A method for detecting olmesartan medoxomil bulk drug and genotoxic impurities

Abstract

The present invention relates to a method for detecting olmesartan medoxomil bulk drug and genotoxic impurities, belonging to the technical field of pharmaceutical detection. The detection method is as follows: (1) Preparation of test solution: Take an appropriate amount of this product, dissolve it in blank solvent and quantitatively dilute, filter, and take the subsequent filtrate for injection; Preparation of reference solution: Take appropriate amounts of reference substances of impurity 1, impurity 2, impurity 3, and impurity 4, dissolve them in blank solvent and quantitatively dilute to obtain a reference solution; (2) Detect by gas chromatography, and the chromatographic conditions are: the detector is a flame ionization detector, and the capillary chromatographic column is CP-Volamine; the inlet temperature is 150-200 °C, the detector temperature is 215-225 °C, and the column temperature is programmed temperature rise. This method has the advantages of simple operation, low cost, good selectivity, high accuracy, and strong universality, and is applicable to the study of genotoxic impurities in olmesartan medoxomil bulk drug and its key starting materials.

Description

Technical Field

[0001] The present invention relates to a method for detecting olmesartan medoxomil bulk drug and genotoxic impurities, and belongs to the technical field of pharmaceutical detection. Background Art

[0002] Olmesartan medoxomil is a drug of the angiotensin II receptor antagonist class, mainly used for the treatment of hypertension. This drug was jointly developed by Japanese Sankyo and US Forest laboratories and was launched in the US in 2002. Compared with similar antihypertensive drugs, it has obvious advantages such as a small dose, rapid onset, long half-life, and low adverse reaction rate.

[0003] Trace residues of genotoxic impurities can cause serious toxic side effects, so the residue limits of such impurities in drugs are usually controlled at a relatively low level (ppm level or lower). Drug regulatory departments and pharmaceutical companies in various countries have a conservative and strict control attitude towards the research of such impurities to ensure the safety of drugs.

[0004] The names and structures of genotoxic impurities involved in the key starting material (4-chloromethyl-5-methyl-1,3-dioxolane-2-one) in the preparation of olmesartan medoxomil bulk drug are as follows:

[0005]

[0006] Impurity 1 and the key starting material of olmesartan medoxomil (4-chloromethyl-5-methyl-1,3-dioxolane-2-one) are isomers. Both it and Impurity 2 are residues of raw materials in the process of synthesizing materials and do not have functional groups participating in the olmesartan medoxomil process reaction. Although they will not participate in the reaction, there is a potential risk of remaining in the bulk drug product in their original form; Impurity 3 and Impurity 4 are a pair of diastereoisomers and are both by-products in the process of synthesizing materials, and there is also a potential risk of remaining in the bulk drug product. Through 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 genotoxic impurities. No toxicological data on these four impurities were obtained through literature research. According to the "Guidance on Limits of Genotoxic Impurities" introduced by the EMA (European Medicines Agency), for impurities without toxicological research data, the TTC can be used to calculate the acceptable intake, 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, so the limits of the above impurities are all 37.5 ppm.

[0007] The limits of genotoxic impurities are low, and conventional detection methods may have insufficient sensitivity. Currently, GC-MS or HPLC-MS is mostly used in the industry for detection, with relatively high testing costs. There is an urgent need to develop a simple, accurate, and low-cost testing method for the detection of genotoxic impurities in olmesartan medoxomil and its key starting materials. Summary of the Invention

[0008] In view of the deficiencies in the prior art, the present invention provides a method for detecting olmesartan medoxomil raw materials and genotoxic impurities, which is simple to operate, low in cost, good in selectivity, high in accuracy, and strong in universality, and effectively studies the genotoxic impurities in olmesartan medoxomil.

[0009] The technical solution of the present invention to solve the above technical problems is as follows: A method for detecting olmesartan medoxomil raw materials and genotoxic impurities, and the detection method is as follows:

[0010] (1) Preparation of solutions:

[0011] Preparation of test solution: Take an appropriate amount of this product, dissolve it with blank solvent and quantitatively dilute it, filter, and take the subsequent filtrate for injection.

