WO2020010516A1 - 一种n-亚硝基二甲胺杂质的检测方法 - Google Patents

一种n-亚硝基二甲胺杂质的检测方法 Download PDF

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WO2020010516A1
WO2020010516A1 PCT/CN2018/095142 CN2018095142W WO2020010516A1 WO 2020010516 A1 WO2020010516 A1 WO 2020010516A1 CN 2018095142 W CN2018095142 W CN 2018095142W WO 2020010516 A1 WO2020010516 A1 WO 2020010516A1
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sample
sartan
nitrosodimethylamine
test solution
ndma
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PCT/CN2018/095142
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English (en)
French (fr)
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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
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浙江华海药业股份有限公司
浙江华海天诚药业有限公司
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Priority to US17/258,226 priority Critical patent/US11519890B2/en
Priority to CN201880094511.0A priority patent/CN112639463A/zh
Priority to EP18926246.2A priority patent/EP3819634B1/en
Publication of WO2020010516A1 publication Critical patent/WO2020010516A1/zh

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers
    • G01N30/7206—Mass spectrometers interfaced to gas chromatograph
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • G01N2030/067—Preparation by reaction, e.g. derivatising the sample
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G01N2030/8872—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample impurities
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers

Definitions

  • the invention relates to the field of chemical analysis, in particular to a method for detecting N-nitrosodimethylamine (NDMA) impurities.
  • NDMA N-nitrosodimethylamine
  • Angiotensin II receptor antagonists include Losartan Potassium, Valsartan, Irbesartan, and Candersartan Celexetil. Ester), etc., they are commonly used in clinical antihypertensive drugs.
  • This class of antihypertensive drugs contains biphenyl tetrazolium groups. The most common construction strategy for this functional group is to use cyanobiphenyl and azide. The tetrazolium ring is synthesized at high temperature. The general industrializable route of this sartan compound is shown as follows:
  • R 1 represents Etc.
  • R 2 stands for Na, K, TMS and the like.
  • the solvent may be selected from N, N-dimethylformamide, toluene, xylene and the like.
  • N, N-dimethylformamide (DMF) has excellent solubility and a relatively high boiling point, it is tetrazole cyclic
  • DMF N, N-dimethylformamide
  • the reactants such as sodium azide and TMSN 3 are used in excess.
  • the compound is quenched, otherwise the remaining azide compound will produce toxic azide acid in the subsequent process; in addition, the material containing the residual azide compound and copper or other transition metal When materials are in contact, they can easily explode.
  • residual azide is usually treated with nitrous acid under acidic conditions.
  • N-nitrosodimethylamine (NDMA)
  • solvents used in the process, sartan APIs or compositions containing sartan APIs quality control is required for N-nitrosodimethylamine in related products ( NDMA).
  • An object of the present invention is to provide a method for detecting N-nitrosodimethylamine (NDMA) impurities in a sample.
  • This method is particularly suitable for the detection of trace N-nitrosodimethylamine (NDMA) impurities; the specific scheme is as follows:
  • a method for detecting N-nitrosodimethylamine impurities includes the following steps:
  • test solution is tested by GC-MS to determine the content of N-nitrosodimethylamine impurities in the sample.
  • the test solution can be prepared directly in a sample bottle or headspace bottle suitable for GC / MS instrument injection; the test solution can also be prepared in another container, and then the test solution can be prepared.
  • the test solution is transferred to a sample bottle or headspace bottle for injection detection.
  • whether a sample bottle or a headspace bottle is used may be determined according to an actual sampling method.
  • the method includes the following steps:
  • test sample containing or possibly containing N-nitrosodimethylamine impurities is dissolved in a diluent to prepare a test solution; when the test sample is a solvent used in the synthesis process of a raw material drug of the sartan type , Then do not dissolve the diluent, directly inject the solvent;
  • sample to be tested may also be referred to as a sample; the diluent may also be referred to as a diluent; and the test solution may also be referred to as a sample solution.
  • step (2) includes: injecting the test solution into the gas chromatography-mass spectrometer for detection, recording the spectrum of the test solution, and according to the previously obtained N-nitrosodimethyl A standard curve of amines to determine the content of N-nitrosodimethylamine in the test sample.
  • recording the spectrum of the test solution can determine the peak area of N-nitrosodimethylamine in the test solution, and then using the standard curve method according to the determined standard curve, the supply of the The content of N-nitrosodimethylamine in the test solution can then be determined by simple conversion to determine the content of N-nitrosodimethylamine impurities in the sample.
  • the standard curve of N-nitrosodimethylamine is determined by the following method:
  • the sample to be tested may be a sample containing or possibly containing N-nitrosodimethylamine (NDMA) impurities, including, but not limited to, the intermediates of the sartan-type APIs, used in the process A solvent, a sartan-type drug substance, or a composition containing a sartan-type drug substance.
  • NDMA N-nitrosodimethylamine
  • the saltan drug substance is selected from the compounds represented by formula I:
  • R 1 represents
  • R 3 represents H or K; herein, n-Bu represents n-butyl.
  • the sartan drug substance is selected from losartan potassium, irbesartan, valsartan, and the like.
  • the intermediates of the sartan APIs refer to compounds used to synthesize the above-mentioned sartan APIs, including but not limited to the compounds represented by Formula II:
  • R 1 represents
  • the solvent used in the process refers to the solvent used in the synthesis of the raw materials of the sartan class, including, but not limited to, ethyl acetate, toluene, xylene, methanol, N, N-dimethylformamide (DMF), formaldehyde Tert-butyl ether, methylene chloride and the like.
  • step (1) when the test sample is solid, step (1) includes: dissolving the test sample in a diluent to obtain a test solution; when the test sample is a liquid, for example, a process In the case of a solvent used in the test, the solvent can be directly used as a test solution.
  • test sample to be tested is a sartan-based API or a sartan-based API
  • test sample is dissolved in a diluent to obtain a test solution
  • the sample to be tested is a composition containing a saltan-type drug substance
  • the composition containing the saltan-type drug substance is disintegrated with a diluent to obtain a test solution
  • test sample is a solvent used in the process
  • the solvent is directly used as a test solution.
  • the method for detecting N-nitrosodimethylamine impurities provided by the present invention may include the following steps:
  • the volume contains the test substance solution of sartan-type API or sartan-type API in an amount of 1 to 5000 mg, preferably 1 to 1000 mg, more preferably 5 to 500 mg, and most preferably 5 to 200 mg;
  • the sartan-type drug substance-containing composition is disintegrated with a diluent and the volume is adjusted to prepare a sartan-type drug substance 1 to 1 mL volume 5000 mg, preferably 1 to 1000 mg, more preferably 5 to 500 mg, and most preferably 5 to 30 mg of a test solution;
  • test sample is a solvent used in the process
  • solvent is directly used as a test solution
  • the diluent is selected from water, a polar organic solvent, or a mixture thereof, and the polar organic solvent is further selected from N, N-dimethylformamide (DMF), N -Methylpyrrolidone, dimethyl sulfoxide (DMSO), methanol, ethanol, isopropanol, acetone, methyl tert-butyl ether, acetonitrile, ethylene glycol, propylene glycol, glycerol, formic acid, acetic acid, propionic acid, formazan One of sulfonic acid, triethylamine, dimethylamine, dimethylpropylamine, pyridine, morpholine, piperazine, tetrahydropyrrole, piperidine, or any combination thereof.
  • DMF N, N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • methanol ethanol
  • ethanol isopropanol
  • acetone methyl tert-but
  • the chromatographic conditions of the GC-MS method are as follows:
  • Analytical column gas chromatography column
  • the stationary phase composition is polysiloxane polymer, cyanopropylphenyldimethylpolysiloxane copolymer, cyanopropyldimethylpolysiloxane copolymer, trifluoropropyl Dimethyl polysiloxane copolymer, phenyldimethyl polysiloxane copolymer, dipropylxylylene polysiloxane copolymer, diphenyldimethyl polysiloxane copolymer, poly One of ethylene glycol or any combination thereof;
  • the stationary phase composition of the gas chromatography column is preferably 14% cyanopropylphenyl-86% dimethylpolysiloxane copolymer, 35% phenyl-65% dimethylpolysiloxane copolymer, 5 % Phenyl-95% dimethyl polysiloxane copolymer, 6% cyanopropyl-94% dimethyl polysiloxane copolymer, 7% cyanopropyl-7% phenyl-86% dimethyl Polysiloxane copolymer, 50% cyanopropyl-50% dimethylpolysiloxane copolymer, and 5% cyanopropyl-95% dimethylpolysiloxane copolymer or polyethylene glycol (molecular weight (Range: 10,000 to 1 million).
