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Method for detecting N-nitrosodimethylamine and N-nitrosodiethylamine in entacapone raw material or preparation thereof

A technology of nitrosodimethylamine and nitrosodiethylamine, which is applied in the field of drug analysis, can solve the problems of ineffective detection of NDMA and NDEA, etc., and is suitable for practical application and promotion, ensuring consistency and stability, Effects that improve clinical safety and efficacy

Inactive Publication Date: 2022-04-26
SHIJIAZHUANG NO 4 PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Aiming at the problem that NDMA and NDEA in entacapone raw materials or preparations cannot be effectively detected in the prior art, the present invention provides a kind of N-nitrosodimethylamine and N-nitrosodimethylamine in entacapone raw materials or its preparations. The detection method of nitrodiethylamine

Method used

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  • Method for detecting N-nitrosodimethylamine and N-nitrosodiethylamine in entacapone raw material or preparation thereof
  • Method for detecting N-nitrosodimethylamine and N-nitrosodiethylamine in entacapone raw material or preparation thereof
  • Method for detecting N-nitrosodimethylamine and N-nitrosodiethylamine in entacapone raw material or preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] 1.1 Preparation of solution

[0056] (1) Blank solution: pure water.

[0057] (2) Reference substance stock solution: Take an appropriate amount of NDMA and NDEA, weigh them accurately, add water to make a mixed solution containing about 100.98ng NDMA and 26.23ng NDEA per 1mL, and use it as the reference substance stock solution.

[0058] (3) Reference substance solution: Take an appropriate amount of the reference substance stock solution, add water to dilute it into a solution containing about 4.8ng of NDMA and 1.3ng of NDEA per 1mL, and use it as the reference substance solution.

[0059] (4) Test product solution: Take about 500 mg of entacapone test product, accurately weigh it, place it in a 10 mL centrifuge tube, add 5.0 mL of water, shake well and filter, and use it as the test product solution.

[0060] (5) The test substance plus reference substance solution: take 0.25mL of the reference substance stock solution and add it to a 10mL centrifuge tube, add about...

Embodiment 2

[0073] Methodology Validation:

[0074] 2.1 Specificity

[0075] Get the blank solution (pure water) prepared in Example 1, reference substance solution, need testing solution and need testing substance plus each 50 μ L of reference substance solution, carry out HPLC-MS / MS detection according to above-mentioned conditions respectively, record chromatogram, each chromatogram Figure such as Figure 1-Figure 4 shown.

[0076] The test results show that the baseline is stable, and the blank solution and entacapone test products have no interference with the detection of NDMA and NDEA, indicating that the method has good specificity and is suitable for the inspection of NDMA and NDEA.

[0077] 2.2 Limit of detection and limit of quantitation

[0078] Detection limit: take the reference substance solution prepared in Example 1, quantitatively dilute it step by step with water, perform HPLC-MS / MS detection, record the chromatogram, and obtain the detection limit according to the s...

Embodiment 3

[0143] Example 3 Sample Detection

[0144] According to the detection method of NDMA and NDEA in the entacapone raw material in Example 1, the contents of NDMA and NDEA in 6 batches of entacapone raw material samples were detected, and the results are shown in Table 11.

[0145] Table 11 Sample Test Results

[0146] batch NDMA content (ng / mg) NDEA content (ng / mg) 1 not detected not detected 2 not detected not detected 3 not detected not detected 4 not detected not detected 5 not detected not detected 6 not detected not detected

[0147] The results showed that the contents of NDMA and NDEA in the 6 batches of entacapone raw material samples were not detected, which met the limit regulations (NDMA≤0.048ppm, NDEA≤0.01325ppm).

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Abstract

The invention relates to the technical field of pharmaceutical analysis, and particularly discloses a method for detecting N-nitrosodimethylamine and N-nitrosodiethylamine in an entacapone raw material or a preparation thereof. According to the method, a high performance liquid chromatography and mass spectrometry combined method is adopted for detection, and liquid chromatography conditions are as follows: a C18 chromatographic column is used, a formic acid aqueous solution with the volume concentration of 0.05%-0.15% is used as a mobile phase A, a methanol solution of formic acid with the volume concentration of 0.05%-0.15% is used as a mobile phase B, and gradient elution is performed; the mass spectrum adopts an APCI ion source and a positive ion detection mode. The method provided by the invention is sensitive, accurate and relatively good in reproducibility, and qualitative and quantitative detection of trace NDMA and NDEA in entacapone can be realized by using a simpler and more convenient method, so that an effective guarantee is provided for improving and better controlling the quality of entacapone drugs, and the clinical safety and effectiveness of entacapone product medication are favorably improved.

Description

technical field [0001] The invention relates to the technical field of drug analysis, in particular to a method for detecting N-nitrosodimethylamine and N-nitrosodiethylamine in entacapone raw materials or preparations thereof. Background technique [0002] Entacapone, the English name is entacapone, the chemical name is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propene Amide, the structural formula is as follows. Entacapone is a highly selective and potent catecholamine oxygen-methyltransferase (COMT) inhibitor, which is mainly used clinically as an adjuvant to levodopa for the treatment of Parkinson's disease. [0003] [0004] The existing process for synthesizing entacapone raw materials may leave two traces of nitrosamine genotoxic impurities in entacapone raw materials: N-nitrosodimethylamine (NDMA) and N-nitroso Diethylamine (NDEA). According to the ICH M7 guideline, the acceptable limit of NDMA in entacapone raw materials = TTC (ng / day) / MDD (mg / ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02G01N30/06G01N30/86G01N30/72
CPCG01N30/02G01N30/06G01N30/8679G01N30/72
Inventor 范燕龙王亚静董海峰荣孜杭安淼王肖刘丹毕贺马明卓孙朝利
Owner SHIJIAZHUANG NO 4 PHARMA