阅读说明：本技术 一种n-亚硝基二甲胺杂质的检测方法 (Method for detecting N-nitrosodimethylamine impurity ) 是由 肖潭 黄天培 林金生 周强 吴桐 叶丹凤 蔡虹 朱文泉 陈文斌 李敏 于 2018-07-10 设计创作，主要内容包括：一种N-亚硝基二甲胺(NDMA)杂质的检测方法,其包括：(1)获得含有待测样品的供试品溶液；(2)采用气质联用法对所述供试品溶液进行检测,以确定样品中N-亚硝基二甲胺杂质的含量。本发明所提供的方法分离效果好,线性范围宽,并且灵敏度高、方法耐用性好,可以快速有效地检测样品中N-亚硝基二甲胺(NDMA)含量。(A method for detecting N-Nitrosodimethylamine (NDMA) impurities, comprising: (1) obtaining a test solution containing a sample to be tested; (2) and detecting the test solution by adopting a gas chromatography-mass spectrometry method to determine the content of N-nitrosodimethylamine impurities in the sample. The method provided by the invention has the advantages of good separation effect, wide linear range, high sensitivity and good durability, and can be used for quickly and effectively detecting the content of N-Nitrosodimethylamine (NDMA) in a sample.)

A method for detecting N-nitrosodimethylamine impurities by gas chromatography-mass spectrometry, wherein the method comprises the following steps:

(1) obtaining a test solution containing a sample to be tested;

(2) and detecting the test solution by adopting a gas chromatography-mass spectrometry method to determine the content of N-nitrosodimethylamine impurities in the sample.

The method according to claim 1, wherein the method comprises the steps of:

(1) dissolving a sample to be tested containing or possibly containing N-nitrosodimethylamine impurities into a diluent to prepare a test solution; when the sample to be detected is a solvent used in the synthetic process of the sartan bulk drug, the solvent is directly injected without being dissolved by a diluent;

(2) transferring the prepared test solution into a sample injection vial or a headspace vial; the solution in the injection vial or headspace vial was subjected to GC analysis.

The method of claim 1 or 2, wherein step (2) comprises: injecting the test solution into a gas chromatograph-mass spectrometer for detection, recording a spectrogram of the test solution, and determining the content of N-nitrosodimethylamine in the sample to be detected according to a pre-obtained standard curve of the N-nitrosodimethylamine.

The method of any one of claims 1-3, wherein the sample to be tested is a sartan drug substance intermediate, a solvent used in a sartan drug substance synthesis process, a sartan drug substance or a composition comprising a sartan drug substance;

preferably, the sartan drug substance is selected from a compound shown in formula I:

wherein R is₁Represents

R ₃Represents H or K;

more preferably, the sartan bulk drug is selected from losartan potassium, irbesartan or valsartan;

preferably, the sartan drug substance intermediate is selected from a compound shown in formula II:

wherein R is₁Represents

The method of any one of claims 1-4, wherein:

when the sample to be detected is a sartan bulk drug intermediate or a sartan bulk drug, dissolving the sample to be detected in a diluent to obtain a test sample solution;

when the sample to be detected is the composition containing the sartan bulk drug, the composition containing the sartan bulk drug is disintegrated by a diluent to obtain a test solution;

and when the sample to be detected is the solvent used in the synthetic process of the sartan bulk drug, directly taking the solvent as a test solution.

The method according to any one of claims 1-5, wherein the method comprises the steps of:

(1) when the sample to be detected is the intermediate of the sartan bulk drug or the sartan bulk drug, dissolving the intermediate of the sartan bulk drug or the sartan bulk drug with a diluent and fixing the volume to prepare a test solution containing 1-5000 mg, preferably 1-1000 mg and most preferably 5-200 mg of the intermediate of the sartan bulk drug or the sartan bulk drug in 1mL volume;

when the sample to be tested is the composition containing the sartan bulk drug, the composition containing the sartan bulk drug is disintegrated by a diluent and subjected to constant volume to prepare a test solution containing 1-5000 mg, preferably 1-1000 mg, more preferably 5-500 mg and most preferably 5-30 mg of the sartan bulk drug in 1mL volume;

when the sample to be detected is a solvent used in the process, directly using the solvent as a test solution;

(2) injecting the test solution into a gas chromatograph-mass spectrometer for detection, recording a spectrogram of the test solution, and determining the content of N-nitrosodimethylamine in the sample to be detected according to a pre-obtained standard curve of the N-nitrosodimethylamine.

The method of claim 5 or 6, wherein the diluent is selected from water, polar organic solvents, or mixtures thereof;

preferably, the polar organic solvent is selected from one of N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, methanol, ethanol, isopropanol, acetone, methyl t-butyl ether, acetonitrile, ethylene glycol, propylene glycol, glycerol, formic acid, acetic acid, propionic acid, methanesulfonic acid, triethylamine, dimethylamine, dimethylpropylamine, pyridine, morpholine, piperazine, tetrahydropyrrole, piperidine, or any combination thereof.

The method of any one of claims 1-7, wherein the chromatography conditions of the gas chromatography-mass spectrometry are as follows:

and (3) analyzing the column: the gas chromatographic column comprises a fixed phase which is one or any combination of polysiloxane polymer, cyanopropyl phenyl dimethyl polysiloxane copolymer, cyanopropyl dimethyl polysiloxane copolymer, trifluoropropyl dimethyl polysiloxane copolymer, phenyl dimethyl polysiloxane copolymer, dipropyl phenyl dimethyl polysiloxane copolymer, diphenyl dimethyl polysiloxane copolymer and polyethylene glycol;

the carrier gas is selected from hydrogen, nitrogen or helium;

column temperature: 30-350 ℃; preferably 40-300 ℃; more preferably 45-250 ℃;

the split ratio is as follows: 1: 1-500: 1; preferably 1:1 to 100: 1; more preferably 1:1 to 50: 1; preferably 3: 1-25: 1;

sample inlet temperature: 100-350 ℃; preferably 150-300 ℃; more preferably 150 to 200 ℃;

and (3) sample introduction mode: directly injecting sample or injecting sample in headspace, preferably injecting sample in headspace;

a detector: and a mass spectrum detector.

The method of claim 8, wherein the stationary phase composition of the gas chromatography column is 14% cyanopropylphenyl-86% dimethylpolysiloxane copolymer, 35% phenyl-65% dimethylpolysiloxane copolymer, 5% phenyl-95% dimethylpolysiloxane copolymer, 6% cyanopropyl-94% dimethylpolysiloxane copolymer, 7% cyanopropyl-7% phenyl-86% dimethylpolysiloxane copolymer, 50% cyanopropyl-50% dimethylpolysiloxane copolymer, and 5% cyanopropyl-95% dimethylpolysiloxane copolymer or polyethylene glycol having a molecular weight of 1 to 100 ten thousand.

The method of claim 8 or 9, wherein the mass spectrometer detector is selected from the group consisting of a single quadrupole mass spectrometer detector, a quadrupole-time-of-flight mass spectrometer detector, and a triple quadrupole mass spectrometer detector.