[0012] Preparation of reference solution: Take appropriate amounts of reference substances of impurity 1, impurity 2, impurity 3, and impurity 4, dissolve them with blank solvent and quantitatively dilute to obtain a reference solution.

[0013] The impurity 1 is 4-chloro-4-methyl-5-enyl-1,3-dioxolane-2-one, the impurity 2 is 4,5-dimethyl-1,3-dioxolene-2-one, the impurity 3 is (4R,5R)-4,5-dichloro-4,5-dimethyl-1,3-dioxolane-2-one, and the impurity 4 is (4S,5R)-4,5-dichloro-4,5-dimethyl-1,3-dioxolane-2-one;

[0014] (2) Detection by gas chromatography, and the chromatographic conditions are as follows:

[0015] The detector is a flame ionization detector, and the capillary chromatographic column is CP-Volamine;

[0016] The injection port temperature is 150 - 200 °C, the detector temperature is 215 - 225 °C, the column temperature is programmed temperature rise, and the carrier gas is nitrogen.

[0017] Further, the blank solvent is any one of dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, chloroform, methanol, ethanol, isopropanol, a combination of chloroform and methanol, a combination of chloroform and ethanol, a combination of chloroform and isopropanol, a combination of dichloromethane and methanol, a combination of dichloromethane and ethanol, a combination of dichloromethane and isopropanol, a combination of dichloromethane, chloroform and methanol, a combination of dichloromethane, chloroform and ethanol, and a combination of dichloromethane, chloroform and isopropanol.

[0018] 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.

[0019] Preferably, the specifications of the CP-Volamine chromatographic column are: 30m × 0.32mm × 5μm.

[0020] Further, the injection method is headspace injection or direct injection.

[0021] Further, the flow rate in step (2) is 0.5 mL / min to 4.0 mL / min.

[0022] Preferably, the flow rate in step (2) is 1.0 mL / min.

[0023] Further, the programmed temperature rise process is as follows:

[0024] 1) The initial temperature is 40°C, and the holding time is 5 - 6 minutes;

[0025] 2) The heating rate is 10°C per minute, and the temperature is raised to 100°C;

[0026] 3) The heating rate is 30°C per minute, and the temperature is raised to 200°C, and the holding time is 10 - 20 minutes.

[0027] Preferably, the programmed temperature rise process is as follows:

[0028] 1) The initial temperature is 40°C, and the holding time is 5 minutes;

[0029] 2) The heating rate is 10°C per minute, and the temperature is raised to 100°C;

[0030] 3) The heating rate is 30°C per minute, and the temperature is raised to 200°C, and the holding time is 20 minutes.

[0031] Preferably, the injection port temperature is 150°C, and the detector temperature is 220°C.

[0032] The beneficial effects of the present invention are:

[0033] 1. The present invention creatively uses gas chromatography to study the genotoxic impurities in olmesartan medoxomil bulk drugs and their key starting materials.

[0034] 2. The present invention adopts a method of mixing two solvents to solve the problem of poor solubility of olmesartan medoxomil, effectively improving the concentration of the test solution.

[0035] 3. The present invention effectively separates the genotoxic impurity from other impurities completely at the baseline. Even if there is a trace amount of impurity residue, the resolution requirement can be met, and it can also provide a technical basis for the separation of other genotoxic impurities.

[0036] 4. The present invention uses a conventional detector to effectively monitor genotoxic impurities, avoiding the use of expensive mass spectrometers. While solving the problems of "low limit and poor sensitivity" of genotoxic impurities, it significantly reduces the test cost and expands the universality of this method.

[0037] 5. The present invention uses gas chromatography, which requires no complex pretreatment, has low cost, strong universality, high precision and good resolution. It can be smoothly transferred to the quality control laboratory of pharmaceutical enterprises for the quality control of olmesartan medoxomil, and thus can ensure its safety, effectiveness and quality controllability. Description of the Drawings

[0038] Figure 1 It is the chromatogram of the blank solution in Example 1;

[0039] Figure 2 It is the chromatogram of the test solution in Example 1;

[0040] Figure 3 It is the chromatogram of the reference solution in Example 1;

[0041] Figure 4 It is the chromatogram of the spiked test solution in Example 1;