  • the carrier gas is selected from hydrogen, nitrogen or helium;
  • Inlet temperature 100-350 ° C; preferably 150-300 ° C; more preferably 150-200 ° C;
  • Injection method direct injection or headspace injection; headspace injection method is preferred;
  • the detector is selected from a mass spectrometric detector (MSD); preferably a single quadrupole mass spectrometer detector, a quadrupole-time of flight mass spectrometer detector (QTOF) or a triple quadrupole mass spectrometer detector (TQS).
  • MSD mass spectrometric detector
  • QTOF quadrupole-time of flight mass spectrometer detector
  • TQS triple quadrupole mass spectrometer detector
  • the method provided by the present invention for detecting N-nitrosodimethylamine impurities by gas-mass spectrometry has good separation effect, simple operation, high sensitivity and wide linear range, and can quickly and effectively detect N-nitrosodimethylamine in a sample Amine (NDMA) content.
  • FIG. 1 is a GC-MS spectrum of N-nitrosodimethylamine (NDMA) detection in the valsartan drug substance of Example 1.
  • FIG. 1 is a GC-MS spectrum of N-nitrosodimethylamine (NDMA) detection in the valsartan drug substance of Example 1.
  • N-nitrosodimethylamine is used as a reference substance for NDMA in sartan APIs, solvents used in the process, sartan APIs, or compositions containing sartan APIs The content is tested as follows:
  • Carrier gas Helium
  • the initial temperature is 60 ° C, hold for 2min, then increase the temperature to 240 ° C at a rate of 15 ° C / min, and hold for 5min.
  • Ion source mode EI, positive ion
  • Quadrupole temperature 150 °C
  • Standard solution preparation of N-nitrosodimethylamine (NDMA) reference substance Weigh an appropriate amount of N-nitrosodimethylamine (NDMA) reference substance and dilute it with a diluent to the NDMA concentration: 0.2, 0.8, 3.2, 6.4, 20 micrograms / mL, shake until completely dissolved and ready to use.
  • NDMA N-nitrosodimethylamine
  • N-nitrosodimethylamine (NDMA) content in valsartan raw materials NDMA
  • valsartan raw material (sample 1), accurately weigh it in a 20mL headspace bottle, and accurately transfer 2mL of the diluent, shake to dissolve, mix well, and use it as the test solution.
  • the above GC-MS method was used to test the test solution and different concentrations of NDMA standard solutions, and the standard curve method was used to calculate the NDMA content in sample 1.
  • N-nitrosodimethylamine (NDMA) in valsartan drug substance (Sample 1) The content was 13.0 ppm.
  • Carrier gas Helium
  • the initial temperature is 60 ° C, hold for 2min, then increase the temperature to 240 ° C at a rate of 15 ° C / min, and hold for 5min.
  • Ion source mode EI, positive ion
  • Quadrupole temperature 160 °C
  • Standard solution preparation of N-nitrosodimethylamine (NDMA) reference substance Weigh an appropriate amount of N-nitrosodimethylamine (NDMA) reference substance and dilute it with a diluent to the NDMA concentration: 0.2, 0.8, 3.2, 6.4, 20 micrograms / mL, shake until completely dissolved and ready to use.
  • NDMA N-nitrosodimethylamine
  • N-nitrosodimethylamine (NDMA) content in valsartan raw materials NDMA
  • Example 2 Weigh 400mg of valsartan raw material (sample 2), accurately weigh it in a 20mL headspace bottle, and then accurately remove 2mL of the diluent, shake to dissolve, and mix as the test solution.
  • the above-mentioned GC-MS method was used to test the test solution and different concentrations of NDMA standard solutions, and the standard curve method was used to calculate the NDMA content in sample 2. (Sample 2) The content was 3.4 ppm.
  • Carrier gas Helium
  • the initial temperature is 55 ° C, hold for 3min, then increase the temperature to 250 ° C at a rate of 15 ° C / min, and hold for 5min.
  • Ion source mode EI, positive ion
  • Quadrupole temperature 150 °C
  • Standard solution preparation of N-nitrosodimethylamine (NDMA) reference substance Weigh an appropriate amount of N-nitrosodimethylamine (NDMA) reference substance and dilute it with a diluent to the NDMA concentration: 0.2, 0.8, 3.2, 6.4, 20 micrograms / mL, shake until completely dissolved and ready to use.
  • NDMA N-nitrosodimethylamine
  • NDMA N-nitrosodimethylamine
  • irbesartan raw material drug (sample 3), accurately weigh it in a 20 mL headspace bottle, and then accurately remove 2 mL of the diluent, shake to dissolve, and mix as the test solution.
  • the above GC-MS method was used to test the test solution and different concentrations of NDMA standard solutions, and the standard curve method was used to calculate the NDMA content in sample 3.
  • N-nitrosodimethylamine (NDMA) was used as the raw material in irbesartan.
  • the content of the drug (Sample 3) was 0.28 ppm.
  • Carrier gas Helium
  • the initial temperature is 60 ° C, hold for 2min, then increase the temperature to 240 ° C at a rate of 15 ° C / min, and hold for 5min.
  • Ion source mode CI, positive ion
  • Quadrupole temperature 170 ° C
  • Standard solution preparation of N-nitrosodimethylamine (NDMA) reference substance Weigh an appropriate amount of N-nitrosodimethylamine (NDMA) reference substance and dilute it with a diluent to the NDMA concentration: 0.2, 0.8, 3.2, 6.4, 20 micrograms / mL, shake until completely dissolved and ready to use.
  • NDMA N-nitrosodimethylamine
  • NDMA N-nitrosodimethylamine
  • Carrier gas Helium
  • the initial temperature is 60 ° C, hold for 2min, then increase the temperature to 240 ° C at a rate of 15 ° C / min, and hold for 5min.
  • Ion source mode EI, positive ion
  • Quadrupole temperature 160 °C
  • Standard solution preparation of N-nitrosodimethylamine (NDMA) reference substance Weigh an appropriate amount of N-nitrosodimethylamine (NDMA) reference substance and dilute it with a diluent to the NDMA concentration: 0.2, 0.8, 3.2, 6.4, 20 micrograms / mL, shake until completely dissolved and ready to use.
  • NDMA N-nitrosodimethylamine
  • N-nitrosodimethylamine (NDMA) content in ethyl acetate of valsartan raw material crystallization solvent NDMA
  • Carrier gas nitrogen
  • the initial temperature is 55 ° C for 6 minutes, and then the temperature is increased to 250 ° C at a rate of 12 ° C / min, and the temperature is maintained for 5 minutes.
  • Ion source mode EI, positive ion
  • Quadrupole temperature 150 °C
  • Standard solution preparation of N-nitrosodimethylamine (NDMA) reference substance Weigh an appropriate amount of N-nitrosodimethylamine (NDMA) reference substance and dilute it with a diluent to the NDMA concentration: 0.2, 0.8, 3.2, 6.4, 20 micrograms / mL, shake until completely dissolved and ready to use.
  • NDMA N-nitrosodimethylamine
  • NDMA N-nitrosodimethylamine
  • Carrier gas Helium
  • the initial temperature is 45 ° C, hold for 5min, then increase the temperature to 200 ° C at a rate of 10 ° C / min, and hold for 5min
  • Ion source mode EI, positive ion
  • Quadrupole temperature 150 °C
  • Standard solution preparation of N-nitrosodimethylamine (NDMA) reference substance Weigh an appropriate amount of N-nitrosodimethylamine (NDMA) reference substance and dilute it with a diluent to the NDMA concentration: 0.2, 0.8, 3.2, 6.4, 20 micrograms / mL, shake until completely dissolved and ready to use.
  • NDMA N-nitrosodimethylamine
  • N-nitrosodimethylamine (NDMA) content in valsartan raw materials NDMA
  • Example 7 Weigh 400 mg of valsartan raw material (sample 7), accurately weigh it in a 20 mL headspace bottle, and then accurately transfer 2 mL of diluent, shake to dissolve, and mix as a test solution.
  • the above-mentioned GC-MS method was used to test the test solution and different concentrations of NDMA standard solution, and the standard curve method was used to calculate the NDMA content in sample 7. (Sample 7)
  • the content was 0.8 ppm.
