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Method for simultaneously determining 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione and related substances thereof

A technique for pomalidomide and pomalidomide, which is applied in the field of separation and determination of pomalidomide and its related substances, can solve the problems of difficult impurities, difficult quality control, hidden dangers of safe drug use, etc., and achieves good repeatability.

Active Publication Date: 2015-03-11
SHENZHEN NEPTUNUS PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is difficult to detect these impurities by using the high-efficiency liquid phase method commonly used to detect related substances at present. It is difficult to completely separate the above known impurities in the same method in the existing known methods, so that the quality control of this product is difficult. relatively high risk

Method used

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  • Method for simultaneously determining 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione and related substances thereof
  • Method for simultaneously determining 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione and related substances thereof
  • Method for simultaneously determining 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione and related substances thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Preparation of system suitability solution

[0031] Take pomalidomide and by-product 2: 5-amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3-dione; appropriate amount, use acetonitrile Dissolve in an appropriate amount, add mobile phase A with acetic acid with a pH of 2.6 to 3.0 to dilute to a solution containing both pomalidomide and by-product 2 at 10 μg / ml. The final volume ratio of acetonitrile and mobile phase A with a pH of 2.6-3.0 acetic acid is 20:80. By-product 2 is the by-product closest to pomalidomide, and is separated from by-product 2, and other impurities can be separated.

Embodiment 2

[0032] Example 2 Screening of Chromatographic Conditions and System Applicability

[0033] 2.1 Selection of mobile phase

[0034] According to the relevant requirements of the mass detector, the separation effect under different mobile phase conditions is selected as follows (see Table 1); the acetic acid solution is water and acetic acid is added to adjust the pH.

[0035] Table 1. Mobile phase selection results

[0036] Mobile phase

seperate effect

Methanol-acetic acid solution (pH2.2) (30:70)

Resolution is 4.3

Methanol-acetic acid solution (pH2.6) (30:70)

Resolution is 8.5

Methanol-acetic acid solution (pH3.0) (30:70)

Resolution is 6.1

Methanol-acetic acid solution (pH2.6) (gradient 1)

The resolution is 11.2

Methanol-acetic acid solution (pH2.6) (Gradient 2)

Resolution is 9.2

[0037] According to the resolution results of the pomalidomide peak and the by-product 2 peak in the system suitability solution measured by different mobile phases (see Table 1), it sho...

Embodiment 3

[0054] Example 3 Preparation of detection limit solution

[0055] Detection limit solution: Precisely measure 0.11ml of the test solution, put it in a 100ml measuring flask, add mobile phase A-mobile phase B (80:20 (v / v)) and dilute to the mark, shake well, and get it.

[0056] System suitability solution: Take proper amount of pomalidomide and by-product 2 and dissolve with proper amount of acetonitrile, add mobile phase B and dilute to a solution containing pomalidomide and by-product 2 at 10 μg / ml respectively.

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Abstract

The invention discloses a method for simultaneously determining 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione and related substances thereof. According to the method, the 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione and the related substances thereof are separated through high performance liquid chromatography, wherein a chromatographic column is bonded by octadecyl silica gel; a mobile phase is a methanol:acetic acid aqueous solution. The flow velocity in the high performance liquid chromatography is 0.5 to 1.2ml / min. The detection wavelength in the high performance liquid chromatography is 226nm. The method is simple, convenient and practical, can be used for quickly achieving the aims of simultaneously determining and separating the 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione and the related substances thereof, can be applied to determination of molecular weights of unknown impurities through liquid chromatography-mass spectrometry (LC-MS), provides a reliable basis for structure inference of the unknown impurities, and facilitates quality control of raw materials and preparations of the 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione.

Description

Technical field [0001] The invention relates to a method for separating and determining pomalidomide and related substances, in particular to a method for simultaneously determining pomalidomide, synthesis starting materials, intermediates, by-products, degradation products and other unknown impurities . Background technique [0002] The chemical name of pomalidomide is 4-amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3-dione, which is a kind of thalidomide The analog is an immunomodulator with anti-tumor activity. In the in vitro cytology test, it can inhibit the proliferation of hematopoietic tumor cells and induce apoptosis. In addition, pomalidomide can inhibit the proliferation of lenalidomide-resistant multiple myeloma cell lines and synergistically induce tumor cell apoptosis in lenalidomide-sensitive and lenalidomide-resistant cell lines and dexamethasone . Pomalidomide enhances T cell- and natural killer (NK) cell-mediated immunity and inhibits monocyte pro-inflamm...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): G01N30/02
Inventor 李勇胥娜刘小柔佘琴唐田王彦青吴婧刘碧秀
Owner SHENZHEN NEPTUNUS PHARM CO LTD
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