[0042] Figure 5 It is the chromatogram of the test solution 1 in Example 2;

[0043] Figure 6 It is the chromatogram of the test solution 2 in Example 2;

[0044] Figure 7 It is the chromatogram of the test solution 3 in Example 2;

[0045] Figure 8 It is the chromatogram of the test solution 4 in Example 2;

[0046] Figure 9 It is the chromatogram of the test solution 5 in Example 2;

[0047] Figure 10Chromatogram of the spiked test sample solution in Example 2;

[0048] Figure 11 Chromatogram of the spiked test sample solution (inlet temperature 150 °C) in Example 3;

[0049] Figure 12 Chromatogram of the spiked test sample solution (inlet temperature 180 °C) in Example 3;

[0050] Figure 13 Chromatogram of the spiked test sample solution (inlet temperature 200 °C) in Example 3;

[0051] Figure 14 Chromatogram of the test sample solution (inlet temperature 200 °C) in Example 3;

[0052] Figure 15 Chromatogram of the test sample solution in Example 4;

[0053] Figure 16 Chromatogram of the spiked test sample solution in Example 4;

[0054] Figure 17 Chromatogram of the material solution in Example 6;

[0055] Figure 18 Chromatogram of the spiked test sample solution in Comparative Example 1;

[0056] Figure 19 Chromatogram of the blank solution in Comparative Example 2;

[0057] Figure 20 Chromatogram of the spiked test sample solution in Comparative Example 4. Detailed implementation manners

[0058] To make the above objects, features, and advantages of the present invention more obvious and understandable, the following provides a detailed description of the specific implementation manners of the present invention. Many specific details are set forth in the following description to fully understand 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 departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which this invention belongs. The terms used in the description of the present invention herein are only for the purpose of describing specific implementation manners and are not intended to limit the present invention.

[0060] A method for detecting olmesartan medoxomil bulk drug and genotoxic impurities, the detection method is as follows:

[0061] (1) Preparation of solutions:

[0062] Preparation of the test solution: Take an appropriate amount of this product, dissolve it with the blank solvent and quantitatively dilute it to prepare a solution containing about 100 mg per 1 mL, filter, and take the subsequent filtrate for injection;

[0063] Preparation of the reference solution: Take appropriate amounts of the reference substances of impurity 1, impurity 2, impurity 3, and impurity 4, dissolve them with the blank solvent and quantitatively dilute them to prepare a reference solution containing about 4 μg of each impurity per 1 mL;

[0064] The said impurity 1 is 4-chloro-4-methyl-5-enyl-1,3-dioxolane-2-one, impurity 2 is 4,5-dimethyl-1,3-dioxolene-2-one, impurity 3 is (4R,5R)-4,5-dichloro-4,5-dimethyl-1,3-dioxolane-2-one, and impurity 4 is (4S,5R)-4,5-dichloro-4,5-dimethyl-1,3-dioxolane-2-one;

[0065] (2) Detection by gas chromatography, and the chromatographic conditions are as follows:

[0066] The detector is a flame ionization detector, and the capillary chromatographic column is CP-Volamine;

[0067] The inlet temperature is 150 - 200 °C, the detector temperature is 215 - 225 °C, the column temperature is programmed temperature rise, and the carrier gas is nitrogen.

[0068] Furthermore, the said blank solvent is any one of dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, chloroform, methanol, ethanol, isopropanol, combinations of chloroform-methanol, combinations of chloroform-ethanol, combinations of chloroform-isopropanol, combinations of dichloromethane-methanol, combinations of dichloromethane-ethanol, combinations of dichloromethane-isopropanol, combinations of dichloromethane-chloroform-methanol, combinations of dichloromethane-chloroform-ethanol, and combinations of dichloromethane-chloroform-isopropanol.

[0069] Preferably, the said 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.

[0070] More preferably, the mass ratio of dichloromethane to isopropanol is 7:3.

[0071] Preferably, the specification of the CP-Volamine chromatographic column is 30 m × 0.32 mm × 5 μm.

[0072] Furthermore, the injection method is headspace injection or direct injection.

[0073] Preferably, the sample injection method is direct injection.