  • Carrier gas Helium
  • the initial temperature is 60 ° C, hold for 2min, then increase the temperature to 240 ° C at a rate of 15 ° C / min, and hold for 5min.
  • Ion source mode EI, positive ion
  • Quadrupole temperature 150 °C
  • Standard solution preparation of N-nitrosodimethylamine (NDMA) reference substance Weigh an appropriate amount of N-nitrosodimethylamine (NDMA) reference substance and dilute it with a diluent to the NDMA concentration: 0.2, 0.8, 3.2, 6.4, 20 micrograms / mL, shake until completely dissolved and ready to use.
  • NDMA N-nitrosodimethylamine
  • N-nitrosodimethylamine (NDMA) content in valsartan tablets NDMA
  • valsartan tablets (specification 80mg, sample 8), accurately weighed in a 20mL headspace bottle, then dilute to the mark with a diluent, and vortex for 30min to completely disintegrate the tablet in the headspace bottle Incubate at 90 ° C for 30 minutes as the test solution.
  • the above GC-MS method was used to test the test solution and different concentrations of NDMA standard solutions, and the standard curve method was used to calculate the NDMA content in sample 8 and N-nitrosite in valsartan tablets (specification 80mg, sample 8). Dimethylamine (NDMA) was not detected.
  • Carrier gas Helium
  • the initial temperature is 45 ° C, keep it for 5min, then raise the temperature to 240 ° C at a rate of 15 ° C / min, and keep it for 5min.
  • Ion source mode EI, positive ion
  • Quadrupole temperature 150 °C
  • Standard solution preparation of N-nitrosodimethylamine (NDMA) reference substance Weigh an appropriate amount of N-nitrosodimethylamine (NDMA) reference substance and dilute it with a diluent to the NDMA concentration: 0.2, 0.8, 3.2, 6.4, 20 micrograms / mL, shake until completely dissolved and ready to use.
  • NDMA N-nitrosodimethylamine
  • N-nitrosodimethylamine (NDMA) content in irbesartan hydrochlorothiazide tablets:
  • irbesartan hydrochlorothiazide tablets (specification: irbesartan 125mg, hydrochlorothiazide 12.5mg, sample 9), accurately weighed in a 20mL headspace bottle, then dilute to the mark with a diluent, and sonicate for 30min to make the tablet Completely disintegrate, incubate in a headspace bottle at 90 ° C for 30 minutes, as a test solution.
  • the above-mentioned GC-MS method was used to test the test solution and different concentrations of NDMA standard solutions, and the NDMA content in sample 9 was calculated by the standard curve method.
  • irbesartan hydrochlorothiazide tablets (specification: irbesartan 125mg, hydrochlorothiazide) 12.5 mg, sample 9) N-nitrosodimethylamine (NDMA) was not detected.
  • Carrier gas Helium
  • the initial temperature is 45 ° C, hold for 5min, then increase the temperature to 200 ° C at a rate of 10 ° C / min, and hold for 5min
  • Ion source mode EI, positive ion
  • Quadrupole temperature 150 °C
  • Standard solution preparation of N-nitrosodimethylamine (NDMA) reference substance Weigh an appropriate amount of N-nitrosodimethylamine (NDMA) reference substance and dilute it to the NDMA concentration with a diluent: 0.05, 0.10, 0.20, 0.40, 2.0 ⁇ g / mL, shake it until it is completely dissolved and use it.
  • NDMA N-nitrosodimethylamine
  • N-nitrosodimethylamine (NDMA) content in valsartan tablets NDMA
  • valsartan tablets (specification 160mg, sample 10), accurately weigh into a 20mL headspace bottle, then dilute to the mark with a diluent, vortex for 30min to completely disintegrate the tablet, and place in the headspace bottle Incubate at 90 ° C for 40min as the test solution.
  • the above GC-MS method was used to test the test solution and NDMA standard solutions of different concentrations, and the NDMA content in sample 10 was calculated by the standard curve method.
  • Dimethylamine (NDMA) content was 0.03 ppm.
  • Carrier gas Helium
  • the initial temperature is 45 ° C, hold for 5min, then increase the temperature to 200 ° C at a rate of 10 ° C / min, and hold for 5min
  • Ion source mode EI, positive ion
  • Quadrupole temperature 150 °C
  • Standard solution preparation of N-nitrosodimethylamine (NDMA) reference substance Weigh an appropriate amount of N-nitrosodimethylamine (NDMA) reference substance and dilute it to the NDMA concentration with a diluent: 0.05, 0.10, 0.20, 0.40, 2.0 ⁇ g / mL, shake it until it is completely dissolved and use it.
  • NDMA N-nitrosodimethylamine
  • NDMA N-nitrosodimethylamine
  • irbesartan drug substance (sample 11), accurately weigh it in a 20mL headspace bottle, then dissolve it with a diluent, and then bring the volume to the mark as the test solution.
  • the above GC-MS method was used to test the test solution and different concentrations of NDMA standard solutions, and the standard curve method was used to calculate the NDMA content in sample 11.
  • the irbesartan drug substance (sample 11) was not detected.
  • Carrier gas Helium
  • the initial temperature is 45 ° C, hold for 5min, then increase the temperature to 200 ° C at a rate of 10 ° C / min, and hold for 5min
  • Ion source mode EI, positive ion
  • Quadrupole temperature 150 °C
  • Standard solution preparation of N-nitrosodimethylamine (NDMA) reference substance Weigh an appropriate amount of N-nitrosodimethylamine (NDMA) reference substance and dilute it with a diluent to the NDMA concentration: 0.02, 0.08, 0.30, 0.64, 2.0 ⁇ g / mL, shake it until it is completely dissolved and use it.
  • NDMA N-nitrosodimethylamine
  • N-nitrosodimethylamine (NDMA) content in valsartan tablets NDMA
  • valsartan tablets (specification 160mg, sample 12), accurately weigh into a 20mL headspace bottle, then dilute to the mark with a diluent, vortex and shake for 30min to completely disintegrate the tablet, and place in the headspace bottle. Incubate at 90 ° C for 40min as the test solution.
  • the above GC-MS method was used to test the test solution and different concentrations of NDMA standard solutions, and the NDMA content was calculated by the standard curve method.
  • N-nitrosodimethylformaldehyde in valsartan tablets (size 160mg, sample 12) Amine (NDMA) was not detected.
  • Carrier gas Helium
  • the initial temperature is 60 ° C, hold for 2min, then increase the temperature to 240 ° C at a rate of 15 ° C / min, and hold for 5min.
  • Ion source mode EI, positive ion
  • MRM Multiple reaction detection mode
  • Ion source temperature 230 ° C
  • Drying gas flow rate 1100L / h
  • Standard solution preparation of N-nitrosodimethylamine (NDMA) reference substance Weigh an appropriate amount of N-nitrosodimethylamine (NDMA) reference substance and dilute it with a diluent to a concentration range of 0.05, 0.10, 0.20, 0.40, 2.0 micrograms / mL, shake until completely dissolved and ready to use.
  • NDMA N-nitrosodimethylamine
  • N-nitrosodimethylamine (NDMA) content in losartan potassium hydrochlorothiazide tablets NDMA
  • losartan potassium hydrochlorothiazide tablets (specification: irbesartan 50mg, hydrochlorothiazide 12.5mg, sample 13), weigh accurately in a 20mL headspace bottle, then dilute to volume with a diluent and vortex for 30min The tablet was completely disintegrated, and kept at 100 ° C. for 30 minutes in a headspace bottle as a test solution.
  • the above-mentioned GC-MS method was used to test the test solution and the NDMA standard solution of different concentrations, and the NDMA content was calculated by the standard curve method.
  • N-nitrosodimethylamine (NDMA) was not detected in sample 13).
  • Carrier gas Helium
  • the initial temperature is 45 ° C, hold for 5min, then increase the temperature to 200 ° C at a rate of 10 ° C / min, and hold for 5min
  • Ion source mode EI, positive ion
  • MRM Multiple reaction detection mode
  • Ion source temperature 230 ° C
  • Standard solution preparation of N-nitrosodimethylamine (NDMA) reference substance Weigh an appropriate amount of N-nitrosodimethylamine (NDMA) reference substance and dilute it with a diluent to a concentration range of 0.05, 0.10, 0.20, 0.40, 2.0 micrograms / mL, shake until completely dissolved and ready to use.
