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Febuxostat crystal and preparation method and application in medicines thereof

A febuxostat and crystal technology, applied in the field of febuxostat crystals, preparation and application in medicine, can solve the problems of unsatisfactory dissolution results and needs to be improved

Active Publication Date: 2010-11-24
CHONGQING SHENGHUAXI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In addition, the Chinese patent literature with publication number CN101085761A also reported a microcrystal and its composition for the purpose of improving the dissolution rate of febuxostat. The microcrystal was prepared from ethyl acetate as a solvent, but tests showed that, Its dissolution results are still unsatisfactory and need to be improved to fully meet and improve the application effect.

Method used

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  • Febuxostat crystal and preparation method and application in medicines thereof
  • Febuxostat crystal and preparation method and application in medicines thereof
  • Febuxostat crystal and preparation method and application in medicines thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Add 10g of the crude febuxostat and 30ml of N,N-dimethylformamide (DMF) into a 250ml round-bottomed flask, stir and raise the temperature to 100°C to make the solids completely dissolved, and then lower the temperature to 20°C. Add 60ml of water while stirring. Incubate and crystallize for 2 hours, filter, wash the filter cake with water, and vacuum dry at 80°C for 10 hours to obtain 7.9 g of light yellow crystalline powder with a purity of ≥99% (HPLC.

[0020] Take a sample to determine the reflection angle 2θ absorption peak of its X-ray powder diffraction as figure 1 As shown, the absorption peak data are shown in Table 1; the infrared spectrogram and the crystal particle size distribution curve are shown in Figure 2 ~ Figure 3 Shown. by figure 1 As can be seen from Table 1, the reflection angle 2θ of the X-ray powder diffraction pattern of the crystal is about 4.99°, 6.90°, 11.68°, 15.89°, 17.54°, 24.87°, 25.24°, 25.82°, 26.18° and 26.76° There are characteristic abs...

Embodiment 2

[0024] Add 10g of the crude febuxostat and 100ml of N,N-dimethylformamide (DMF) into a 1000ml round bottom flask, stir and raise the temperature to 60~80℃, so that the solids are fully dissolved, keep at 55℃~60℃, and stir. 600ml of water was added dropwise to the bottom, the temperature was kept for 1 hour to crystallize, filtered, the filter cake was washed with water, and dried under vacuum at 80°C for 15 hours to obtain 8.2 g of light yellow crystalline powder with a purity of ≥99% (HPLC normalization method). Sampling and testing showed the same N crystal form; particle size analysis showed the same crystallite state.

[0025] Table 1 Reflection angle 2θ absorption peak data of crystal X-ray powder diffraction

[0026]

[0027] Table 2 Test results of particle size distribution

[0028]

Embodiment 3

[0030] Add 10g of the crude febuxostat and 50ml of N,N-dimethylacetamide to a 500ml round-bottomed flask in turn, stir and raise the temperature to 80-100°C to dissolve the solids, and cool down to -5°C to 0°C in an ice bath. 500ml of water was added dropwise with stirring, the temperature was kept for 1 hour to crystallize, filtered, the filter cake was washed with water, and vacuum dried at 80°C for 12 hours to obtain 9.0 g of light yellow crystalline powder with a purity of ≥99% (HPLC normalization method). Sampling and testing showed that the formation was crystal form N; particle size analysis showed that it was microcrystalline.

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Abstract

The invention relates to a febuxostat crystal and a preparation method and medical composite thereof. Characteristic absorption peaks appear on the crystal X-ray powder diffraction pattern at the following reflection angle 2 theta: 4.99 degrees, 6.90 degrees, 11.68 degrees, 15.89 degrees, 17.54 degrees, 24.87 degrees, 25.24 degrees, 25.82 degrees, 26.18 degrees and 26.76 degrees; characteristic absorption peaks appear on the infrared spectrogram when the values of wave number are separately about 3535cm<-1>, 3462 cm<-1>, 2962cm<-1>, 2875cm<-1>, 1681cm<-1>, 825cm<-1>, 765cm<-1> and 727cm<-1>; the grain size distribution range measured by the laser diffraction method is 0.5-50mu m, the statistical grain size D90 is less than 40mu m, and the average grain size is less than 20mu m. The febuxostat crystal can be obtained by recrystallizing febuxostat in N,N-dimethylformamide or N,N-dimethylacetamide. The febuxostat crystal and pharmaceutically acceptable auxiliary components can form the corresponding pharmaceutical preparation for use; the pharmaceutical preparation can have satisfactory dissolution rate; and the dissolution rate in 5 minutes of the tablet in phosphate buffer solution medium with a pH value of 7.2 is not less than 45% and in 35 minute is not less than 95%.

Description

Technical field [0001] The invention relates to a new crystal (N-type) of the compound to be used, febuxostat, its preparation method, and its application in related medicines. Background technique [0002] Febuxostat (FEBUXOSTAT), 2-(3-cyano-4-isobutoxy)phenyl-4-methyl-5-thiazolecarboxylic acid whose structure is represented by formula (I), is a new generation of yellow Purine oxidase inhibitors are currently clinically mainly used to treat gout and other diseases caused by hyperuric acid. [0003] [0004] The Chinese patent document with publication number CN1275126A discloses that febuxostat has multiple crystal forms (A, B, C, D, G) and amorphous compounds, mainly with methanol-water or isopropanol-water as the solvent Prepared. [0005] In order to solve the problem of low solubility of febuxostat in water, the publication number CN1970547A Chinese patent document also reported the three crystal forms of the compound H, I, J and the preparation method thereof. The crystal for...

Claims

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Application Information

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IPC IPC(8): C07D277/56A61K31/426A61P19/06
Inventor 李能刚贾春荣
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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