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Method for simultaneously determining cabozantinib analogue and related substances thereof

A technology of cabozantinib and analogs, applied in the field of drug analysis and detection, to achieve the effect of strong practicability, rapid time and good reproducibility

Active Publication Date: 2022-04-15
SHENZHEN NEPTUNUS PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, relevant standards are not included in the pharmacopoeias and patent documents of various countries in the world

Method used

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  • Method for simultaneously determining cabozantinib analogue and related substances thereof
  • Method for simultaneously determining cabozantinib analogue and related substances thereof
  • Method for simultaneously determining cabozantinib analogue and related substances thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] [Example 1] Preparation of detection solution

[0105] 1.1 Preparation of impurity stock solution

[0106] Weigh about 10 mg of each impurity reference substance in the above table, put them in different 20ml measuring bottles, add acetonitrile to dissolve and dilute to the mark, shake well, and use as each impurity stock solution respectively.

[0107] 1.2 Preparation of the test solution

[0108] Accurately weigh about 50 mg of the cabozantinib analog bulk drug, put it in a 100ml measuring bottle, dissolve it with a solvent and dilute to the mark, and shake it up to obtain the test solution.

[0109] 1.3 Preparation of spiked test solution

[0110] Accurately weigh about 50 mg of the raw material drug of cabozantinib analogue, put it in a 100ml measuring bottle, add an appropriate amount of solvent to dissolve it, pipette 1ml each of the impurity A stock solution and the impurity B stock solution and place it in the measuring bottle, add solvent to dilute to scale,...

Embodiment 2

[0111] [Example 2] Screening of chromatographic conditions

[0112] 2.1 Selection of chromatographic column

[0113] Get the need testing solution prepared by embodiment 1 and the need testing solution of standard addition, be divided into 5 groups, utilize the chromatographic column shown in table 1 respectively, detect according to following chromatographic conditions, obtain chromatogram respectively as attached Figure 1~5 shown.

[0114] Table 1 Columns

[0115]

[0116] Mobile phase A: phosphate buffered saline solution (take about 2.72 g of potassium dihydrogen phosphate, add 1000 ml of water to dissolve, adjust the pH value to 3.0 with 10% phosphoric acid);

[0117] Mobile phase B: acetonitrile;

[0118] Flow rate 1.0ml / min, column temperature 30°C, detection wavelength 254nm, follow the gradient elution procedure shown in Table 2:

[0119] Table 2 Gradient elution

[0120]

[0121] The retention time of the main peak, the number of theoretical plates, the t...

Embodiment 3

[0167] [Example 3] Forced degradation test

[0168] After the product is destroyed by high temperature, acid, alkali, oxidation, light and other severe conditions, the relevant substances are determined to check whether the selected chromatographic conditions can detect the possible degradation products of the product, as follows:

[0169] (1) Undestroyed test solution: take about 10 mg of this product, weigh it accurately, put it in a 20 ml measuring bottle, add 30% acetonitrile to dissolve and dilute to the mark, shake well, and filter to obtain.

[0170] (2) Preparation of test solution for high temperature destruction: Take about 10 mg of this product, weigh it accurately, put it in a 20 ml measuring bottle, add appropriate amount of 30% acetonitrile to dissolve, heat in a water bath at 90°C for 7 hours, take it out and let it cool, add 30% acetonitrile to dilute To the scale, shake well and filter, that is.

[0171] (3) Light damage the test solution: take about 10mg of ...

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Abstract

The invention discloses a high performance liquid chromatography analysis method for simultaneously determining cabozantinib analogues and related substances thereof, and the chromatographic conditions are as follows: a chromatographic column is an octadecyl silane bonded silica gel column, acetate buffer solution-acetonitrile (70: 30) is used as a mobile phase A, acetonitrile is used as a mobile phase B, gradient elution is performed, the concentration of the acetate buffer solution is 0.005-0.01 mol / L, the pH value is 8.5-9.5, the column temperature is 25-35 DEG C, the flow velocity is 0.9-1.1 ml / min, the column temperature is 25-35 DEG C, the column temperature is 25-35 DEG C, the column temperature is 25-35 DEG C, the column temperature is 25-35 DEG C, the column temperature is 25-35 DEG C, the column temperature is 25-35 DEG C, the column temperature is 25-35 DEG C, and the column temperature is the detection wavelength is 254 nm, the temperature of a sample injector is 2-20 DEG C, and the sample injection amount is 10 microliters. The determination method provided by the invention can rapidly and accurately detect the cabozantinib analogue and the related substances thereof, is simple to operate, good in reproducibility and high in sensitivity, can better control the quality of a cabozantinib analogue bulk drug product, and provides a guarantee for optimization of a synthesis process.

Description

technical field [0001] The invention relates to an analysis method of a cabozantinib analog bulk drug, in particular to a method for determination by a high-performance liquid chromatography gradient method, which belongs to the field of drug analysis and detection. Background technique [0002] The cabozantinib analog of the present invention is (S)-2-(4-(7-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1 -Carboxamide)phenoxy)thieno[3,2-b]pyridin-2-yl)-1H-pyrazolyl-1-yl)ethanol valine ester hydrochloride, the molecular formula is C 34 h 33 CIF 2 N 6 o 5 S, its chemical structural formula is as shown in (I). [0003] [0004] Cabozantinib analogues are a new class of drugs. At present, relevant standards are not included in the pharmacopoeias and patent documents of various countries in the world. [0005] In this paper, by investigating different mobile phase compositions, ratios, different elution methods, different chromatographic columns and different i...

Claims

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Application Information

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IPC IPC(8): G01N30/02G01N30/06G01N30/34G01N30/86
CPCY02P20/55
Inventor 郭青石涛李汉然孔萌卢晓莹冯贻东黄汉敏
Owner SHENZHEN NEPTUNUS PHARMA RES INST CO LTD
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