[0074] Furthermore, the flow rate in step (2) is 0.5 mL / min to 4.0 mL / min.

[0075] Preferably, the flow rate in step (2) is 1.0 mL / min.

[0076] Furthermore, the programmed temperature rise process is as follows:

[0077] 1) The initial temperature is 40°C, and the holding time is 5 - 6 minutes;

[0078] 2) The heating rate is 10°C per minute, and it is heated to 100°C;

[0079] 3) The heating rate is 30°C per minute, and it is heated to 200°C, and the holding time is 10 - 20 minutes.

[0080] Preferably, the programmed temperature rise process is as follows:

[0081] 1) The initial temperature is 40°C, and the holding time is 5 minutes;

[0082] 2) The heating rate is 10°C per minute, and it is heated to 100°C;

[0083] 3) The heating rate is 30°C per minute, and it is heated to 200°C, and the holding time is 20 minutes.

[0084] Preferably, the injection port temperature is 150°C, and the detector temperature is 220°C.

[0085] Test procedure:

[0086] Precisely measure the reference solution and the test solution in step (1), inject directly, and record the chromatogram. Calculate the impurity content by the external standard method. The calculation formula is:

[0087] Impurity content (%) = A 供 × c 对 / A 对 / c 供 × 100%;

[0088] In the formula:

[0089] A 供 : The peak area of the test solution pA*min;

[0090] A 对 : The peak area of the reference solution pA*min;

[0091] c 供 : The concentration of the test solution μg / mL;

[0092] c 对 : Concentration of reference substance, μg / mL.

[0093] I. Detection Examples

[0094] Example 1

[0095] (1) Solution preparation:

[0096] Blank solvent: Dichloromethane and isopropanol are mixed evenly according to the volume ratio of 7:3 to obtain the blank solvent.

[0097] Preparation of test solution: Take an appropriate amount of this product (olmesartan medoxomil to be tested), dissolve it with the blank solvent and quantitatively dilute it to prepare a solution containing about 100 mg per 1 mL, filter, and take the subsequent filtrate for injection.

[0098] Preparation of reference solution: Take appropriate amounts of reference substances of impurity 1, impurity 2, impurity 3, and impurity 4, dissolve them with the blank solvent and quantitatively dilute them to prepare a solution containing about 4 μg each per 1 ml.

[0099] Spiked test solution: Take an appropriate amount of this product, dissolve it with the reference solution and quantitatively dilute it to prepare a solution containing about 100 mg of olmesartan medoxomil and about 4 μg of each genotoxic impurity per 1 mL, filter, and take the subsequent filtrate for injection.

[0100] (2) Detection is carried out using a gas chromatograph, and the gas chromatography conditions are as follows:

[0101] The chromatographic column is a capillary column dedicated to the analysis of amine compounds (CP-Volamine, 30 m × 0.32 mm, 5 μm); the injection port temperature is 150 °C; the detector is a flame ionization detector, and the temperature is 220 °C. The carrier gas is nitrogen, and the flow rate is 1.0 mL / min.

[0102] The programmed temperature rise process is as follows:

[0103] 1) The initial temperature is 40 °C, and the holding time is 5 minutes;

[0104] 2) The temperature is raised at a rate of 10 °C per minute to 100 °C;

[0105] 3) The temperature is raised at a rate of 30 °C per minute to 200 °C, and the holding time is 20 minutes.

[0106] (3) Conclusion: The specific detection chromatogram is as shown in Figures 1 - 4 It can be seen from Figures 1 - 4 that the resolution between genotoxic impurities meets the requirements, and these four impurities are not detected in the test solution.

[0107] Example 2

[0108] (1) Solution preparation:

[0109] Blank solvent 1: N,N-dimethylformamide.

[0110] Preparation of test solution 1: Take an appropriate amount of this product (olmesartan medoxomil to be tested), dissolve it in blank solvent 1 and quantitatively dilute to prepare a solution containing about 100 mg per 1 mL, filter, and take the subsequent filtrate for injection.

[0111] Blank solvent 2: Dimethyl sulfoxide.