  • NDMA N-nitrosodimethylamine
  • N-nitrosodimethylamine (NDMA) content in irbesartan raw material drug 500mg irbesartan raw material drug (sample 14), accurately weighed in a 20mL headspace bottle, and then accurately remove 2mL of diluent , Shake to dissolve, mix well, as a test solution.
  • the above-mentioned GC-MS method was used to test the test solution and different concentrations of NDMA standard solutions, and the NDMA content was calculated by the standard curve method.
  • N-nitrosodimethylamine (NDMA) was used in the irbesartan drug substance (sample 14) The content is 0.02 ppm.
  • the detection method provided by the present invention can detect the content of NDMA impurities in the ppm level, or even one hundredth of a ppm, with the lowest detection limit and high sensitivity; particularly suitable for samples Detection of trace impurities in NDMA.
  • the detection method provided by the present invention has a linear range of at least 0.02-2.0 ⁇ g / mL and a wide linear range; as can be seen from FIG. 1, the detection method provided by the present invention , Good separation effect. In addition, the method provided by the present invention has good durability.

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Abstract

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。

Description

一种N-亚硝基二甲胺杂质的检测方法
本申请要求于2018年07月07日提交中国专利局、申请号为201810740353.3发明名称为“一种气质联用法检测样品中微量N-亚硝基二甲胺(NDMA)杂质的分析方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及化学分析领域，特别涉及一种N-亚硝基二甲胺(NDMA)杂质的检测方法。
背景技术
血管紧张素II受体拮抗剂(ARBs)，代表性的产品有氯沙坦钾(Losartan Potassium)、缬沙坦(Valsartan)、厄贝沙坦(Irbesartan)、及坎地沙坦酯(Candersartan Celexetil Ester)等,它们均是临床上常用的抗高血压药，本类抗高血压药均含有联苯四氮唑基团，此官能团最普遍的构建策略就是采用氰基联苯化物与叠氮化物高温下合成四氮唑环，此沙坦类化合物通用的可工业化路线表示如下：
Figure PCTCN2018095142-appb-000001
其中，R 1代表
Figure PCTCN2018095142-appb-000002
等，R 2代表Na、K、TMS等。溶剂可以选自N,N-二甲基甲酰胺、甲苯或二甲苯等。
在上述沙坦类API(原料药)产品的合成路线中，由于N,N-二甲基甲酰胺(DMF)具有优良的溶解性及相对较高的沸点，因此它是四氮唑成环的工序中最常用的溶剂；同时为保证氰基联苯中间体在反应过程中充分转化，反应 中使用叠氮化钠、TMSN 3等反应物都是过量的，反应结束后需要对残存的叠氮化合物进行淬灭处理，否则残存的叠氮化合物在后续工序中将会产生毒性较强的叠氮酸；另外，含有残存的叠氮化合物的物料传输转移过程中与含铜或其它过渡金属材质的材料接触时，也很容易产生爆炸。在现有技术中，通常是用亚硝酸在酸性条件下处理残留的叠氮化物。
发明内容
本申请的发明人发现，在上述的合成路线中，当采用DMF作为溶剂时，DMF在反应过程中容易分解产生二甲胺，其与亚硝酸盐反应会产生毒性很强的N-亚硝基二甲胺(NDMA)杂质，其结构式如下：
Figure PCTCN2018095142-appb-000003
通过进一步的深入研究发现，当工艺流程设置不合理或工艺参数控制不到位时，沙坦类API产品中即会产生微量的N-亚硝基二甲胺(NDMA)，因此，为了能够实现对沙坦类原料药中间体、工艺中所使用的溶剂、沙坦类原料药或含沙坦类原料药的组合物进行质量控制，需要对相关产品的中的N-亚硝基二甲胺(NDMA)进行检测。
本发明的目的是提供一种检测样品中N-亚硝基二甲胺(NDMA)杂质的方法。该方法尤其适用于微量N-亚硝基二甲胺(NDMA)杂质的检测；具体方案如下：
一种N-亚硝基二甲胺杂质的检测方法，其中所述方法包括以下步骤：
(1)获得含有待测样品的供试品溶液；
(2)采用气质联用法(GC-MS)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。
在本发明的一些实施试中，供试品溶液可以直接在适用于气质联用仪进样的样品瓶或顶空瓶中制备；也可以在其它容器中制备出供试品溶液，然后再将供试品溶液转移至样品瓶或顶空瓶中进行进样检测。在具体实施过程中， 具体是采用样品瓶还是顶空瓶，可以根据实际的进样方式来确定。
在本发明的一些具体实施方式中，所述方法包括以下步骤：
(1)将含有或可能含有N-亚硝基二甲胺杂质的待测样品溶解于稀释剂中以制备供试品溶液；当待测样品为沙坦类原料药合成工艺中使用的溶剂时，则不用稀释剂溶解，直接将溶剂进样；
(2)将制备出来的供试品溶液转移至进样小瓶或顶空瓶中；对进样小瓶或顶空瓶中的溶液进行气质联用分析。
本文中，所说的待测样品，也可称为样品；所说的稀释剂也可称为稀释液；所说的供试品溶液也可称为样品溶液。
在本发明的一些实施方式中，步骤(2)包括：将供试品溶液注入气质联用仪中进行检测，记录供试品溶液的谱图，并根据预先获得的N-亚硝基二甲胺的标准曲线，确定待测样品中N-亚硝基二甲胺的含量。
在具体实施过程中，记录供试品溶液的谱图可以确定供试品溶液中N-亚硝基二甲胺的峰面积，再根据已确定的标准曲线，采用标准曲线法，即可确定供试品溶液中N-亚硝基二甲胺的含量，再经简单换算，即可确定样品中N-亚硝基二甲胺杂质的含量。
需要说明的是，标准曲线法是所属领域的一种公知的定量方法，本发明在此不进行限定。
在本发明的一些具体实施方式中，N-亚硝基二甲胺的标准曲线通过以下方法确定：
配制一系列具有不同已知浓度的N-亚硝基二甲胺的标准溶液；
将各N-亚硝基二甲胺的标准溶液分别液注入气质联用仪中进行检测，记录谱图，并根据各谱图中N-亚硝基二甲胺的峰面积以及对应的N-亚硝基二甲胺的浓度，确定N-亚硝基二甲胺的标准曲线；例如，可以以N-亚硝基二甲胺的浓度作为横坐标或纵坐标，以N-亚硝基二甲胺的峰面积作为纵坐标或横坐标，确定N-亚硝基二甲胺的标准曲线。
