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Method for detecting genetic toxic impurities of Afatinib dimaleate

A technology of afatinib maleate and genotoxicity, which is applied in the field of detection of genotoxic impurities of afatinib maleate, which can solve the problems of uncontrolled detection cost, low detection method sensitivity, and lack of in-depth research , to achieve the effects of short detection time, good peak shape symmetry, precision and accuracy

Pending Publication Date: 2022-01-11
南京安杰新生物医药有限公司 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Patent CN105588893B announced the detection method of intermediate V system suitability solution 0.75ug / mL (30ppm), but there is no in-depth research, the detection method has low sensitivity, the detection time reaches 100min, and it takes a long time, and the detection cost cannot be controlled, so it cannot be widely used

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  • Method for detecting genetic toxic impurities of Afatinib dimaleate
  • Method for detecting genetic toxic impurities of Afatinib dimaleate
  • Method for detecting genetic toxic impurities of Afatinib dimaleate

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Experimental program
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Effect test

Embodiment 1

[0036] Embodiment 1: chromatographic conditions and chromatographic system of detection method of the present invention

[0037] Instrument: Thermo Fisher High Performance Liquid Chromatography

[0038] Chromatographic column: YMC Triart C18 column (4.6mm×250mm, 3μm)

[0039] Mobile phase A: 0.01mol / L potassium dihydrogen phosphate solution, adjust the pH value to 3.0 with phosphoric acid

[0040] Mobile Phase B: Acetonitrile

[0041] The gradient program is as follows:

[0042] In terms of volume ratio, start elution with mobile phase A 75%, mobile phase B 25%, gradually reduce the proportion of mobile phase A, gradually increase the proportion of mobile phase B, until 25 minutes mobile phase A reaches 35%, mobile phase B reaches 65% %, continue elution for 10 minutes to 35 minutes, increase the proportion of mobile phase A, reduce the proportion of mobile phase B, and adjust mobile phase A to 75% and mobile phase B to 25% at 36 minutes, and continue elution for 9 minutes....

Embodiment 2

[0057] Embodiment 2: detection method specificity test of the present invention

[0058] Diluent: Acetonitrile-Water (30:70)

[0059] Intermediate V solution: Take an appropriate amount of Intermediate V, weigh it accurately, add a diluent to make a solution of about 5 μg per 1 mL.

[0060] Maleic acid positioning solution: Take an appropriate amount of maleic acid, weigh it accurately, add a diluent to make a solution containing about 200 μg per 1 mL, and use it as the maleic acid positioning solution.

[0061] Impurity Interference Solution: Take another appropriate amount of impurities A, B, C, D, E, F, G, H, and I, add diluent to make a mixed solution containing about 0.5 μg of each impurity per 1 mL as the impurity interference solution.

[0062] Afatinib maleate sample solution: take an appropriate amount of this product, weigh it accurately, add a diluent to make a solution containing about 0.5mg per 1mL, and use it as the afatinib maleate sample solution.

[0063] In...

Embodiment 3

[0067] Embodiment 3: Quantitation limit and detection limit test of detection method of the present invention

[0068] Limits of detection (LOD) and limits of quantitation (LOQ) were determined by the signal-to-noise ratio method. The intermediate V solution was diluted step by step, the measured signal was compared with the baseline noise, and the lowest concentration that could be reliably detected was calculated. The results are shown in Table 2.

[0069] Table 2: LOQ and LOD Results

[0070]

[0071] The quantitative limit concentration of intermediate V is lower than the quality control limit of intermediate V, and the detection limit concentration is lower than 1 / 10 of the quality control limit of intermediate V, ensuring that intermediate V can be effectively detected above the quality control limit of 1 / 10 out, from Table 2 and Image 6 It can be seen that the high performance liquid chromatography disclosed by the present invention can detect 2.6-8.0ppm of interm...

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Abstract

The invention discloses a method for detecting genetic toxic impurities of Afatinib dimaleate. According to the method, a high performance liquid chromatography method is adopted, a 0.01 mol / L Potassium dihydrogen phosphate solution is taken as a mobile phase A, acetonitrile is taken as a mobile phase B, the pH value, the flow velocity, the column temperature, the detection wavelength and the sample size of the mobile phase A are set, and gradient elution is carried out through using a C18 chromatographic column. By adopting the high performance liquid chromatography, an Afatinib dimaleate genetic poison impurity intermediate V, the Afatinib dimaleate and other known impurities can be effectively separated, the peak pattern symmetry is relatively good, the peak appearance is fast, the genetic poison impurity intermediate V lower than 1 / 10 of a quality control limit can be rapidly detected, the method has the advantages of high specificity, high quantitation limit, high detection limit, high linear range and high repeatability, has the advantages of shorter detection time, higher precision and accuracy, high repeatability, high system applicability and the like, and provides an important method detection reference basis for quality control of afatinib drugs.

Description

technical field [0001] The invention relates to the field of drug analysis, in particular to a method for detecting genotoxic impurities of afatinib maleate. Background technique [0002] Afatinib dimaleate, the chemical name is (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydrofuran-3 -yl]oxy]quinazolin-6-yl]-4-(dimethylamino)-2-butenamide bismaleate, developed by Boehringer Ingelheim, Germany, and approved by the US FDA in July 2013 Approved for marketing, the trade name is Gilotrif, and the dosage form is film-coated tablets, with 3 specifications of 20, 30 and 40 mg. Afatinib is an irreversible dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2) for EGFR exon 19 deletion and exon 21(L858R) substitution mutation in the first-line treatment of patients with metastatic non-small-cell lung cancer (NSCLC). The currently known main impurities of afatinib maleate are impurity A, impurity B...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02G01N30/06G01N30/30G01N30/32G01N30/34G01N30/74G01N30/86
CPCG01N30/02G01N30/34G01N30/06G01N30/74G01N30/32G01N30/30G01N30/8679G01N2030/047G01N2030/324G01N2030/3007
Inventor 徐进王子月叶志兵李龙霞姚书扬汤怀松
Owner 南京安杰新生物医药有限公司
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