CN101139325B - 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid crystal form and preparation method thereof - Google Patents

Abstract

The invention discloses two crystal forms of antihyperuricemia drug 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid and a preparation method thereof. The preparation method of the crystal form generally uses ethanol, ethyl acetate or acetone with low toxicity as a solvent, and the safety is relatively high. In addition, the two crystal forms have low hygroscopicity in a high-humidity environment, and are suitable for making stable pharmaceutical preparations.

Description

2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid crystal form and preparation method thereof

technical field

The invention relates to two crystal forms of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid and a preparation method thereof.

Background technique

The general name of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid is Febuxostat, which is mainly used for the treatment of hyperuricemia.

EP 513379 reports the synthesis method of febuxostat, in which it is mentioned that recrystallization with ethanol is used to obtain the final product, but the problem of the crystal form is not described. In Chinese patent CN1275126, it is recorded that febuxostat has five crystal forms A, B, C, D, G and an amorphous form, wherein crystal A is the relatively stable crystal form, crystal D is methanolate, and crystal G The crystals are hydrates. This patent uses a solvent system of methanol/water or isopropanol/water for crystallization, and can perform crystal transformation according to different drying methods.

Contents of the invention

The object of the present invention is to provide two new febuxostat crystal forms, namely crystal forms I and II. Another object of the present invention is to provide a method for preparing febuxostat crystal form.

Features of Febuxostat Form I:

Its X-ray powder diffraction pattern at the reflection angle 2θ is about: 6.60±0.2, 7.20±0.2, 11.84±0.2, 12.82±0.2, 13.26±0.2, 16.46±0.2, 17.82±0.2, 19.04±0.2, 19.56±0.2, 21.94±0.2, 22.72±0.2, 23.80±0.2, 24.28±0.2, 24.68±0.2, 25.88±0.2, 26.68±0.2, 37.76±0.2 (±2 is the acceptable error range of 2θ value, the same below). Its X-ray powder diffraction pattern is shown in Figure 1.

Features of Febuxostat Form II:

Its X-ray powder diffraction pattern at reflection angle 2θ is about: 4.78±0.2, 6.82±0.2, 8.30±0.2, 9.58±0.2, 11.74±0.2, 13.74±0.2, 14.60±0.2, 15.92±0.2, 16.68±0.2, 17.56±0.2, 21.26±0.2, 23.64±0.2, 24.80±0.2, 25.20±0.2, 25.78±0.2, 26.08±0.2, 26.66±0.2, 28.66±0.2, 31.64±0.2. Its X-ray powder diffraction pattern is shown in Figure 2.

Crystal form I is obtained by heating and dissolving febuxostat and ethyl acetate, followed by recrystallization. The amount of ethyl acetate is 10 to 100 times that of febuxostat, preferably 40 times; the temperature required for heating is about 20 to 80°C, preferably 40°C.

The crystal form II is obtained by heating, mixing and dissolving febuxostat with ethanol and sodium hydroxide solution, making it alkaline to a pH of 8-9, and then adjusting it to an acidic pH of 2-3 with a hydrochloric acid solution to crystallize the compound. The product was obtained after filtration and drying. The amount of ethanol in the above process is 10 to 40 times the weight of febuxostat, preferably 20 to 30 times; the heating temperature is 20 to 80°C, preferably 40°C; the concentration of sodium hydroxide solution used for alkalization is 0.5mol/L～ 2.0 mol/L, preferably 1.0 mol/L; the concentration of hydrochloric acid used for acidification is 0.5 mol/L-4 mol/L, preferably 1.0 mol/L. The drying condition is 20-80°C, preferably 50°C.

The used solvent of Chinese patent CN1275126 crystallization is methanol and water, wherein the toxicity of methanol to human body is relatively large, and the product for medicinal use requires the residue of methanol to be less than 0.03%. Esters or acetone are used as solvents, so the safety is relatively high.

In addition, after comparison of hygroscopicity tests, febuxostat crystal form I is the most stable under high humidity conditions, crystal forms II and D are slightly hygroscopic, and crystal A is the most hygroscopic. The specific data are shown in Table 1 below.

Table 1 Hygroscopicity of each crystal form after being placed under the conditions of 75% and 92.5% humidity for 24 hours:

It can be seen from Table 1 that in an environment with high humidity, the crystalline form I and the crystalline form II provided by the present invention, especially the crystalline form I, are relatively stable forms, which shows that they are suitable for making stable pharmaceutical preparations .

The present invention also obtains crystal forms consistent with crystal forms A, B, and D in Chinese patent CN1275126 through different crystallization methods.

Description of drawings:

The drawings included in this application are an integral part of the description, and together with the description and the claims, the drawings are used to illustrate the essence of the present invention, so as to better understand the present invention.

Fig. 1 is the X-ray powder diffraction pattern of febuxostat crystal form I;

Fig. 2 is the X-ray powder diffraction pattern of febuxostat crystal form II;

Fig. 3 is the X-ray powder diffraction pattern of febuxostat crystal form A;

Fig. 4 is the X-ray powder diffraction pattern of febuxostat crystal form B;

Fig. 5 is the X-ray powder diffraction pattern of febuxostat crystal form D;

Detailed ways

The present invention will be further described below in conjunction with examples, but these examples do not constitute any limitation to the present invention. The analytical instruments adopted in the following examples are the following models:

X-ray: Cu K-ALPHA1/40kV/60mA

Example 1

The preparation method of febuxostat crystal form I:

Add 1.7 g of febuxostat to 30 ml of ethyl acetate to dissolve under reflux, then cool to room temperature while stirring, and filter after 2 hours. Dry at 60°C for 2 hours. 1.5 g of a sample of crystal form I was obtained. The melting point is 208-209°C.

