Method for detecting related substances of perampanel bulk drug

Abstract

The invention provides a method for detecting related substances of a perampanel bulk drug, which is characterized in that separation and detection are carried out by adopting a high performance liquid chromatography method, taking a silica gel bonded octadecylsilane column as a chromatographic column, taking a certain proportion of inorganic salt buffer solution-organic phase as a mobile phase and adopting a gradient elution mode. According to the method for detecting the related substances of the perampanel bulk drug, 10 impurities in the bulk drug can be detected at a time, the specificity is high, the precision is high, the repeatability is good, the quality of the drug can be effectively controlled, and the safety of the drug is guaranteed.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical drug analysis, and in particular to a method for detecting related substances of a perampanel raw material drug. The method uses high performance liquid chromatography to perform qualitative or quantitative analysis on perampanel and related substances, thereby effectively controlling the quality of the perampanel raw material drug. Background Art

[0002] Perampanel, English name Perampanel, chemical name: 2-(2-oxido-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridine-3) benzonitrile hydrate (3 / 4), its molecular formula is C 23 H 15 N3O·3 / 4H2O, molecular weight is 362.90 (3 / 4 hydrate); 349.38 (anhydrous).

[0003] The structural formula of Perampanel (hydrate) is:

[0004] Perampanel is a drug developed by Japan's Eisai Co., Ltd., which works by non-competitively inhibiting the AMPA-type glutamate receptor group. Perampanel tablets were approved for marketing in the European Union and the United States in 2012 for the treatment of partial seizures in patients with epilepsy over 12 years old. This drug is the first anti-epileptic drug with this mechanism of action approved by the FDA. So far, it has been approved in more than 50 countries.

[0005] Related substances are starting materials, intermediates, side reaction products and degradation impurities introduced during the drug synthesis production process. Detection of related substances can control the quality and safety of drugs. For related impurities introduced in the synthesis of perampanel, quality control is required in the raw materials. Therefore, separation of perampanel and other related substances and accurate quantification are of great practical significance in the quality control of the perampanel synthesis process. Summary of the invention

[0006] The present invention provides a method for detecting related substances of a perampanel raw material drug, thereby being able to quickly, effectively and accurately monitor the purity of perampanel and achieve quality control of the final product raw material drug.

[0007] The invention provides a method for detecting related substances in a perampanel raw material drug, which adopts high performance liquid chromatography, uses a chromatographic column with silica gel bonded with octadecylsilane as the stationary phase, uses a certain proportion of an inorganic salt buffer solution as a mobile phase A and an organic phase as a mobile phase B, and performs isocratic elution.

[0008] The present invention provides a method for detecting related substances in a perampanel raw material drug, wherein the isocratic elution procedure is:

[0009] Preferably, the inorganic salt buffer solution is phosphate, specifically potassium dihydrogen phosphate, with a concentration of 0.01 mol / L and a pH value of 4.5.

[0010] Preferably, the organic phase is acetonitrile.

[0011] Preferably, the chromatographic column provided is 00F-4251-E0 Luna (4.6 mm×150 mm, 3 µm).

[0012] The separation and determination method of the present invention can be implemented according to the following method: (1) Take an appropriate amount of perampanel sample and dissolve it in 70% acetonitrile to prepare a sample solution containing 0.2 mg of perampanel per 1 ml.

[0013] (2) Set the mobile phase flow rate to 0.5-1.5 mL / min, preferably 1.0 mL / min, the detection wavelength to 220-260 nm, with the optimal detection wavelength being 254 nm, and the column oven temperature to 20-50 °C, with the optimal column oven temperature being 30 °C.

[0014] Take 10 to 50 μl of the sample solution (1) above and inject it into a liquid chromatograph to separate and determine perampanel and related substances.

[0015] The detection method of the present invention has strong specificity and high stability. The detection method has good reproducibility and can effectively separate the related substances of perampanel. The present invention solves the problem of separation and determination of the related substances of perampanel, thereby reducing the occurrence of side reactions, improving the yield and purity of the product, and ensuring the controllable quality of perampanel. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 This is the HPLC chart of the blank solvent of perampanel in Example 1.

[0017] Figure 2 This is the HPLC chart of the perampanel intermediate and its related substances in Example 1.

[0018] Figure 3 This is the HPLC chart of the blank solvent of perampanel in Example 2.

[0019] Figure 4 This is the HPLC chart of the perampanel intermediate and its related substances in Example 2.

[0020] [ Figure 5 This is the HPLC chart of the blank solvent of perampanel in Example 3.

[0021] Figure 6This is the HPLC chart of the perampanel intermediate and its related substances in Example 3. DETAILED DESCRIPTION

[0022] The following examples are used to further understand the present invention, but are not intended to limit the scope of this embodiment. Example

[0023] Instruments and conditions High performance liquid chromatograph: Agilent 1260 InfinityII; Column: 00F-4251-E0 Luna (4.6 mm × 150 mm, 3 µm); Mobile phase A: 0.01 mol / L potassium dihydrogen phosphate buffer solution (weigh 1.36 g potassium dihydrogen phosphate, dissolve in water and dilute to 1000 ml, adjust pH to 4.4 with phosphoric acid); mobile phase B: acetonitrile; elution is performed according to the following gradient:

[0024] Flow rate: 1.0 mL / min; column temperature: 30°C; detection wavelength: 220 nm; injection volume: 10 μl.