[0112] Preparation of test solution 2: Take an appropriate amount of this product (olmesartan medoxomil to be tested), dissolve it in blank solvent 2 and quantitatively dilute to prepare a solution containing about 100 mg per 1 mL, filter, and take the subsequent filtrate for injection.

[0113] Blank solvent 3: n-Heptane.

[0114] Preparation of test solution 3: Take an appropriate amount of this product (olmesartan medoxomil to be tested), dissolve it in blank solvent 3 and quantitatively dilute to prepare a solution containing about 100 mg per 1 mL, filter, and take the subsequent filtrate for injection.

[0115] Blank solvent 4: A blank solvent 4 is obtained by mixing dichloromethane, chloroform and isopropanol in a volume ratio of 7:7:3 evenly.

[0116] Preparation of test solution 4: Take an appropriate amount of this product (olmesartan medoxomil to be tested), dissolve it in blank solvent 4 and quantitatively dilute to prepare a solution containing about 100 mg per 1 mL, filter, and take the subsequent filtrate for injection.

[0117] Blank solvent 5: A blank solvent 5 is obtained by mixing ethanol and dichloromethane in a volume ratio of 1:1 evenly.

[0118] Preparation of test solution 5: Take an appropriate amount of this product (olmesartan medoxomil to be tested), dissolve it in blank solvent 5 and quantitatively dilute to prepare a solution containing about 100 mg per 1 mL, filter, and take the subsequent filtrate for injection.

[0119] Preparation of reference solution: Take appropriate amounts of reference substances of impurity 1, impurity 2, impurity 3 and impurity 4, dissolve them in blank solvent 5 and quantitatively dilute to prepare a solution containing about 4 μg of each per 1 mL.

[0120] Spiked test solution: Take an appropriate amount of this product, dissolve it in the reference solution and quantitatively dilute to prepare a solution containing about 100 mg of olmesartan medoxomil and about 4 μg of each genotoxic impurity per 1 mL, filter, and take the subsequent filtrate for injection.

[0121] (2) Use a gas chromatograph for detection, and the gas chromatography conditions are as follows:

[0122] The chromatographic column is a capillary column dedicated to the analysis of amine compounds (CP-Volamine, 30 m × 0.32 mm, 5 μm); the inlet temperature is 200 °C; the detector is a flame ionization detector with a temperature of 220 °C. The carrier gas is nitrogen with a flow rate of 1.0 mL / min.

[0123] The temperature programming process is as follows:

[0124] 1) The initial temperature is 40 °C and the holding time is 5 minutes;

[0125] 2) The temperature is raised at a rate of 10 °C per minute to 100 °C;

[0126] 3) The temperature is raised at a rate of 30 °C per minute to 200 °C and the holding time is 20 minutes.

[0127] (3) Conclusion: The specific detection chromatogram is as Figures 5 - 10 shown. It can be seen from Figures 5 - 10 that the resolution between genotoxic impurities meets the requirements, and these four impurities are not detected in the test solution.

[0128] Example 3

[0129] (1) Solution preparation:

[0130] Blank solvent: Chloroform and isopropanol are mixed evenly in a volume ratio of 7:3 to obtain the blank solvent.

[0131] Preparation of test solution: An appropriate amount of this product (the to-be-tested olmesartan medoxomil) is taken, dissolved in the blank solvent and quantitatively diluted to prepare a solution containing about 100 mg per 1 mL, filtered, and the subsequent filtrate is injected.

[0132] Preparation of reference solution: Appropriate amounts of the reference stock solutions of impurity 1, impurity 2, impurity 3, and impurity 4 are taken, dissolved in the blank solvent and quantitatively diluted to prepare a solution containing about 4 μg per 1 mL for each.

[0133] Spiked test solution: An appropriate amount of this product is taken, dissolved in the reference solution and quantitatively diluted to prepare a solution containing about 100 mg of olmesartan medoxomil and about 4 μg of each genotoxic impurity per 1 mL, filtered, and the subsequent filtrate is injected.

[0134] (2) Detection is performed using a gas chromatograph. The gas chromatography conditions are as follows:

[0135] The chromatographic column is a capillary column dedicated to the analysis of amine compounds (CP-Volamine, 30 m × 0.32 mm, 5 μm); the inlet temperatures are 150 °C, 180 °C, and 200 °C respectively; the detector is a flame ionization detector with a temperature of 220 °C. The carrier gas is nitrogen with a flow rate of 1 mL / min.

