A method for detecting related substances of ambrisentan

A technology related to substances and detection methods, applied in the field of analytical chemistry, can solve problems such as ghost peaks, inaccurate detection results, incomplete separation, etc., and achieve the effects of high precision, high peak symmetry, and high system adaptability

Active Publication Date: 2016-03-30
JIANGSU KANION PHARMA CO LTD
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Problems solved by technology

[0006] In the document "Quality Specification for Import Drugs-Compound Ambrisentanttablets" (Quality Standard for Imported Drugs--Ambrisentant Tablets, [S].JX20090317.), the registration standard for Ambrisentan Tablets imported drugs was eluted with a gradient of acetonitrile-phosphate buffered saline, but in the absence of When the sample space runs the gradient program, ghost peaks appear, which affects the inspection of impurities
Meanwhile, the pH value of its phosphate buffered saline solution is 6.5, and the ambrisentan molecule (pKa is 4.0) is separated on the reversed-phase chromatographic column in the form of ions, and the chromatographic peak of ambrisentan is severely tailed, which is not conducive to the detection of substance content
Although the detection method in the literature (M.B.V.Narayana1, K.B.ChandrasekharandB.M.Rao.AValidatedSpecificStability-IndicatingRP-HPLCAssayMethodforAmbrisentanandItsRelatedSubstances[J].JournalofChromatographicScience, 2013, 1-8) adjusts the pH value of potassium dihydrogen phosphate solution to 2.5, but in the absence of Ghost peaks still appear when running the gradient program in the sample space, which affects the inspection of impurities
And the chromatographic conditions adopted in the above two detection methods, such as mobile phase and gradient elution mode, all retain weaker impurity phenylethylamine (DP1), which is not completely separated from the solvent peak, which also makes the detection result inaccurate
The existing detection methods are poor in system applicability, repeatability, linear range, limit of quantification, limit of detection, etc. due to poor chromatographic conditions and methods

Method used

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  • A method for detecting related substances of ambrisentan
  • A method for detecting related substances of ambrisentan
  • A method for detecting related substances of ambrisentan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: detection method of the present invention

[0052] Instrument: Shimadzu high performance liquid chromatography

[0053] Chromatographic column: WatersAtlantisT3 (4.6×250mm, 5μm)

[0054] Mobile phase A: 0.02% trifluoroacetic acid in water

[0055] Mobile phase B: 0.01% trifluoroacetic acid in acetonitrile

[0056] Detection wavelength: 220nm

[0057] Flow rate: 1.0ml / min

[0058] Injection volume: 20μl

[0059] Column temperature: 30°C

[0060] Autosampler temperature control: 5°C

[0061] The elution program is shown in Table 1:

[0062] Table 1 Elution program

[0063] time (min)

[0064] The test solution: take 12.5mg of ambrisentan sample, put it in a 50ml measuring bottle, add 12.5ml of 0.01% trifluoroacetic acid acetonitrile solution to dissolve, add 0.02% trifluoroacetic acid aqueous solution to dilute to the mark, shake well, and use it as the test sample solution.

[0065] Reference substance solution: Take 1.0ml of the test so...

Embodiment 2

[0072] Embodiment 2: detection method system adaptability detection of the present invention

[0073] Dilute solution: 0.01% trifluoroacetic acid in acetonitrile solution - 0.02% trifluoroacetic acid aqueous solution (25:75) (V / V)

[0074] Blank solution: dilute solution

[0075] Impurity stock solution: Take 12.5mg each of impurities SRS1, SRS2, SRS3, SRS4, and dp1, accurately weigh them in a 100ml measuring bottle, dissolve them with diluent solution and dilute to the mark, and shake well.

[0076] Resolution solution: Take about 12.5mg of ambrisentan, put it in a 50ml measuring bottle, add 12.5ml of 0.01% trifluoroacetic acid acetonitrile solution to dissolve, add 1.0ml of impurity stock solution, dilute to the mark with 0.02% trifluoroacetic acid aqueous solution, Shake well.

[0077] According to the chromatographic conditions of Example 1, sample blank solution and resolution solution were respectively injected, and the chromatogram was recorded, see figure 1 and fi...

Embodiment 3

[0082] Embodiment 3: Specific detection of the detection method of the present invention

[0083] The strong degradation test is to accelerate the destruction of ambrisentan under strong conditions, such as strong acid, strong alkali, strong oxidation, high temperature, and strong light. The separation status of the analysis method is compared with the amount of impurities generated and the reduction of the main component to evaluate the effectiveness and applicability of the analytical method. At the same time, the DAD detector is used to check the peak purity: in the spectrum obtained from the degradation test, when the purity factor of the main component is greater than the threshold, it can be judged that the chromatographic peak does not contain other impurity peaks, and the chromatographic peak purity meets the requirements. The specific test results are shown in the table 4. The corresponding chromatograms are shown in Figure 3-8 .

[0084] Table 4 specificity test r...

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Abstract

The invention relates to the field of analytical chemistry, and in particular relates to a detection method of ambrisentan related substances. The detection method comprises the following steps: preparing a solution for test products by using a to-be-detected ambrisentan product, diluting the solution for the test products for 100 times to be used as a reference solution, then respectively performing HPLC (High Performance Liquid Chromatography) detection by using a trifluoroacetic acid aqueous solution as a mobile phase A and a trifluoroacetic acid acetonitrile solution as a mobile phase B, and measuring the content of the related substances according to a self-contrasted method of main components added with correction factors. The detection method disclosed by the invention adopts an acetonitrile-water-trifluoroacetic acid gradient elution system, and ensures that a chromatographic peak of ambrisentan has higher separation degree with other related substance peaks, and the chromatographic peak of ambrisentan is relatively high in peak type symmetry, so that the detection method is beneficial to detection on the related substances, has relatively high system suitability, also shows incomparable advantages in specificity, quantitation limit, detection limit, linear range and repeatability, and has relatively high precision degree.

Description

technical field [0001] The invention relates to the field of analytical chemistry, in particular to a method for detecting ambrisentan-related substances. Background technique [0002] Ambrisentan, known as Ambrisentan in English, is indicated for the treatment of pulmonary arterial hypertension patients with WHO grade II or III symptoms, to improve exercise capacity and delay clinical deterioration. When the drug is used as a drug, the content of ambrisentan is required to be no less than 98.5%, and the content of related substances is strictly limited. [0003] The main known related substances of ambrisentan are SRS1, SRS2, SRS3, SRS4 and DP1, which come from synthetic raw materials, resolution reagents, intermediates and degradation products. The structural formula is as follows: [0004] [0005] In view of the current strict requirements for ambrisentan products, the content of related substances needs to be tested after the synthesis of ambrisentan, in order to me...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): G01N30/02
Inventor 萧伟陈保来李家春黄文哲
Owner JIANGSU KANION PHARMA CO LTD
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