[0025] Take an appropriate amount of perampanel and its impurities, dissolve the sample in 70% acetonitrile, and prepare a sample solution containing 0.2 mg / mL perampanel and an appropriate concentration of its impurities. Perform HPLC analysis under the above conditions and record the chromatogram. The results are shown in the attached Figure 1 and 2 , Figure 2 The chromatographic peak with a retention time of 19.319 min is perampanel, and the other chromatographic peaks are the chromatographic peaks of various impurities of perampanel.

[0026] Example 2 Instruments and conditions High performance liquid chromatograph: Agilent 1260 InfinityII; Column: 00F-4251-E0 Luna (4.6 mm × 150 mm, 3 µm); Mobile phase A: 0.01 mol / L potassium dihydrogen phosphate buffer solution (weigh 1.36 g potassium dihydrogen phosphate, dissolve in water and dilute to 1000 ml, adjust pH to 4.5 with phosphoric acid); mobile phase B: acetonitrile; elution is performed according to the following gradient:

[0027] Flow rate: 1.0 mL / min; column temperature: 30°C; detection wavelength: 220 nm; injection volume: 10 μl; Take an appropriate amount of perampanel and its impurities, dissolve the sample in 70% acetonitrile, and prepare a sample solution containing 0.2 mg / mL perampanel and an appropriate concentration of its impurities. Perform HPLC analysis under the above conditions and record the chromatogram. The results are shown in the attached Figure 3 and 4 , Figure 4 The chromatographic peak with a retention time of 19.673 min is perampanel, and the other chromatographic peaks are the chromatographic peaks of various impurities of perampanel.

[0028] Example 3 Instruments and conditions High performance liquid chromatograph: Agilent 1260 InfinityII; Column: 00F-4251-E0 Luna (4.6 mm × 150 mm, 3 µm); Mobile phase A: 0.01 mol / L potassium dihydrogen phosphate buffer solution (weigh 1.36 g potassium dihydrogen phosphate, dissolve in water and dilute to 1000 ml, adjust pH to 4.6 with phosphoric acid); mobile phase B: acetonitrile; elution according to the following gradient:

[0029] Flow rate: 1.0 mL / min; Column temperature: 30°C; Detection wavelength: 220nm; Injection volume: 10 μl; Take an appropriate amount of perampanel and its impurities, dissolve the sample in 70% acetonitrile, and prepare a sample solution containing 0.2 mg / mL perampanel and an appropriate concentration of its impurities. Perform HPLC analysis under the above conditions and record the chromatogram. The results are shown in the attached Figure 5 and 6 , Figure 6 The chromatographic peak with a retention time of 19.337 min is perampanel, and the other chromatographic peaks are the chromatographic peaks of various impurities of perampanel.

[0030] from Figure 1 - Figure 6 It is shown that the method of the present invention can separate perampanel from its impurities and can accurately perform quantitative detection, thereby effectively controlling the product quality of perampanel.

Claims

1. A method for separating the related substances of perampanel raw materials, using high performance liquid chromatography, a chromatographic column is a silica gel bonded octadecylsilane column, a certain proportion of inorganic salt buffer solution-organic phase as the mobile phase, and gradient elution is performed to separate perampanel from various impurities.

2. The method for analyzing and detecting related substances of the perampanel bulk drug according to claim 1, characterized in that: The organic phase is selected from one of the following compounds: methanol and acetonitrile.

3. The method for analyzing and detecting related substances of the perampanel raw material drug according to claim 1, characterized in that: The inorganic salt buffer solution is selected from one of the following inorganic salts: citrate, phosphate, and perchlorate.

4. The method for analyzing and detecting related substances of the perampanel raw material drug according to claim 1, characterized in that: The isocratic process is: 。 5. The method for analyzing and detecting related substances of the perampanel raw material drug according to claim 1, characterized in that: The chromatographic column preferably has a length of 150 mm, a diameter of 4.6 mm, and a filler particle size of 3 μm.

6. The method for analyzing and detecting related substances of the perampanel raw material drug according to claims 1 and 3, characterized in that: The inorganic salt buffer solution is preferably phosphate, with an optimal concentration of 0.01 mol / L and a pH value of 4.

5.

7. The method for analyzing and detecting related substances of the perampanel raw material drug according to claims 1 and 2, characterized in that: The organic phase is preferably acetonitrile.

8. The method for analyzing and detecting related substances of the perampanel raw material drug according to claim 1, characterized in that: The method comprises the following steps: ① setting the flow rate to 0.5-1.5 ml / min; ② setting the detection wavelength to 210-250 nm; ③ setting the column temperature to 20-50° C.; and ④ setting the injection volume to 5-20 μl.

9. The method for analyzing and detecting related substances of the perampanel raw material drug according to claim 8, characterized in that: The chromatographic conditions are as follows: ① the flow rate is preferably 1.0 ml / min; ② the wavelength is preferably 220 nm; ③ the column temperature is preferably 30°C; ④ the injection volume is preferably 10 µl.

10. The method for analyzing related substances of the perampanel bulk drug according to claim 1, characterized in that: The impurities are:

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