[0136] The temperature programming process is as follows:

[0137] 1) The initial temperature is 40°C, and the holding time is 5 minutes;

[0138] 2) The heating rate is 10°C per minute, and it is heated to 100°C;

[0139] 3) The heating rate is 30°C per minute, and it is heated to 200°C, and the holding time is 20 minutes.

[0140] (3) Conclusion: The specific detection chromatogram is as Figures 11 - 14 shown. It can be seen from Figures 11 - 14 that the resolution between genotoxic impurities meets the requirements, and these four impurities are not detected in the test solution.

[0141] Example 4

[0142] (1) Solution preparation:

[0143] Blank solvent: Ethanol and dichloromethane are mixed evenly according to the volume ratio of 1:1 to obtain the blank solvent.

[0144] Preparation of test solution: Take an appropriate amount of this product (olmesartan medoxomil to be tested), dissolve it with the blank solvent and quantitatively dilute it to a solution containing about 100 mg per 1 mL, filter, and take the subsequent filtrate for injection.

[0145] Preparation of reference solution: Take appropriate amounts of reference substances of impurity 1, impurity 2, impurity 3, and impurity 4, dissolve them with the blank solvent and quantitatively dilute them to a solution containing about 4 μg per 1 mL each.

[0146] Spiked test solution: Take an appropriate amount of this product, dissolve it with the reference solution and quantitatively dilute it to a solution containing about 100 mg of olmesartan medoxomil and about 4 μg of each genotoxic impurity per 1 mL, filter, and take the subsequent filtrate for injection.

[0147] (2) Detection is carried out using a gas chromatograph, and the gas chromatographic conditions are as follows:

[0148] The chromatographic column is a capillary column dedicated to the analysis of amine compounds (CP-Volamine, 30 m × 0.32 mm, 5 μm); the injection port temperature is 200°C; the detector is a flame ionization detector, and the temperature is 220°C. The carrier gas is nitrogen, and the flow rate is 1.0 mL / min.

[0149] The temperature programming process is as follows:

[0150] 1) The initial temperature is 40°C, and the holding time is 5 minutes;

[0151] 2) The heating rate is 10°C per minute, and it is heated to 200°C, and the holding time is 15 minutes.

[0152] (3) Conclusion: The specific detection chromatogram is as shown in Figures 15 - 16 as follows. It can be seen from Figures 15 - 16 that the resolution between genotoxic impurities meets the requirements, and these four impurities are not detected in the test solution.

[0153] II. Method Validation Example

[0154] Example 5

[0155] The method in Example 1 was validated, and the validation results are shown in Table 1 below. It can be seen from Table 1 that all validations of this method can meet the standard requirements, indicating that this method can meet the detection requirements for genotoxic impurities in olmesartan medoxomil and its starting materials.

[0156] Table 1 Method Validation Results

[0157]

[0158] III. Detection of Key Starting Material (4-Chloromethyl-5-methyl-1,3-dioxol-2-one)

[0159] Example 6

[0160] (1) Solution Preparation:

[0161] Blank Solvent: Dichloromethane.

[0162] Preparation of Material Solution: Take an appropriate amount of 4-chloromethyl-5-methyl-1,3-dioxol-2-one, dissolve it with the blank solvent and quantitatively dilute it to make a solution containing about 200 mg per 1 mL.

[0163] (2) Gas Chromatography Conditions:

[0164] Chromatographic Column: A capillary column dedicated to the analysis of amine compounds (CP-Volamine, 30 m × 0.32 mm, 5 μm); the injection port temperature is 200 °C; the detector is a flame ionization detector, and the temperature is 220 °C. The carrier gas is nitrogen.

[0165] The programmed temperature rise process is as follows:

[0166] 1) The initial temperature is 40 °C, and the holding time is 5 minutes;

[0167] 2) The temperature is raised at a rate of 10 °C per minute to 100 °C;

[0168] 3) The temperature is raised at a rate of 30 °C per minute to 200 °C, and the holding time is 20 minutes.