在本发明的一些实施方式中，待测样品可以是含有或可能含有N-亚硝基 二甲胺(NDMA)杂质的样品，包括但不限于沙坦类原料药中间体、工艺中所使用的溶剂、沙坦类原料药或含沙坦类原料药的组合物。
在本发明的一些实施方式中，沙坦类原料药选自式I所示的化合物：
Figure PCTCN2018095142-appb-000004
其中，R 1代表
Figure PCTCN2018095142-appb-000005
R 3代表H或K；本文中，n-Bu代表正丁基。
更具体地，沙坦类原料药选自氯沙坦钾、厄贝沙坦或缬沙坦等。
在本文中，沙坦类原料药中间体是指用于合成上述沙坦类原料药的化合物，包括但不限于式II所示的化合物：
Figure PCTCN2018095142-appb-000006
其中，R 1代表
Figure PCTCN2018095142-appb-000007
工艺中所使用的溶剂是指沙坦类原料药合成工艺中所使用的溶剂，包括 但不限于乙酸乙酯、甲苯、二甲苯、甲醇、N,N-二甲基甲酰胺(DMF)、甲基叔丁基醚、二氯甲烷等。
在本发明的一些实施方式工中，当待测样品为固体时，步骤(1)包括：将待测样品溶解于稀释剂中，得到供试品溶液；当待测样品为液体时，例如工艺中所使用的溶剂时，可以直接将该溶剂作为供试品溶液。
更为具体地，当所述待测样品为沙坦类原料药中间体或沙坦类原料药时，将待测样品溶解于稀释剂中，获得供试品溶液；
当所述待测样品为含沙坦类原料药的组合物时，将含沙坦类原料药的组合物用稀释剂崩解，获得供试品溶液；
当所述待测样品为工艺中所使用的溶剂时，将所述溶剂直接作为供试品溶液。
在本发明的一些实施方式中，本发明提供的N-亚硝基二甲胺杂质的检测方法，其可以包括以下步骤：
(1)当所述待测样品为沙坦类原料药中间体或沙坦类原料药时，将沙坦类原料药中间体或沙坦类原料药用稀释剂溶解并定容，配制成1mL体积中含沙坦类原料药中间体或沙坦类原料药1～5000mg、优选为1～1000mg、更优选为5～500mg、最优选为5～200mg的供试品溶液；
当所述待测样品为含沙坦类原料药的组合物时，将含沙坦类原料药的组合物用稀释剂崩解并定容，配制成1mL体积中含沙坦类原料药1～5000mg、优选为1～1000mg、更优选为5～500mg最优选为5～30mg的供试品溶液；
当所述待测样品为工艺中所使用的溶剂时，将所述溶剂直接作为供试品溶液；
(2)将供试品溶液注入气质联用仪中进行检测，记录供试品溶液的谱图，并根据预先获得的N-亚硝基二甲胺的标准曲线，确定待测样品中N-亚硝基二甲胺的含量。
在本发明的一些具体实施方式中，所述稀释剂选自水、极性有机溶剂或它们的混合物，所述极性有机溶剂进一步选自N,N-二甲基甲酰胺(DMF)、 N-甲基吡咯烷酮、二甲亚砜(DMSO)、甲醇、乙醇、异丙醇、丙酮、甲基叔丁基醚、乙腈、乙二醇、丙二醇、丙三醇、甲酸、乙酸、丙酸、甲磺酸、三乙胺、二甲胺、二甲基丙基胺、吡啶、吗啉、哌嗪、四氢吡咯、哌啶中的一种或其任意组合。
在本发明前述的气质联用法检测N-亚硝基二甲胺杂质的方法中，气质联用法的色谱条件如下：
分析柱：气相色谱柱，固定相组成为聚硅氧烷聚合物、氰丙基苯基二甲基聚硅氧烷共聚物、氰丙基二甲基聚硅氧烷共聚物、三氟丙基二甲基聚硅氧烷共聚物、苯基二甲基聚硅氧烷共聚物、二丙基苯二甲基聚硅氧烷共聚物、二苯基二甲基聚硅氧烷共聚物、聚乙二醇中的一种或其任意组合；
所述的气相色谱柱的固定相组成优选为14％氰丙基苯基-86％二甲基聚硅氧烷共聚物、35％苯基-65％二甲基聚硅氧烷共聚物、5％苯基-95％二甲基聚硅氧烷共聚物、6％氰丙基-94％二甲基聚硅氧烷共聚物、7％氰丙基-7％苯基-86％二甲基聚硅氧烷共聚物、50％氰丙基-50％二甲基聚硅氧烷共聚物、及5％氰丙基-95％二甲基聚硅氧烷共聚物或聚乙二醇(分子量范围：1万至100万)。
载气选自氢气、氮气或氦气；
柱温：30～350℃；优选为40～300℃；更优选为45～250℃；
分流比：1:1～500:1；优选为1:1～100:1；更优选为1:1～50:1；还优选为3:1～25:1；
进样口温度：100～350℃；优选为150～300℃；更优选为150～200℃；
进样方式：直接进样或顶空进样；优选顶空进样法；
检测器选自质谱检测器(MSD)；优选单四级杆质谱检测器、四级杆-飞行时间质谱检测器(QTOF)或三重四级杆质谱检测器(TQS)。
本发明提供的气质联用法检测N-亚硝基二甲胺杂质的方法，分离效果好，操作简单，并且方法灵敏度高，线性范围宽，可以快速有效地检测样品中N-亚硝基二甲胺(NDMA)含量。
附图说明
为了更清楚地说明本发明实施例和现有技术的技术方案，下面对实施例和现有技术中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为实施例1中缬沙坦原料药中N-亚硝基二甲胺(NDMA)检测的GC-MS图谱。
具体实施方式
为使本发明的目的、技术方案、及优点更加清楚明白，以下参照附图并举实施例，对本发明进一步详细说明。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
利用N-亚硝基二甲胺(NDMA)作为对照品，对沙坦类原料药中间体、工艺中所使用的溶剂、沙坦类原料药或含沙坦类原料药的组合物中的NDMA含量进行检测如下：
实施例1
色谱条件：
仪器：安捷伦气相色谱单四级杆质谱联用仪(Agilent 7697A/5975C/7890A)
色谱柱：DB-624,30m×0.32mm,1.8μm(固定相组成：6％氰丙基-94％二甲基聚硅氧烷共聚物)
载气：氦气
线速度：1.0mL/min
进样口温度：160℃
进样体积：1.0μL
分流比：10:1
升温程序：
起始温度60℃，保持2min，然后以15℃/min的速率升温至240℃，保温5min
离子源模式：EI，正离子
离子源：230℃
四级杆温度：150℃
相对电压：200V
扫描模式：单离子抽提模式(SIM)
SIM离子流：m/z 74.0
稀释剂：DMSO
空白溶液：同稀释剂
N-亚硝基二甲胺(NDMA)对照品的标准溶液配制：称取适量的N-亚硝基二甲胺(NDMA)对照品，用稀释剂稀释至NDMA浓度分别为：0.2、0.8、3.2、6.4、20微克/mL，振摇至完全溶解后即可使用。
缬沙坦原料药中N-亚硝基二甲胺(NDMA)含量检测：
称取400mg缬沙坦原料药(样品1)，精密称定于20mL顶空瓶中，再准确移取2mL稀释剂，振摇使溶解，混匀，作为供试品溶液。用上述的GC-MS方法对供试品溶液及不同浓度的NDMA标准溶液进行检测，并用标准曲线法计算样品1中NDMA含量，N-亚硝基二甲胺(NDMA)在缬沙坦原料药(样品1)中含量为13.0ppm。
缬沙坦原料药(样品1)中N-亚硝基二甲胺(NDMA)的GC-MS图谱如1所示。
实施例2
色谱条件：
仪器：ThermoFischer气相色谱单四级杆质谱联用仪(Trace 1300 & ISQLT)
色谱柱：DB-1701,60m×0.32mm,1.8μm(14％氰丙基苯基-86％二甲基聚硅氧烷共聚物)
载气：氦气
线速度：1.0mL/min
进样口温度：180℃
进样体积：2.0μL
分流比：25:1
升温程序：
起始温度60℃，保持2min，然后以15℃/min的速率升温至240℃，保温5min
离子源模式：EI，正离子
离子源：250℃
四级杆温度：160℃
相对电压：200V
扫描模式：单离子抽提模式(SIM)
SIM离子流：m/z 74.0
稀释剂：DMSO
空白溶液：同稀释剂
N-亚硝基二甲胺(NDMA)对照品的标准溶液配制：称取适量的N-亚硝基二甲胺(NDMA)对照品，用稀释剂稀释至NDMA浓度分别为：0.2、0.8、3.2、6.4、20微克/mL，振摇至完全溶解后即可使用。
缬沙坦原料药中N-亚硝基二甲胺(NDMA)含量检测：
称取400mg缬沙坦原料药(样品2)，精密称定于20mL顶空瓶中，再准确移取2mL稀释剂，振摇使溶解，混匀，作为供试品溶液。用上述的GC-MS 方法对供试品溶液及不同浓度的NDMA标准溶液进行检测，并用标准曲线法计算样品2中NDMA含量，N-亚硝基二甲胺(NDMA)在缬沙坦原料药(样品2)中含量为3.4ppm。
