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A kind of tofacitinib citrate crystal form compound and preparation method thereof

A technology of tofacitinib and citric acid, which is applied in the field of medicine, can solve the problems of not meeting the requirements of active ingredients, large crystal particle size, unstable crystal particles, etc., to improve the quality of drug production, good fluidity, The effect of improving bioavailability

Active Publication Date: 2019-05-03
SHANDONG YUXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] PCT application WO2003048162 discloses a new crystal form of tofacitinib citrate and its preparation method, but the crystal particle size prepared according to the method is relatively large, and its color will become darker after standing for a period of time, therefore, WO2003048162 The disclosed crystalline particles are unstable and cannot meet the requirements for the active ingredient in the formulation

Method used

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  • A kind of tofacitinib citrate crystal form compound and preparation method thereof
  • A kind of tofacitinib citrate crystal form compound and preparation method thereof
  • A kind of tofacitinib citrate crystal form compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: Preparation of tofacitinib citrate crystal compound

[0038] Take tofacitinib citrate 100g in the reaction flask, add 1000ml of water and ethanol mixed solution (the volume ratio of water and ethanol is 3:1), heat to 70°C, stir to dissolve, filter while hot; , while cooling down to 20°C (the cooling rate is 2°C every 10 minutes), add 2000ml of pre-cooled mixed solvent B (the volume ratio of ethanol and acetone is 1:3) to the solution at a flow rate of 1.0mL / min until crystallization , continue to cool down to -5°C (the cooling range is 1°C every 10 minutes), stir for 3h, and grow crystals for 4h. After vacuum filtration, the filter cake was vacuum-dried at 50° C. for 6 hours to obtain 90.6 g of white solid.

Embodiment 2

[0039] Embodiment 2: Preparation of tofacitinib citrate crystal compound

[0040]Take tofacitinib citrate 100g in the reaction flask, add 1500ml of water and ethanol mixed solution (the volume ratio of water and ethanol is 2:1), heat to 60°C, stir to dissolve, filter while hot; , while cooling down to 25°C (the cooling range is 2°C every 10 minutes), add 3000ml of pre-cooled mixed solvent B (the volume ratio of ethanol and acetone is 1:5) to the solution at a flow rate of 1.5mL / min until crystallization , continue to cool down to -10°C (the cooling range is 2°C every 10 minutes), stir for 2h, and grow crystals for 8h. After vacuum filtration, the filter cake was vacuum-dried at 50° C. for 4 hours to obtain 89.4 g of white solid. The X-ray powder diffraction spectrum of the obtained crystal measured by Cu-Kα rays is similar to that of Example 1.

Embodiment 3

[0041] Embodiment 3: Preparation of tofacitinib citrate crystal compound

[0042] Take 150g of tofacitinib citrate in a reaction flask, add 1500ml of a mixed solution of water and ethanol (the volume ratio of water and ethanol is 2:1), heat to 65°C, stir to dissolve, and filter while hot; , while cooling down to 30°C (the cooling range is 1°C every 10 minutes), add 3000ml of pre-cooled mixed solvent B (the volume ratio of ethanol and acetone is 1:5) to the solution at a flow rate of 2mL / min until crystallization occurs, Continue to cool down to 0°C (1°C every 10 minutes), stir for 2 hours, and grow crystals for 6 hours. After vacuum filtration, the filter cake was vacuum-dried at 50° C. for 5 hours to obtain 138 g of white solid. The X-ray powder diffraction spectrum obtained by measuring the prepared tofacitinib citrate crystals using Cu-Kα rays is similar to that of Example 1.

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Abstract

The invention belongs to the technical field of medicine and discloses a tofacitinib crystal form compound and a preparation method thereof. The X-ray powder diffraction spectrum shown by the 2 theta +-0.2 degree diffraction angle shows characteristic diffraction peaks at 2.42 degrees, 3.25 degrees, 4.23 degrees, 5.04 degrees, 6.12 degrees, 7.08 degrees, 8.02 degrees, 9.72 degrees, 10.63 degrees, 12.90 degrees, 14.35 degrees, 15.71 degrees, 17.82 degrees, 18.34 degrees, 19.24 degrees, 22.46 degrees, 24.56 degrees, 26.62 degrees, 30.75 degrees and 32.45 degrees, and the X-ray powder diffraction spectrum obtained by Cu-K alpha ray measurement and shown by the figure I is totally different from the prior art. The tofacitinib crystal form compound has better water solubility and high stability, the preparation method is simple and easy to operate, the medication safety is improved greatly after the compound is prepared into a drug composition, and the compound is very suitable for clinical application.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a tofacitinib citrate crystal compound and a preparation method thereof. Background technique [0002] The U.S. Food and Drug Administration approved Pfizer's Xeljanz (tofacitinib, tofacitinib citrate) in November 2012 for moderately to severely active rheumatoid arthritis ( RA) for the treatment of adult patients. RA is an autoimmune disease in which the immune system mistakenly attacks, causing inflammation in the joints and surrounding tissues. According to the CDC, about 1.5 million people in the United States suffer from RA. Tofacitinib citrate will compete with Abbott's blockbuster drug adalimumab (Humira), which is predicted by industry insiders as a potential blockbuster drug. [0003] Tofacitinib citrate, chemical name: 3-[(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- Amino]-piperidin-1-yl]-3-oxo-propionitrile citrate, molecular formula: C16H20N6O C6H8...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/519A61P29/00A61P19/02A61P37/02
CPCC07B2200/13C07D487/04
Inventor 侯俊凯刘强孙恒
Owner SHANDONG YUXIN PHARMA CO LTD
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