[0169] (3)Conclusion: Under this chromatographic condition, the separation of genotoxic impurities from surrounding impurities in the key starting material meets the requirements. Therefore, this method can also be used to detect genotoxic impurities in the key starting material (see the attached figure Figure 17 ).

[0170] Comparative Example 1

[0171] Gas chromatography detection was performed using the same spiked test solution as in Example 1.

[0172] (1)Gas chromatography conditions:

[0173] The chromatographic column was a capillary column of dimethyl polysiloxane (30 m × 0.32 mm, 0.25 μm); the initial temperature was 40 °C, maintained for 5 minutes, then heated at a rate of 15 °C per minute to 300 °C and maintained for 10 minutes; the injection port temperature was 300 °C; the detector was a flame ionization detector with a temperature of 320 °C; the injection volume was 1 μL; the concentration of the mixed solution was 10 mg / mL.

[0174] (2)Conclusion: This method uses the conventional gas chromatography method, and the resolution between the genotoxic impurity peak and the surrounding peaks does not meet the requirements, and it cannot meet the detection requirements of genotoxic impurities in olmesartan medoxomil (see the attached figure Figure 18 ).

[0175] Comparative Example 2

[0176] (1)Solution preparation:

[0177] Blank solvent: N-methylpyrrolidone.

[0178] Preparation of test solution: Take an appropriate amount of this product, dissolve it with the blank solvent and quantitatively dilute it to a solution containing about 100 mg per 1 mL, filter, and take the subsequent filtrate for injection.

[0179] (2)Gas chromatography conditions:

[0180] The chromatographic column was a special column for the analysis of amine compounds (CP-Volamine, 30 m × 0.32 mm, 5 μm) capillary column; the injection port temperature was 200 °C; the detector was a flame ionization detector with a temperature of 220 °C. The carrier gas was nitrogen with a flow rate of 1.0 mL / min.

[0181] The programmed temperature rise process was as follows:

[0182] 1)The initial temperature was 40 °C and the holding time was 5 minutes;

[0183] 2)The heating rate was 10 °C per minute and it was heated to 100 °C;

[0184] 3)The heating rate was 30 °C per minute and it was heated to 200 °C, and the holding time was 20 minutes.

[0185] (3)Conclusion: The specific detection chromatogram is as Figure 19 shown. From the comparison result with the spiked test solution detected under the same chromatographic conditions ( Figure 19 ), it can be seen that the blank solvent interferes with the detection of impurities. Figure 10

[0186] Comparative Example 3

[0187] (1)Solution preparation:

[0188] Blank solvent: Acetonitrile and aniline are mixed evenly according to a volume ratio of 9:1 to obtain the blank solvent.

[0189] Preparation of test solution: Take an appropriate amount of this product, dissolve it with the blank solvent and quantitatively dilute it to make a solution containing about 10 mg per 1 mL.

[0190] (2)Gas chromatography conditions:

[0191] The chromatographic column is a capillary column dedicated to the analysis of amine compounds (CP-Volamine, 30 m × 0.32 mm, 5 μm); the injection port temperature is 150 °C; the detector is a flame ionization detector, and the temperature is 220 °C. The carrier gas is nitrogen, and the flow rate is 1.0 mL / min.

[0192] The programmed temperature rise process is as follows:

[0193] 1) The initial temperature is 40 °C, and the holding time is 5 minutes;

[0194] 2) The temperature is raised at a rate of 10 °C per minute to 100 °C;

[0195] 3) The temperature is raised at a rate of 30 °C per minute to 200 °C, and the holding time is 20 minutes.

[0196] (3)Conclusion: When the sample is dissolved with the solvent in the literature, the concentration of the test solution cannot meet the requirements of impurity detection sensitivity under this condition.

[0197] Comparative Example 4

[0198] The same spiked test solution as in Example 4 was used for gas chromatography detection.

[0199] (1)Detection was carried out using a gas chromatograph, and the gas chromatography conditions were as follows:

[0200] The chromatographic column is a capillary column dedicated to the analysis of amine compounds (CP-Volamine, 30 m × 0.32 mm, 5 μm); the injection port temperature is 200 °C; the detector is a flame ionization detector, and the temperature is 220 °C. The carrier gas is nitrogen, and the flow rate is 2.0 mL / min.