实施例3
色谱条件：
仪器：安捷伦气相色谱单四级杆质谱联用仪(Agilent 7697A/5975C/7890A)
色谱柱：HP-5,30m×0.32mm,1.5μm(固定相组成：5％苯基-95％二甲基聚硅氧烷共聚物)
载气：氦气
线速度：1.0mL/min
进样口温度：180℃
进样体积：1.0μL
分流比：10:1
升温程序：
起始温度55℃，保持3min，然后以15℃/min的速率升温至250℃，保温5min
离子源模式：EI，正离子
离子源：240℃
四级杆温度：150℃
相对电压：220V
扫描模式：单离子抽提模式(SIM)
SIM离子流：m/z 74.0
稀释剂：DMSO
空白溶液：同稀释剂
N-亚硝基二甲胺(NDMA)对照品的标准溶液配制：称取适量的N-亚硝基二甲胺(NDMA)对照品，用稀释剂稀释至NDMA浓度分别为：0.2、0.8、3.2、6.4、20微克/mL，振摇至完全溶解后即可使用。
厄贝沙坦原料药中N-亚硝基二甲胺(NDMA)含量检测：
称取400mg厄贝沙坦原料药(样品3)，精密称定于20mL顶空瓶中，再准确移取2mL稀释剂，振摇使溶解，混匀，作为供试品溶液。用上述的GC-MS方法对供试品溶液及不同浓度的NDMA标准溶液进行检测，并用标准曲线法计算样品3中NDMA含量，N-亚硝基二甲胺(NDMA)在厄贝沙坦原料药(样品3)中含量为0.28ppm。
实施例4
色谱条件：
仪器：ThermoFischer气相色谱单四级杆质谱联用仪(Trace 1300 & ISQLT)
色谱柱：OV-1701,30×0.25mm,1.8μm(固定相组成：7％氰丙基-7％苯基-86％二甲基聚硅氧烷共聚物)
载气：氦气
线速度：1.0mL/min
进样口温度：180℃
进样体积：2.0μL
分流比：25:1
升温程序：
起始温度60℃，保持2min，然后以15℃/min的速率升温至240℃，保温5min
离子源模式：CI，正离子
碰撞气：甲烷
离子源：250℃
四级杆温度：170℃
相对电压：200V
扫描模式：单离子抽提模式(SIM)
SIM离子流：m/z 105.0或m/z 75.0
稀释剂：N-甲基吡咯烷酮
空白溶液：同稀释剂
N-亚硝基二甲胺(NDMA)对照品的标准溶液配制：称取适量的N-亚硝基二甲胺(NDMA)对照品，用稀释剂稀释至NDMA浓度分别为：0.2、0.8、3.2、6.4、20微克/mL，振摇至完全溶解后即可使用。
缬沙坦粗品(原料药溶剂结晶之前的物料)中N-亚硝基二甲胺(NDMA)含量检测：
称取400mg缬沙坦粗品(样品4)，精密称定于20mL顶空瓶中，再准确移取2mL稀释剂，振摇使溶解，混匀，作为供试品溶液。用上述的GC-MS方法对供试品溶液及不同浓度的NDMA标准溶液进行检测，并用标准曲线法计算样品4中NDMA含量，N-亚硝基二甲胺(NDMA)在缬沙坦粗品(样品4)中含量为27.5ppm。
实施例5
色谱条件：
仪器：安捷伦气相色谱单四级杆质谱联用仪(Agilent 7697A/5975C/7890A)
色谱柱：DB-624,30m×0.32mm,1.8μm(固定相组成：6％氰丙基-94％二甲基聚硅氧烷共聚物)
载气：氦气
线速度：1.0mL/min
进样口温度：160℃
进样体积：1.0μL
分流比：10:1
升温程序：
起始温度60℃，保持2min，然后以15℃/min的速率升温至240℃，保温5min
离子源模式：EI，正离子
离子源：230℃
四级杆温度：160℃
相对电压：210V
扫描模式：单离子抽提模式(SIM)
SIM离子流：m/z 74.0
稀释剂：DMSO
空白溶液：同稀释剂
N-亚硝基二甲胺(NDMA)对照品的标准溶液配制：称取适量的N-亚硝基二甲胺(NDMA)对照品，用稀释剂稀释至NDMA浓度分别为：0.2、0.8、3.2、6.4、20微克/mL，振摇至完全溶解后即可使用。
缬沙坦原料药结晶溶剂乙酸乙酯中N-亚硝基二甲胺(NDMA)含量检测：
准确量取10mL乙酸乙酯(样品5)于20mL顶空瓶中，振摇使混匀，作为供试品溶液。用上述的GC-MS方法对供试品溶液及不同浓度的NDMA标准溶液进行检测，并用标准曲线法计算样品5中NDMA含量，在乙酸乙酯(样品5)中N-亚硝基二甲胺(NDMA)未检出。
实施例6
色谱条件：
仪器：ThermoFischer气相色谱单四级杆质谱联用仪(Trace 1300 & ISQLT)
色谱柱：DB-225,30m×0.25mm,1.8μm(固定相组成：50％氰丙基-50％二甲基聚硅氧烷共聚物)
载气：氮气
线速度：1.5mL/min
进样口温度：170℃
进样体积：2.0μL
分流比：20:1
升温程序：
起始温度55℃，保持6min，然后以12℃/min的速率升温至250℃，保温5min
离子源模式：EI，正离子
离子源：230℃
四级杆温度：150℃
相对电压：200V
扫描模式：单离子抽提模式(SIM)
SIM离子流：m/z 74.0
稀释剂：DMSO
空白溶液：同稀释剂
N-亚硝基二甲胺(NDMA)对照品的标准溶液配制：称取适量的N-亚硝基二甲胺(NDMA)对照品，用稀释剂稀释至NDMA浓度分别为：0.2、0.8、3.2、6.4、20微克/mL，振摇至完全溶解后即可使用。
氯沙坦钾原料药中N-亚硝基二甲胺(NDMA)含量检测：
称取400mg氯沙坦钾原料药(样品6)，精密称定于20mL顶空瓶中，再准确移取2mL稀释剂，振摇使溶解，混匀，作为供试品溶液。用上述的GC-MS方法对供试品溶液及不同浓度的NDMA标准溶液进行检测，并用标准曲线法计算样品6中NDMA含量，在氯沙坦钾原料药(样品6)中N-亚硝基二甲胺(NDMA)未检出。
实施例7
色谱条件：
仪器：安捷伦气相色谱单四级杆质谱联用仪(Agilent 7697A/5975C/7890A)
色谱柱：DB-1701,30m×0.32mm,1.0μm(14％氰丙基苯基-86％二甲基聚硅氧烷共聚物)
载气：氦气
线速度：1.0mL/min
进样口温度：200℃
进样体积：2.0μL
分流比：3:1
升温程序：
起始温度45℃，保持5min，然后以10℃/min的速率升温至200℃，保温5min
离子源模式：EI，正离子
离子源：230℃
四级杆温度：150℃
相对电压：200V
扫描模式：单离子抽提模式(SIM)
溶剂延迟：13min
SIM离子流：m/z 74.0
稀释剂：DMSO
空白溶液：同稀释剂
N-亚硝基二甲胺(NDMA)对照品的标准溶液配制：称取适量的N-亚硝基 二甲胺(NDMA)对照品，用稀释剂稀释至NDMA浓度分别为：0.2、0.8、3.2、6.4、20微克/mL，振摇至完全溶解后即可使用。
缬沙坦原料药中N-亚硝基二甲胺(NDMA)含量检测：
称取400mg缬沙坦原料药(样品7)，精密称定于20mL顶空瓶中，再准确移取2mL稀释剂，振摇使溶解，混匀，作为供试品溶液。用上述的GC-MS方法对供试品溶液及不同浓度的NDMA标准溶液进行检测，并用标准曲线法计算样品7中NDMA含量，N-亚硝基二甲胺(NDMA)在缬沙坦原料药(样品7)中含量为0.8ppm。
实施例8
色谱条件：
仪器：安捷伦气相色谱单四级杆质谱联用仪(Agilent 7697A/5975C/7890A)
色谱柱：DB-624,30m×0.32mm,1.8μm(固定相组成：6％氰丙基-94％二甲基聚硅氧烷共聚物)
载气：氦气
线速度：1.8mL/min
进样口温度：150℃
进样体积：1.0μL
分流比：3:1
升温程序：
起始温度60℃，保持2min，然后以15℃/min的速率升温至240℃，保温5min
离子源模式：EI，正离子
离子源：230℃
四级杆温度：150℃
相对电压：200V
扫描模式：单离子抽提模式(SIM)
SIM离子流：m/z 74.0
稀释剂：DMSO：水＝1:1
空白溶液：同稀释剂
