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

Active Publication Date: 2014-03-19
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

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The preparation of embodiment 1 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 value of 2.6 to 3.0, and 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 value of 2.6 to 3.0 acetic acid is 20:80. By-product 2 is the by-product closest to pomalidomide, and when it is separated from by-product 2, other impurities can be separated.

Embodiment 2

[0032] The screening of embodiment 2 chromatographic conditions and system suitability

[0033] 2.1 Selection of mobile phase

[0034] According to the relevant requirements of the mass spectrometry detector, the separation effects under different mobile phase conditions are as follows (see Table 1); the acetic acid solution is water to which 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)

The resolution is 4.3

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

Separation is 8.5

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

Separation is 6.1

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

Resolution is 11.2

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

The resolution is 9.2

[0037] According to the separation results of pomalidomide peak and by-product 2 peak in the system su...

Embodiment 3

[0054] The preparation of embodiment 3 detection limit solution

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

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

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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 measuring pomalidomide and its related substances, in particular to a method for simultaneously determining pomalidomide, synthetic 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 analogue is an immunomodulator with anti-tumor activity. In vitro cytological tests, 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 with dexamethasone in lenalidomide-sensitive and lenalidomide-resistant cell lines . Pomalidomide enhances T cell- and natural killer (NK) cell-mediated immunity and suppresses proinflamma...

Claims

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Application Information

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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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