[0201] The temperature programming process is as follows:

[0202] 1) The initial temperature is 40°C, and the holding time is 5 minutes;

[0203] 2) The heating rate is 10°C per minute, heating to 200°C, and the holding time is 15 minutes.

[0204] (2) Conclusion: The specific detection spectra are as shown in Figure 20 As can be seen from Figure 20 : The resolution between the genotoxic impurity peak and the surrounding peaks does not meet the requirements, and it cannot meet the detection requirements of genotoxic impurities in olmesartan medoxomil.

[0205] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope recorded in this specification.

[0206] The above-described embodiments only represent several implementation manners of the present invention, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the present invention patent should be subject to the appended claims.

Claims

1. A method for detecting olmesartan medoxomil raw material drug and genotoxic impurities, characterized in that The detection method is as follows: (1) Preparation of solutions: Preparation of test solution: Take an appropriate amount of this product, dissolve it with blank solvent and quantitatively dilute, filter, and take the subsequent filtrate for injection; Preparation of reference solution: Take appropriate amounts of reference substances of impurity 1, impurity 2, impurity 3, and impurity 4, dissolve them with blank solvent and quantitatively dilute to obtain a reference solution; The impurity 1 is 4-chloro-4-methyl-5-enyl-1,3-dioxolane-2-one, impurity 2 is 4,5-dimethyl-1,3-dioxolene-2-one, impurity 3 is (4R,5R)-4,5-dichloro-4,5-dimethyl-1,3-dioxolane-2-one, and impurity 4 is (4S,5R)-4,5-dichloro-4,5-dimethyl-1,3-dioxolane-2-one; (2) Detection is carried out by gas chromatography, and the chromatographic conditions are as follows: The detector is a flame ionization detector, and the capillary chromatographic column is CP-Volamine; The injection port temperature is 150 - 200 °C, the detector temperature is 215 - 225 °C, the column temperature is programmed temperature rise, and the carrier gas is nitrogen; The process of the programmed temperature rise is as follows: 1) The initial temperature is 40 °C, and the holding time is 5 - 6 minutes; 2) The temperature is raised at a rate of 10 °C per minute to 100 °C; 3) The temperature is raised at a rate of 30 °C per minute to 200 °C, and the holding time is 10 - 20 minutes; The blank solvent is any one of the combinations of chloroform - methanol, chloroform - ethanol, chloroform - isopropanol, dichloromethane - methanol, dichloromethane - ethanol, dichloromethane - isopropanol, dichloromethane - chloroform - methanol, dichloromethane - chloroform - ethanol, and dichloromethane - chloroform - isopropanol.

2. The detection method of an olmesartan medoxomil raw material drug and a genotoxic impurity according to claim 1, wherein, 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.

3. The detection method of an olmesartan medoxomil raw material drug and a genotoxic impurity according to claim 1, wherein, The specification of the CP-Volamine chromatographic column is 30m × 0.32mm × 5μm.

4. The detection method of an olmesartan medoxomil raw material drug and a genotoxic impurity according to claim 1, wherein The injection method is headspace injection or direct injection.

5. The detection method of an olmesartan medoxomil bulk drug and genotoxic impurities according to claim 1, wherein The flow rate in step (2) is 0.5 mL / min - 4.0 mL / min.

6. The detection method of an olmesartan medoxomil raw material drug and a genotoxic impurity according to claim 1, wherein The flow rate in step (2) is 1.0 mL / min.

7. The detection method of an olmesartan medoxomil bulk drug and genotoxic impurities according to claim 1, wherein, The process of the programmed temperature rise is as follows: 1) The initial temperature is 40 °C, and the holding time is 5 minutes; 2) The temperature is raised at a rate of 10 °C per minute to 100 °C; 3) The temperature is raised at a rate of 30 °C per minute to 200 °C, and the holding time is 20 minutes.

8. The detection method of an olmesartan medoxomil raw material drug and a genotoxic impurity according to claim 1, characterized in that, The injection port temperature is 150 °C, and the detector temperature is 220 °C.

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