N-亚硝基二甲胺(NDMA)对照品的标准溶液配制：称取适量的N-亚硝基二甲胺(NDMA)对照品，用稀释剂稀释至NDMA浓度分别为：0.2、0.8、3.2、6.4、20微克/mL，振摇至完全溶解后即可使用。
缬沙坦片中N-亚硝基二甲胺(NDMA)含量检测：
取4片缬沙坦片(规格80mg，样品8)，精密称定于20mL顶空瓶中，接着用稀释剂定容至刻度，涡旋振摇30min使片剂完全崩解，顶空瓶中90℃保温30min，作为供试品溶液。用上述的GC-MS方法对供试品溶液及不同浓度的NDMA标准溶液进行检测，并用标准曲线法计算样品8中NDMA含量，在缬沙坦片(规格80mg，样品8)中N-亚硝基二甲胺(NDMA)未检出。
实施例9
色谱条件：
仪器：安捷伦气相色谱单四级杆质谱联用仪(Agilent 7697A/5975C/7890A)
色谱柱：HP-INNOWax,60m×0.32mm,1.8μm(固定相组成：聚乙二醇，PEG-20M)
载气：氦气
线速度：1.8mL/min
进样口温度：160℃
进样体积：1.0μL
分流比：3:1
升温程序：
起始温度45℃，保持5min，然后以15℃/min的速率升温至240℃，保温 5min
离子源模式：EI，正离子
离子源：230℃
四级杆温度：150℃
相对电压：200V
扫描模式：单离子抽提模式(SIM)
SIM离子流：m/z 74.0
稀释剂：DMF
空白溶液：同稀释剂
N-亚硝基二甲胺(NDMA)对照品的标准溶液配制：称取适量的N-亚硝基二甲胺(NDMA)对照品，用稀释剂稀释至NDMA浓度分别为：0.2、0.8、3.2、6.4、20微克/mL，振摇至完全溶解后即可使用。
厄贝沙坦氢氯噻嗪片中N-亚硝基二甲胺(NDMA)含量检测：
取4片厄贝沙坦氢氯噻嗪片(规格：厄贝沙坦125mg，氢氯噻嗪12.5mg，样品9)，精密称定于20mL顶空瓶中，接着用稀释剂定容至刻度，超声30min使片剂完全崩解，顶空瓶中90℃保温30min，作为供试品溶液。用上述的GC-MS方法对供试品溶液及不同浓度的NDMA标准溶液进行检测，并用标准曲线法计算样品9中NDMA含量，在厄贝沙坦氢氯噻嗪片(规格：厄贝沙坦125mg，氢氯噻嗪12.5mg，样品9)中N-亚硝基二甲胺(NDMA)未检出。
实施例10
色谱条件：
仪器：安捷伦气相色谱四级杆-飞行时间质谱联用仪(GC-QTOF，Agilent 7697A/7200C/7890B)
色谱柱：DB-1701,30m×0.32mm,1.0μm(14％氰丙基苯基-86％二甲基聚硅氧烷共聚物)
载气：氦气
线速度：1.0mL/min
进样口温度：200℃
进样体积：2.0μL
分流比：3:1
升温程序：
起始温度45℃，保持5min，然后以10℃/min的速率升温至200℃，保温5min
离子源模式：EI，正离子
离子源：230℃
四级杆温度：150℃
相对电压：200V
扫描模式：单离子抽提模式(SIM)
溶剂延迟：13min
SIM离子流：m/z 74.048
抽提离子误差：10ppm
分辨率：12500
稀释剂：DMSO
空白溶液：同稀释剂
N-亚硝基二甲胺(NDMA)对照品的标准溶液配制：称取适量的N-亚硝基二甲胺(NDMA)对照品，用稀释剂稀释至NDMA浓度分别为：0.05、0.10、0.20、0.40、2.0微克/mL，振摇至完全溶解后即可使用。
缬沙坦片中N-亚硝基二甲胺(NDMA)含量检测：
取2片缬沙坦片(规格160mg，样品10)，精密称定于20mL顶空瓶中，接着用稀释剂定容至刻度，涡旋振摇30min使片剂完全崩解，顶空瓶中90℃保温40min，作为供试品溶液。用上述的GC-MS方法对供试品溶液及不同浓度的NDMA标准溶液进行检测，并用标准曲线法计算样品10中NDMA含量，在缬沙坦片(规格160mg，样品10)中N-亚硝基二甲胺(NDMA)含量为0.03ppm。
实施例11
色谱条件：
仪器：安捷伦气相色谱四级杆-飞行时间质谱联用仪(GC-QTOF，Agilent 7697A/7200C/7890B)
色谱柱：Thermo Trace TR-Wax MS,60m×0.32mm,1.0μm(聚乙二醇，PEG-20W)
载气：氦气
线速度：1.0mL/min
进样口温度：200℃
进样体积：2.0μL
分流比：3:1
升温程序：
起始温度45℃，保持5min，然后以10℃/min的速率升温至200℃，保温5min
离子源模式：EI，正离子
离子源：230℃
四级杆温度：150℃
扫描模式：单离子抽提模式(SIM)
溶剂延迟：13min
SIM离子流：m/z 74.048
抽提离子误差：10ppm
分辨率：13000
稀释剂：N-甲基吡咯烷酮
空白溶液：同稀释剂
N-亚硝基二甲胺(NDMA)对照品的标准溶液配制：称取适量的N-亚硝基二甲胺(NDMA)对照品，用稀释剂稀释至NDMA浓度分别为：0.05、0.10、0.20、0.40、2.0微克/mL，振摇至完全溶解后即可使用。
厄贝沙坦原料药中N-亚硝基二甲胺(NDMA)含量检测：
取500mg厄贝沙坦原料药(样品11)，精密称定于20mL顶空瓶中，接着用稀释剂溶解后再定容至刻度，作为供试品溶液。用上述的GC-MS方法对供试品溶液及不同浓度的NDMA标准溶液进行检测，并用标准曲线法计算样品11中NDMA含量，在厄贝沙坦原料药(样品11)，中N-亚硝基二甲胺(NDMA)未检出。
实施例12
色谱条件：
仪器：安捷伦气相色谱四级杆-飞行时间质谱联用仪(GC-QTOF，Agilent 7697A/7200C/7890B)
色谱柱：TR-MS Wax,30m×0.32mm,1.0μm(聚乙二醇，PEG-20W)
载气：氦气
线速度：1.0mL/min
进样口温度：200℃
进样体积：2.0μL
分流比：3:1
升温程序：
起始温度45℃，保持5min，然后以10℃/min的速率升温至200℃，保温5min
离子源模式：EI，正离子
离子源：230℃
四级杆温度：150℃
扫描模式：单离子抽提模式(SIM)
溶剂延迟：13min
SIM离子流：m/z 74.048
抽提离子误差：10ppm
分辨率：13000
稀释剂：N-甲基吡咯烷酮
空白溶液：同稀释剂
N-亚硝基二甲胺(NDMA)对照品的标准溶液配制：称取适量的N-亚硝基二甲胺(NDMA)对照品，用稀释剂稀释至NDMA浓度分别为：0.02、0.08、0.30、0.64、2.0微克/mL，振摇至完全溶解后即可使用。
缬沙坦片中N-亚硝基二甲胺(NDMA)含量检测：
取2片缬沙坦片(规格160mg，样品12)，精密称定于20mL顶空瓶中，接着用稀释剂定容至刻度，涡旋振摇30min使片剂完全崩解，顶空瓶中90℃保温40min，作为供试品溶液。用上述的GC-MS方法对供试品溶液及不同浓度的NDMA标准溶液进行检测，并用标准曲线法计算NDMA含量，在缬沙坦片(规格160mg，样品12)中N-亚硝基二甲胺(NDMA)未检出。
实施例13
色谱条件：
仪器：安捷伦气相色谱三重四级杆质谱联用仪(GC-TQS，Agilent 7600A/7000C/7890B)
色谱柱：DB-624,30m×0.32mm,1.8μm(固定相组成：6％氰丙基-94％二甲基聚硅氧烷共聚物)
载气：氦气
线速度：1.8mL/min
进样口温度：150℃
进样体积：1.0μL
分流比：3:1
升温程序：
起始温度60℃，保持2min，然后以15℃/min的速率升温至240℃，保温5min
离子源模式：EI，正离子
碰撞气：氮气
检测模式：多反应检测模式(MRM)
离子源温度：230℃
干燥气温度：550℃
干燥气流速：1100L/h
锥孔电压：20V
锥孔气流速：50L/h
毛细管电压：2200V
碰转能：6eV
SIM离子流：m/z 74.0(母离子)，m/z 42.0(子离子)
稀释剂：DMSO
空白溶液：同稀释剂
N-亚硝基二甲胺(NDMA)对照品的标准溶液配制：称取适量的N-亚硝基二甲胺(NDMA)对照品，用稀释剂稀释至浓度范围至0.05、0.10、0.20、0.40、2.0微克/mL，振摇至完全溶解后即可使用。
