Method for separating and measuring tofacitinib citrate and optical isomer of tofacitinib citrate by adopting liquid chromatography

A technology of optical isomers and tofacitinib, applied in the field of analytical chemistry, can solve problems such as failure to reach the detection limit, inability to accurately determine the content of optical isomers, and inability to effectively control the quality of tofacitinib citrate

Inactive Publication Date: 2015-06-03
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It has been verified that this method can separate the RR configuration of tofacitinib citrate from other configurations, and the peak order is SR configuration, RR configuration, SS configuration and RS configuration, but there are two disadvantages: One is that when this analysis method separates the four optical isomers, the four components cannot achieve baseline separation from each other, and the SS configuration and RS configuration partially overlap and cannot be completely separated; the second is to use this analysis method When other configurations were added to the RR configuration of tofacitinib citrate, the ideal detection limit (≤0.10%) was not reached, resulting in a low detection limit and the inability to accurately determine the content of optical isomers in the finished product , cannot effectively control the quality of tofacitinib citrate

Method used

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  • Method for separating and measuring tofacitinib citrate and optical isomer of tofacitinib citrate by adopting liquid chromatography
  • Method for separating and measuring tofacitinib citrate and optical isomer of tofacitinib citrate by adopting liquid chromatography
  • Method for separating and measuring tofacitinib citrate and optical isomer of tofacitinib citrate by adopting liquid chromatography

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Instruments and Conditions

[0033] High performance liquid chromatograph: Agilent 1260 high performance liquid chromatograph

[0034] Chromatographic column: Daicel CHIRALPAK IC chiral column (250mm×4.6mm)

[0035] Column temperature: 40°C

[0036] Mobile phase: n-hexane (0.1% diethylamine) - absolute ethanol (65:35)

[0037] Flow rate: 1.0ml / min

[0038] Detection wavelength: 289nm

[0039] Injection volume: 20μl

[0040] Implementation steps

[0041] Take tofacitinib citrate (RR configuration) 12.5mg, tofacitinib citrate enantiomer (SS configuration) 12.5mg and tofacitinib citrate diastereoisomer Racemate (SR configuration and RS configuration) 25mg, put in the same 25ml measuring bottle, add absolute ethanol (0.1% diethylamine) to dissolve and dilute to the mark, shake well, as the test solution.

[0042] Take the reagent blank solvent anhydrous ethanol (0.1% diethylamine) and the test solution respectively, carry out high performance li...

Embodiment 2

[0047] Instruments and Conditions

[0048] High performance liquid chromatograph: Agilent 1260 high performance liquid chromatograph

[0049] Chromatographic column: Daicel CHIRALPAK IC (250mm×4.6mm)

[0050] Column temperature: 40°C

[0051] Mobile phase: n-hexane (0.1% diethylamine) - absolute ethanol (65:35)

[0052] Flow rate: 1.0ml / min

[0053] Detection wavelength: 289nm

[0054] Injection volume: 20μl

[0055] Implementation steps

[0056] Take 25mg of tofacitinib citrate, put it in a 50ml measuring bottle, add absolute ethanol (0.1% diethylamine) to dissolve and dilute to the mark, shake well, and use it as the test solution.

[0057] Get need testing solution, carry out high performance liquid chromatography analysis by above-mentioned condition, record chromatogram, the result sees image 3 .

[0058] image 3 It is proved that the optical purity of tofacitinib citrate meets the requirements of raw materials, and this method can be used for...

Embodiment 3

[0061] Instruments and Conditions

[0062] High performance liquid chromatograph: Agilent 1260 high performance liquid chromatograph

[0063] Chromatographic column: Daicel CHIRALPAK IC (250mm×4.6mm)

[0064] Column temperature: 40°C

[0065] Mobile phase: n-hexane (0.1% diethylamine) - absolute ethanol (65:35)

[0066] Flow rate: 1.0ml / min

[0067] Detection wavelength: 289nm

[0068] Injection volume: 20μl

[0069] Implementation steps

[0070] Take tofacitinib citrate enantiomer 15mg, put it in a 100ml measuring bottle, add absolute ethanol (0.1% diethylamine) to dissolve and dilute to the mark, shake well, and get tofacitinib citrate Ni enantiomer stock solution.

[0071] Take tofacitinib citrate diastereomer racemate 15mg, put it in a 50ml measuring bottle, add absolute ethanol (0.1% diethylamine) to dissolve and dilute to the mark, shake well, and then get Citron Tofacitinib diastereomer racemate stock solution.

[0072] Accurately measure 5ml of tofacit...

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Abstract

The invention relates to a method for separating and measuring tofacitinib citrate and an optical isomer of the tofacitinib citrate by adopting a liquid chromatography. The method is characterized in that a chiral chromatographic column taking tri(3,5-dichlorophenyl)-carbamate cellulose or tri(3,5-dimethyl phenyl)-carbamate cellulose as filler is adopted, and a normal hexane-low alcohol-amine solution is taken as a mobile phone, wherein amine is diethylamine or triethylamine, the concentration of the amine is 0.05%-0.5%V / V of that of normal hexane, and the volume ratio of the normal hexane to low alcohol is (55 to 45) to (85 to 15). The method is stable in lower base line, relatively good in main peak shape and relatively high in detection limit, so that the mass of the tofacitinib citrate can be accurately controlled.

Description

[0001] technical field [0002] The invention belongs to the field of analytical chemistry, and in particular relates to a method for separating and measuring tofacitinib citrate and its optical isomers by liquid chromatography. [0003] Background technique [0004] Tofacitinib citrate is a drug for the treatment of rheumatoid arthritis, the main mechanism is JAK-1 and -3 tyrosine kinase inhibitors, its chemical name is 3-((3R,4R)-4-methyl Base-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropionitrile citrate (1:1 ), the English name is Tofacitinib Citrate, and the molecular formula is C 16 h 20 N 6 O·C 6 h 8 o 7 , the structural formula is: [0005] [0006] The molecule of tofacitinib citrate contains 2 chiral carbon atoms, and there are four optical isomers, RR, RS, SR, and SS, among which the RR configuration is an effective inhibitor of JAK-1 and -3 tyrosine kinases However, other configurations are not bioequivalent. Therefore, str...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02G01N30/60
Inventor 段玉娟孙攀胡芃张道林付晓泰
Owner CHONGQING PHARMA RES INST
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