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Method for analyzing N-nitrosodimethylamine and N-nitrosodiethylamine in argatroban bulk drug or preparation

A technology of nitrosodimethylamine and nitrosodiethylamine, which is applied in the field of drug analysis, can solve problems such as no reports, and achieve the effects of simple operation, good stability and accurate detection results

Active Publication Date: 2021-06-11
CSPC OUYI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Yet, the method for the content determination of impurity N-nitrosodimethylamine, N-nitrosodiethylamine in argatroban crude drug or preparation is also not reported at home and abroad at present

Method used

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  • Method for analyzing N-nitrosodimethylamine and N-nitrosodiethylamine in argatroban bulk drug or preparation
  • Method for analyzing N-nitrosodimethylamine and N-nitrosodiethylamine in argatroban bulk drug or preparation
  • Method for analyzing N-nitrosodimethylamine and N-nitrosodiethylamine in argatroban bulk drug or preparation

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0061] Preparation of test product (argatroban bulk drug) solution 1: Accurately weigh about 100 mg of argatroban bulk drug 1 and place in a 10ml measuring bottle, add methanol to dissolve and dilute to the scale, shake well, and obtain a concentration of 10 mg / ml The test solution 1.

[0062] Preparation of the test product (argatroban injection) solution 2: take argatroban injection (10mg / 2ml) and inject directly.

[0063] The prescription of argatroban injection is: 2ml injection contains argatroban raw material drug 1 10mg, ethanol 300mg, glycerin 900mg, and the rest is water for injection.

Embodiment 1

[0064] Example 1: System Suitability

[0065] (1) Chromatographic conditions:

[0066] Detection instrument: Waters XEVO TQ-S ultra-high performance liquid mass spectrometer

[0067] Ultra-high performance liquid chromatography conditions:

[0068] Chromatographic column: phenyl chromatographic column: ACE 5phenyl 4.6×100mm, 5μm (particle size);

[0069] Flow rate: 0.8ml / min; Column temperature: 30°C; Injection volume: 10μl;

[0070] Mobile phase A: Precisely measure 0.5g of formic acid, dissolve in 500ml of ultrapure water, and degas it by ultrasonic;

[0071] Mobile phase B: methanol, ultrasonic degassing;

[0072] Gradient elution table:

[0073] time (min) Mobile phase A(%) Mobile phase B(%) 0 90 10 6 10 90 12 10 90 12.1 90 10 15 90 10

[0074] The mass spectrometry conditions are as follows:

[0075] Mass Spectrometer: Triple Quadrupole Mass Spectrometer; Mass Spectrometry Method Mode: Multiple Reaction Monitoring Scan...

Embodiment 2

[0089] Example 2: Specificity

[0090] (1) Test method:

[0091] The chromatographic conditions are the same as those in Example 1, and an appropriate amount of N-nitrosodimethylamine reference substance stock solution and N-nitrosodiethylamine reference substance stock solution are taken respectively, and diluted with methanol respectively to obtain N-nitrosodimethylamine Amine-specific solution, N-nitrosodiethylamine-specific solution.

[0092] Inject blank solution (methanol), blank excipients (mixed solution of ethanol and glycerin), N-nitrosodimethylamine specific solution, N-nitrosodiethylamine specific solution, and argatroban reference substance solution.

[0093] Wherein the detection method of argatroban reference substance solution is high performance liquid chromatography, chromatographic column, flow rate, column temperature, injection volume, mobile phase A, mobile phase B, gradient elution method are the same as before; detection wavelength 226nm.

[0094] (2...

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Abstract

The invention provides a method for analyzing N-nitrosodimethylamine and N-nitrosodiethylamine in an argatroban bulk drug or preparation, which adopts an ultra-high performance liquid chromatography (UPLC) and mass spectrometry combined method, and comprises the following steps: (1) preparing a test solution and a reference solution: dissolving a sample to be detected by using methanol as a solvent to prepare the test solution; dissolving standard substances of N-nitrosodimethylamine and N-nitrosodiethylamine by taking methanol as a solvent to prepare a reference substance solution; (2) taking the test solution and the reference substance solution, respectively injecting samples, detecting by using an ultra-high performance liquid chromatography-mass spectrometer, and recording a chromatogram map; and calculating the contents of N-nitrosodimethylamine and N-nitrosodiethylamine according to an external standard method. According to the liquid chromatography-mass spectrometry method provided by the invention, the sample treatment process is simple to operate, the sensitivity is high, the detection result is accurate, the stability is good, and the method can be used for quality control of argatroban bulk drugs or preparations.

Description

technical field [0001] The invention belongs to the technical field of drug analysis, and in particular relates to an analysis method for impurities N-nitrosodimethylamine and N-nitrosodiethylamine in argatroban bulk medicine or preparations. Background technique [0002] The chemical name of argatroban is (2R,4R)-4-methyl-1-[N-[(3-methyl-1,2,3,4-tetrahydro-8-quinolyl)sulfonyl] -L-Arginyl]-2-piperidinecarboxylic acid, whose chemical structure is shown in formula I, is a direct thrombin inhibitor developed by Mitsubishi Tanabe Company. Approved by the US FDA in 2009. Mainly used for: (1) movement disorder and improvement of daily life quality in patients with acute cerebral thrombosis within 48 hours after onset; (2) chronic arterial occlusive disease, improving limb ulcers, rest pain and cool feeling; (3) preventing dialysis patients Blood coagulation in extracorporeal circulation; (4) Treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT) type II;...

Claims

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Application Information

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IPC IPC(8): G01N30/02G01N30/72
CPCG01N30/02G01N30/72Y02A50/30
Inventor 郭倩白卫娜高玉静李静薛娇陈立立
Owner CSPC OUYI PHARM CO LTD
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