氯沙坦钾氢氯噻嗪片中N-亚硝基二甲胺(NDMA)含量检测：
取3片氯沙坦钾氢氯噻嗪片(规格：厄贝沙坦50mg，氢氯噻嗪12.5mg，样品13)，精密称定于20mL顶空瓶中，接着用稀释剂定容至刻度，涡旋振摇30min使片剂完全崩解，顶空瓶中100℃保温30min，作为供试品溶液。用上述的GC-MS方法对供试品溶液及不同浓度的NDMA标准溶液进行检测，并用标准曲线法计算NDMA含量，在氯沙坦钾氢氯噻嗪片(规格：厄贝沙坦50mg，氢氯噻嗪12.5mg，样品13)中N-亚硝基二甲胺(NDMA)未检出。
实施例14
色谱条件：
仪器：安捷伦气相色谱三重四级杆质谱联用仪(GC-TQS，Agilent 7600A/7000C/7890B)
色谱柱：DB-1701,30m×0.32mm,1.0μm(14％氰丙基苯基-86％二甲基聚硅氧烷共聚物)
载气：氦气
线速度：1.0mL/min
进样口温度：200℃
进样体积：2.0μL
分流比：3:1
升温程序：
起始温度45℃，保持5min，然后以10℃/min的速率升温至200℃，保温5min
离子源模式：EI，正离子
碰撞气：氮气
检测模式：多反应检测模式(MRM)
离子源温度：230℃
干燥气温度：600℃
干燥气流速：1000L/h
锥孔电压：22V
锥孔气流速：45L/h
毛细管电压：2500V
碰转能：8eV
SIM离子流：m/z 74.0(母离子)，m/z 42.0(子离子)
稀释剂：DMSO
空白溶液：同稀释剂
N-亚硝基二甲胺(NDMA)对照品的标准溶液配制：称取适量的N-亚硝基二甲胺(NDMA)对照品，用稀释剂稀释至浓度范围至0.05、0.10、0.20、0.40、2.0微克/mL，振摇至完全溶解后即可使用。
厄贝沙坦原料药中N-亚硝基二甲胺(NDMA)含量检测：500mg厄贝沙坦原料药(样品14)，精密称定于20mL顶空瓶中，再准确移取2mL稀释剂，振摇使溶解，混匀，作为供试品溶液。用上述的GC-MS方法对供试品溶液及不同浓度的NDMA标准溶液进行检测，并用标准曲线法计算NDMA含量，N-亚硝基二甲胺(NDMA)在厄贝沙坦原料药(样品14)中含量为0.02ppm。
由上述各实施例可以看出，本发明提供的检测方法，可以检测出样品中ppm级,甚至ppm的百分之一的NDMA杂质的含量，最低检测限很小，灵敏度很高；特别适合样品中NDMA微量杂质的检测。
而且，从实施例中可以看出，本发明提供的检测方法，其线性范围至少 在0.02-2.0微克/mL的范围内，线性范围宽；从图1中可以看出，本发明提供的检测方法，分离效果好。另外，本发明提供的方法耐用性好。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明保护的范围之内。

Claims (10)

  1. 一种气质联用法检测N-亚硝基二甲胺杂质的方法，其中所述方法包括以下步骤：
    (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。
  2. 根据权利要求1所述的方法，其中所述方法包括以下步骤：
    (1)将含有或可能含有N-亚硝基二甲胺杂质的待测样品溶解于稀释剂中以制备供试品溶液；当待测样品为沙坦类原料药合成工艺中使用的溶剂时，则不用稀释剂溶解，直接将溶剂进样；
    (2)将制备出来的供试品溶液转移至进样小瓶或顶空瓶中；对进样小瓶或顶空瓶中的溶液进行气质联用分析。
  3. 根据权利要求1或2所述的方法，其中步骤(2)包括：将供试品溶液注入气质联用仪中进行检测，记录供试品溶液的谱图，并根据预先获得的N-亚硝基二甲胺的标准曲线，确定待测样品中N-亚硝基二甲胺的含量。
  4. 根据权利要求1-3中任一项所述的方法，其中所述待测样品为沙坦类原料药中间体、沙坦类原料药合成工艺中所使用的溶剂、沙坦类原料药或含沙坦类原料药的组合物；
    优选地，所述沙坦类原料药选自式I所示的化合物：
    Figure PCTCN2018095142-appb-100001
    其中，R 1代表
    Figure PCTCN2018095142-appb-100002
    R 3代表H或K；
    更优选地，所述沙坦类原料药选自氯沙坦钾、厄贝沙坦或缬沙坦；
    优选地，所述沙坦类原料药中间体选自式II所示的化合物：
    Figure PCTCN2018095142-appb-100003
    其中，R 1代表
    Figure PCTCN2018095142-appb-100004
  5. 根据权利要求1-4中任一项所述的方法，其中：
    当所述待测样品为沙坦类原料药中间体或沙坦类原料药时，将待测样品溶解于稀释剂中，获得供试品溶液；
    当所述待测样品为含沙坦类原料药的组合物时，将含沙坦类原料药的组合物用稀释剂崩解，获得供试品溶液；
    当所述待测样品为沙坦类原料药合成工艺中所使用的溶剂时，将所述溶剂直接作为供试品溶液。
  6. 根据权利要求1-5中任一项所述的方法，其中所述方法包括如下步骤：
    (1)当所述待测样品为沙坦类原料药中间体或沙坦类原料药时，将沙坦类原料药中间体或沙坦类原料药用稀释剂溶解并定容，配制成1mL体积中含沙坦类原料药中间体或沙坦类原料药1～5000mg、优选为1～1000mg、最优选为5～200mg的供试品溶液；
    当所述待测样品为含沙坦类原料药的组合物时，将含沙坦类原料药的组合物用稀释剂崩解并定容，配制成1mL体积中含沙坦类原料药1～5000mg、优选为1～1000mg、更优选为5～500mg、最优选为5～30mg的供试品溶液；
    当所述待测样品为工艺中所使用的溶剂时，将所述溶剂直接作为供试品溶液；
    (2)将供试品溶液注入气质联用仪中进行检测，记录供试品溶液的谱图，并根据预先获得的N-亚硝基二甲胺的标准曲线，确定待测样品中N-亚硝基二甲胺的含量。
  7. 根据权利要求5或6所述的方法，其中所述稀释剂选自水、极性有机溶剂，或它们的混合物；
    优选地，所述极性有机溶剂选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、二甲亚砜、甲醇、乙醇、异丙醇、丙酮、甲基叔丁基醚、乙腈、乙二醇、丙二醇、丙三醇、甲酸、乙酸、丙酸、甲磺酸、三乙胺、二甲胺、二甲基丙基胺、吡啶、吗啉、哌嗪、四氢吡咯、哌啶中的一种或其任意组合。
  8. 根据权利要求1-7中任一项所述的方法，其中所述气质联用法的色谱条件如下：
    分析柱：气相色谱柱，固定相组成为聚硅氧烷聚合物、氰丙基苯基二甲基聚硅氧烷共聚物、氰丙基二甲基聚硅氧烷共聚物、三氟丙基二甲基聚硅氧烷共聚物、苯基二甲基聚硅氧烷共聚物、二丙基苯二甲基聚硅氧烷共聚物、二苯基二甲基聚硅氧烷共聚物、聚乙二醇中的一种或其任意组合；
    载气选自氢气、氮气或氦气；
    柱温：30～350℃；优选为40～300℃；更优选为45～250℃；
    分流比：1:1～500:1；优选为1:1～100:1；更优选为1:1～50:1；还优选为3:1～25:1；
    进样口温度：100～350℃；优选为150～300℃；更优选为150～200℃；
    进样方式：直接进样或顶空进样，优选为顶空进样；
    检测器：质谱检测器。
  9. 根据权利要求8所述的方法，其中所述的气相色谱柱的固定相组成为14％氰丙基苯基-86％二甲基聚硅氧烷共聚物、35％苯基-65％二甲基聚硅氧烷 共聚物、5％苯基-95％二甲基聚硅氧烷共聚物、6％氰丙基-94％二甲基聚硅氧烷共聚物、7％氰丙基-7％苯基-86％二甲基聚硅氧烷共聚物、50％氰丙基-50％二甲基聚硅氧烷共聚物、及5％氰丙基-95％二甲基聚硅氧烷共聚物或分子量为1万至100万的聚乙二醇。
  10. 根据权利要求8或9所述的方法，其中所述的质谱检测器选自单四级杆质谱检测器、四级杆-飞行时间质谱检测器或三重四级杆质谱检测器。
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