Crystal of febuxostat, preparation method and application in medicaments

A technology of febuxostat and crystal, which is applied to the field of febuxostat crystal, preparation and application in medicine, and can solve problems such as unsatisfactory dissolution results and need to be improved, etc.

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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  • Crystal of febuxostat, preparation method and application in medicaments
  • Crystal of febuxostat, preparation method and application in medicaments
  • Crystal of febuxostat, preparation method and application in medicaments

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Add 10g of febuxostat and 500ml of toluene into a 1L round-bottomed flask, heat and stir at 90-100°C until the solids are completely dissolved, then cool naturally to room temperature, a large amount of crystals will precipitate out quickly, in order to increase the yield, continue to cool in an ice bath To -5 ~ 0 ° C, heat preservation, stirring and crystallization for 2 hours, filter, wash the filter cake with a small amount of toluene, and dry it in vacuum at 80 ° C for 8 hours to obtain 7.8 g of light yellow crystalline powder with a purity of ≥ 99% (HPLC. Normalization method ).

[0020] Sampling to determine the reflection angle 2θ absorption peak of its X-ray powder diffraction is as follows: figure 1 Shown, the data of absorption peak is shown in Table 1; Figure 2 ~ Figure 3 shown. Depend on figure 1 As can be seen from Table 1, the reflection angle 2θ of the crystal X-ray powder diffraction pattern is about 2.98°, 5.84°, 11.19°, 14.04°, 14.54°, 16.75°, 18.4...

Embodiment 2

[0022] Add 10g of febuxostat and 20ml of toluene into a 250ml round-bottomed flask, stir and raise the temperature to reflux. After all the solids are dissolved, cool naturally to room temperature (15-30°C). Yield: keep stirring and crystallize for 2 hours, filter, wash the filter cake with a small amount of toluene, and dry at 80°C for 8 hours in vacuum to obtain 8.8 g of light yellow crystalline powder with a purity of ≥99% (HPLC. Normalization method). Corresponding X-ray powder diffraction patterns, infrared spectrograms and other detections show that it is a microcrystalline state that also conforms to the relevant characteristics of the M-type crystals mentioned in the present invention.

Embodiment 3

[0024] Prescription: febuxostat M type microcrystal 406g prepared in embodiment 1,

[0025] Medicinal lactose 900g,

[0026] Pregelatinized starch 300g,

[0027] Sodium starch glycolate 120g,

[0028] Magnesium stearate 1g.

[0029] Mix all components except magnesium stearate in the prescription raw materials evenly, use an appropriate amount of 75% ethanol solution as a binder to make a soft material, extrude through a 14-mesh sieve to make wet granules, and place it in a ventilated and dried state at 80°C for 2 hour, the dry granules are granulated through a 14 mesh sieve, add the remaining magnesium stearate, mix uniformly, fill in No. 2 gelatin capsules, and make 1000 capsule medicines altogether.

[0030] Table 1 Crystal X-ray powder diffraction reflection angle 2θ absorption peak data

[0031]

[0032] The detection result of table 2 particle size distribution

[0033...

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Abstract

The invention relates to a crystal (type M) of febuxostat, a preparation method and an application in medicaments. The reflected angle 2theta of the crystal X-ray powder diffraction pattern has characteristic absorption peak at about 2.95 degrees, 5.84 degrees, 11.19 degrees, 14.04 degrees, 14.54 degrees, 16.75 degrees, 18.47 degrees, 20.81 degrees, 22.72 degrees, 24.34 degrees and 25.62 degrees, wherein the reflected angle 2theta has three strongest peaks at 11.19 degrees, 2.98 degrees and 5.84 degrees; in an infrared spectrum pattern, the characteristic absorption peak occurs at about 3425cm<1>, 2964cm<1>, 2873cm<1>, 1689cm<1>, 835cm<1>, 815cm<1>, 765cm<1> and 729cm<1>; the particle diameter measured with a laser diffraction method ranges from 0.5 mu m to 50 mu m, the counting particle diameter D90 is less than 40 mu m and the average particle diameter is less than 20 mu m. The crystal can be obtained by recrystalling the febuxostat with toluene; the crystal and pharmaceutically acceptable auxiliary parts can form the useable corresponding medicinal preparation with satisfactory dissolving rate; the dissolution of a tablet in phosphate buffer solution medium with the pH value of 7.2 is greater than or equal to 45% within five minutes and greater than or equal to 95% within 35 minutes.

Description

technical field [0001] The present invention relates to a new crystal (type M) of febuxostat to be used, 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 with the structure shown in formula (I), is a new generation of yellow Purine oxidase inhibitors are currently clinically used to treat gout and other diseases caused by excessive uric acid. [0003] [0004] The Chinese patent literature with the publication number CN1275126A discloses that febuxostat has various crystal forms (A, B, C, D, G) and amorphous compounds, mainly using 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 literature has reported the H, I, J three crystal forms of the compound and their preparation methods. The crystal for...

Claims

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Application Information

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