Example 2

The preparation method of febuxostat crystal form I:

Add 0.5 g of febuxostat to 5 ml of ethyl acetate and reflux to dissolve, then cool to room temperature under stirring, after 2 hours, filter and dry at 60 ° C for 2 hours to obtain 0.4 g of a sample of crystal form I. The melting point is 208-209 ° C.

Example 3

The preparation method of febuxostat crystal form I:

Add 1.0 g of febuxostat to 100 ml of ethyl acetate and heat to dissolve at 20°C, then cool to room temperature while stirring, and filter after 2 hours. Dry at 60°C for 2 hours. A 0.9 g sample of Form I was obtained. The melting point is 208-209°C.

Example 4

The preparation method of febuxostat crystal form II:

Mix 4.0 g of febuxostat with 16 ml of 1 mol/L sodium hydroxide solution and 80 ml of ethanol, heat to 40°C, stir and dissolve, and the pH value is 9. After cooling to 20°C, adjust the pH to 2 with 19ml of 1mol/L hydrochloric acid, stir for 30 minutes, filter, wash with water, and dry at 50°C for 24 hours to obtain 3.6g of white solid. The melting point is 201-203°C.

Example 5

The preparation method of febuxostat crystal form II:

Mix 1.0 g of febuxostat with 4 ml of 1 mol/L sodium hydroxide solution and 10 ml of ethanol, heat to 78°C, and stir to dissolve. Add 5ml of 1mol/L hydrochloric acid, stir for 30 minutes, filter, wash with water, and dry at 50°C for 24 hours to obtain 0.9g of white solid. The melting point is 201-203°C.

Example 6

The preparation method of febuxostat crystal form II:

Mix 1.0 g of febuxostat with 4 ml of 1 mol/L sodium hydroxide solution and 40 ml of ethanol, heat to 30°C, stir and dissolve, and the pH value is 9. Add 4ml of 1mol/L hydrochloric acid, stir for 30 minutes, filter, wash with water, and dry at 50°C for 24 hours to obtain 0.8g of white solid. The melting point is 201-203°C.

Example 7

The preparation method of febuxostat crystal form A:

2 g of febuxostat and 20 ml of acetone were heated under reflux to dissolve, stirred and crystallized, cooled to 20°C and then stirred for 1 hour, filtered, washed with acetone, and dried at 60°C for 24 hours to obtain 1 g of white solid. Melting point: 208-209°C.

Powder X-ray diffraction 2θ is 6.64, 7.2, 12.84, 13.26, 16.52, 19.62, 21.98, 22.76, 25.92, 26.72, 29.20, 36.74.

Example 8

The preparation method of febuxostat crystal form B:

Heat 20ml of febuxostat and 20ml of acetone under reflux to dissolve, lower the temperature to 60°C and stir for 30 minutes, a solid precipitates, stop heating and then stir for 2.5 hours, filter, wash with 5ml of ethanol, and vacuum dry at 25°C for 3 hours. 1.5 g of white solid were obtained. The melting point is 207-209°C.

Powder X-ray diffraction 2θ is 4.90, 6.68, 7.26, 11.64, 12.18, 12.86, 13.36, 16.20, 16.48, 19.10, 19.64, 21.02, 22.00, 22.80, 23.06, 23.88, 24.78, 25.92, 26.76.

Example 9

The preparation method of febuxostat crystal form D:

Add 2 g of febuxostat into 13 ml of ethanol, reflux to dissolve, then quickly cool to 5°C with ice water and stir for 2 minutes, filter, and vacuum-dry at 25°C for 12 hours. 1.4 g of a white solid was obtained with a melting point of 207-209°C.

Powder X-ray diffraction 2θ is 7.92, 8.14, 9.54, 12.86, 17.12, 19.20, 21.58, 23.42, 24.30, 25.94, 30.12, 33.54.

Claims (4)

1. the crystal formation I of a 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid, this crystalline X-ray powder diffraction pattern is 6.60 ± 0.2,7.20 ± 0.2 at 2 θ, 11.84 ± 0.2,12.82 ± 0.2,13.26 ± 0.2,16.46 ± 0.2,17.82 ± 0.2,19.04 ± 0.2,19.56 ± 0.2,21.94 ± 0.2,22.72 ± 0.2,23.80 ± 0.2,24.28 ± 0.2,24.68 ± 0.2,25.88 ± 0.2,26.68 ± 0.2,37.76 ± 0.2.

2. crystal formation I as claimed in claim 1 is characterized in that, the fusing point of described crystal formation is 208～209 ℃.

3. the preparation method of the crystal formation I of the described 2-of claim 1 (3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid, obtain product by crystalline method that described compound heating for dissolving is laid equal stress on, it is characterized in that using ethyl acetate to make solvent, wherein the consumption of ethyl acetate is 10～100 times of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid weight; Heating required temperature is 20～80 ℃.

4. preparation method as claimed in claim 3 is characterized in that, the consumption of ethyl acetate is 40 times of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid weight; Heating required temperature is 40 ℃.

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