genotoxic impurities according to claim 1, characterized in that: The flow rate in step (2) is 0.5 mL / min to 4.0 mL / min.

7. A method for detecting olmesartan medoxomil API and genotoxic impurities according to claim 1, characterized in that: The flow rate in step (2) was 1.0 mL / min.

8. A method for detecting olmesartan medoxomil API and genotoxic impurities according to claim 1, characterized in that: The programmed temperature rise process is: 1) The starting temperature is 40°C and the maintenance time is 5-6 minutes; 2) The heating rate is 10°C per minute to 100°C; 3) The heating rate is 30°C per minute, the temperature is raised to 200°C, and the maintenance time is 10-20 minutes.

9. A method for detecting olmesartan medoxomil API and genotoxic impurities according to claim 8, characterized in that: The programmed temperature rise process is: 1) The starting temperature is 40°C and the maintenance time is 5 minutes; 2) The heating rate is 10°C per minute to 100°C; 3) The heating rate is 30°C per minute, the temperature is raised to 200°C, and the maintenance time is 20 minutes.

10. The method for detecting Olmesartan Medoxomil API and genotoxic impurities according to claim 1, characterized in that: The injection port temperature was 150 °C and the detector temperature was 220 °C.

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