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High performance liquid chromatography (HPLC) for fast separating and analyzing zafirlukast and isomers thereof

A technology for separation and analysis of isomers, applied in the field of high performance liquid chromatography, can solve the problems of inability to apply product quality control and release, complicated methods, and failure to effectively control the quality of zafirlukast, and meet the requirements of the product. Effects of quality control and release requirements

Active Publication Date: 2012-12-19
北京京卫燕康药物研究所有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] From the structure of the above chemical components, the structures are similar; especially zafirlukast and its isomers m-zafirlukast and p-zafirlukast are very similar in structure, so when using the HPLC method, the It is quite difficult to effectively separate the above components on the same chromatographic column. In fact, the results are not very satisfactory by changing the ratio of binary or ternary mobile phase, pH value, ionic strength, etc.
[0014] There is a report on the method of determining zafirlukast and its related substances by HPLC method, that is, "RP-HPLC method to determine the content of zafirlukast and its related substances, Yang Weifeng, Li Huilin, Journal of Pharmaceutical Analysis 2008, 28 (7)" , the report carried out the separation of zafirlukast and synthetic intermediates, without considering the side reaction products in the synthesis, so no specific impurities m-zafirlukast and p-zafirlukast were found in zafirlukast; and Using this condition, the isomers of zafirlukast could not be separated, and the quality of zafirlukast could not be effectively controlled
In the literature "Identification, characterization and synthesis of impurities of zafirlukast, G.Goverdhan, et al., J.Pharm.Biomed.Anal. (2009), doi: 10.1016", the gradient elution method was used to carry out the analysis of zafirlukast and zafirlukast. Its isomers are separated, but the method is complicated and the analysis time is too long (about 100 minutes, including gradient elution time of 85 minutes), which is only suitable for laboratory research and cannot be applied in daily production Product Quality Control and Release
So far, there is no literature report on the method of rapid isocratic elution separation and analysis of zafirlukast and its isomers, and there is an urgent need for such a technology to be applied to the quality control of zafirlukast

Method used

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  • High performance liquid chromatography (HPLC) for fast separating and analyzing zafirlukast and isomers thereof
  • High performance liquid chromatography (HPLC) for fast separating and analyzing zafirlukast and isomers thereof
  • High performance liquid chromatography (HPLC) for fast separating and analyzing zafirlukast and isomers thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] 1. Instruments and conditions

[0040] High performance liquid chromatography: SHIMADZU LC-20AT, SPD-M20A, SIL-20A, CBM-20A, DGU-20A 3 ;

[0041] Column: C 18 (150mm×4.6mm, 5μm);

[0042] Mobile phase: acetate buffer (0.05mol / L sodium acetate, adjust pH to 3.8 with acetic acid)-acetonitrile (47:53);

[0043] Flow rate: 1.0ml / min; detection wavelength: 210nm; column temperature: room temperature; injection volume: 20μl.

[0044] 2. Experimental steps

[0045] Mix zafirlukast intermediate-6, o-toluenesulfonamide and zafirlukast crude product (including m-zafirlukast and p-zafirlukast), dissolve the sample with acetonitrile, and perform HPLC under the above conditions. Chromatography, record chromatograms. see attached results figure 2 .

[0046] 3. Method validation

[0047] 3.1 Selection of detection wavelength

[0048] Take an appropriate amount of zafirlukast and its intermediates, add acetonitrile to dissolve and dilute to make a solution of about 20μg / mL p...

Embodiment 2

[0071] 1. Instruments and conditions

[0072] High performance liquid chromatography: SHIMADZU LC-20AT, SPD-M20A, SIL-20A, CBM-20A, DGU-20A 3 ;

[0073] Column: C 18 (150mm×4.6mm, 3.5μm);

[0074] Mobile phase: phosphate buffer (0.02mol / L disodium hydrogen phosphate, phosphoric acid to adjust pH to 4.2)-acetonitrile (47:53);

[0075] Flow rate: 1.0ml / min; detection wavelength: 210nm; column temperature: room temperature; injection volume: 20μl.

[0076] 2. Experimental steps

[0077] Mix zafirlukast intermediate-6, o-toluenesulfonamide and zafirlukast crude product (including m-zafirlukast and p-zafirlukast), dissolve the sample with acetonitrile, and perform HPLC under the above conditions. Chromatography, record chromatograms. see attached results image 3 .

Embodiment 3

[0079] 1. Instruments and conditions

[0080] High performance liquid chromatography: SHIMADZU LC-20AT, SPD-M20A, SIL-20A, CBM-20A, DGU-20A 3 ;

[0081] Column: C 18 (150mm×4.6mm, 5μm);

[0082] Mobile phase: phosphate buffer (0.05mol / L potassium dihydrogen phosphate, adjust pH to 4.0 with phosphoric acid)-acetonitrile (47:53);

[0083] Flow rate: 1.0ml / min; detection wavelength: 210nm; column temperature: room temperature; injection volume: 20μl.

[0084] 2. Experimental steps

[0085] Mix zafirlukast intermediate-6, o-toluenesulfonamide and zafirlukast crude product (including m-zafirlukast and p-zafirlukast), dissolve the sample with acetonitrile, and perform HPLC under the above conditions. Chromatography, record chromatograms. see attached results Figure 4 .

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Abstract

The invention relates to a high performance liquid chromatography (HPLC) for fast separating and analyzing zafirlukast and isomers thereof and discloses a method for the separation and assay determination of the zafirlukast and the isomers thereof. The HPLC is used under the conditions that a C18, C8 or phenyl column serves as a chromatographic column, and the pH value of a mobile aqueous phase is 2 to 7, wherein the aqueous phase and one or two organic solvents compose a binary or ternary mobile phase system in a certain proportion for isocratic elution, and the flow rate of the mobile phase is 0.6ml / min to 2.0ml / min, so that the zafirlukast and the isomers thereof can be fast and effectively separated and analyzed by the method.

Description

technical field [0001] The invention relates to a high-performance liquid chromatography analysis method, in particular to the separation, analysis and determination of zafirlukast and its isomers. Background technique [0002] Zafirlukast is a leukotriene receptor antagonist that competitively inhibits leukotriene activity and is suitable for the prevention and long-term treatment of asthma. During the chemical synthesis, the last step intermediate [Intermediate-6, chemical name: 4-(5-cyclopentanoylamino-1-methylindol-3-ylmethyl)-3-methoxybenzoic acid ] can generate zafirlukast through condensation reaction with o-toluenesulfonamide, because the purity of the reaction raw material o-toluenesulfonamide itself cannot reach 100%, and often contains impurities (two isomers): m-toluene Sulfonamide, p-toluenesulfonamide. Therefore, in the last step of the reaction, intermediate-6 will react with the impurities m-toluenesulfonamide and p-toluenesulfonamide in o-toluenesulfonamid...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): G01N30/02G01N30/28G01N30/50
Inventor 张彦源王宾冯志媛
Owner 北京京卫燕康药物研究所有限公司