CN112390766A

CN112390766A - Preparation method of febuxostat crystal form A

Info

Publication number: CN112390766A
Application number: CN201910746024.4A
Authority: CN
Inventors: 彭灵超; 黄福良; 王臻; 朱国荣; 屠勇军
Original assignee: Zhejiang Tianyu Pharmaceutical Co Ltd
Current assignee: Zhejiang Tianyu Pharmaceutical Co Ltd
Priority date: 2019-08-13
Filing date: 2019-08-13
Publication date: 2021-02-23
Anticipated expiration: 2039-08-13
Also published as: CN112390766B

Abstract

The invention provides a preparation method of febuxostat crystal form A, which comprises the steps of firstly dissolving febuxostat in methanol to obtain methanol solution, and then sequentially adding a first volume V at different dropping speeds₁And a second volume V₂After the dropwise addition, the temperature is reduced, the heat preservation and the crystallization are carried out, and the obtained crystal is collected, namely the febuxostat crystal form A. The preparation method provided by the invention effectively inhibits the generation of crystal transformation phenomenon by accurately controlling the dripping speed and the dripping volume of the poor solvent before crystallization and in the crystallization process, and the prepared febuxostat crystal is of a single crystal form A, has good purity and high yield.

Description

Preparation method of febuxostat crystal form A

Technical Field

The invention relates to the field of medicine preparation, and in particular relates to a preparation method of febuxostat crystal form A.

Background

Febuxostat, named Febuxostat in the British name and 2- [ 3-cyano-4- (2-methylpropoxy) phenyl ] -4-methyl-5-thiazole carboxylic acid in the chemical name, is a non-purine xanthine oxidase inhibitor developed by Teijin pharmaceutical company of Japan and can effectively block the formation of uric acid. The medicine is registered for the first time in European Union in 2008 and is mainly used for treating gout clinically, and the chemical structural formula of the medicine is as follows:

the pharmaceutical company of Imperial discloses a polymorphic form of febuxostat in WO 99/65885, including forms A, B, C, D, G and amorphous form, wherein, form A is prepared by using a mixed solvent of methanol/water, the patent discloses that the proportion range of methanol/water corresponds to the phase diagram of the form, wherein, form A can be obtained in the range of I area, form D can be obtained in the range of II area, and form G can be obtained in the range of III area, but the patent does not disclose detailed process parameters such as crystallization temperature, dropping speed of poor solvent water before crystal precipitation and the like, the method of the patent is easy to generate crystal transformation phenomenon in the crystallization process, and even in the solvent proportion range of form A, a single form A is difficult to obtain.

The detailed process for preparing febuxostat crystal form A is disclosed in WO 2007/148787 by the Kirschner pharmaceutical company, the febuxostat is dissolved in methanol or a mixed solvent of methanol and water (the volume ratio of the MeOH to the water is more than 90/10), then water is added until the ratio of the methanol to the water reaches 7/3, the temperature of a crystallization solution is kept at 40 ℃ in the water adding process, micro crystal seeds of the febuxostat crystal form A (0.25 mg/mL-1.25 mg/mL) are added within a specific time period (within 40-50 min) in the water adding process, the initial concentration range of the crystallization solution is 0.024 +/-0.008 mol/L, and the adding speed range of the water is 0.007-0.01175 mL/min/mL. The process conditions are harsh, the time for adding the crystal seed A is not easy to control, and the crystal transformation phenomenon is easy to occur when the crystal seed A exceeds the range.

Based on the defects of the prior art, a method for conveniently and stably obtaining a single febuxostat crystal form A is urgently needed to be developed.

Disclosure of Invention

In order to overcome the defects in the prior art, the invention aims to provide a preparation method of febuxostat crystal form A.

The preparation method of the febuxostat crystal form A provided by the invention comprises the following steps:

s1: dissolving febuxostat in methanol to obtain a methanol solution;

s2: controlling the temperature of the methanol solution obtained in the step S1 to be 60-65 ℃, and dropwise adding a first volume V into the methanol solution₁Wherein the volume ratio of the first volume of water to the methanol is 1: 7.0-7.2, and the dropping speed is 4.4-5.2% V₁/min；

S3: controlling the temperature of the feed liquid obtained in the step S2 to be 60-65 ℃, and dropwise adding a second volume V into the feed liquid₂Wherein the volume ratio of the second volume of water to the methanol is 1: 1.0-1.2, and the dropping speed is 1.0-1.1% V₂Min; and

s4: and after the water drops with the second volume are added, cooling to 20-25 ℃, preserving heat and crystallizing, and collecting the obtained crystal, namely the febuxostat crystal form A.

The inventor of the invention finds that the crystal type of the obtained crystal is obviously influenced by the adding speed of water before and during the crystallization of febuxostat by adding water, and the crystal is rotated when the speed is too high or too low, so that the mixed crystal of the crystal form A and the crystal form B or the crystal form A and the crystal form G is obtained, and the purity of the crystal is influenced. According to the preparation method, the poor solvent is divided into two parts and added into the crystallization system at different adding speeds, the needle-shaped crystal is separated out after the water with the first volume is added, the seed crystal is not required to be added, and the crystal transformation can be obviously inhibited in the whole crystallization process, so that the single crystal form A can be obtained.

In some embodiments, in step S1, the ratio of the febuxostat to the methanol is 1: 12.0-12.5 (g/mL), i.e., 12.0-12.5 mL of methanol is added per gram of febuxostat. In some preferred embodiments, the ratio of the amount of febuxostat to the amount of methanol is 1:12.22(g/mL), i.e., 12.22mL of methanol is added per gram of febuxostat.

In some embodiments, in step S2, the volume ratio of the first volume of water to the methanol is 1: 7.14.

In some embodiments, the first volume of water is added dropwise at a constant rate.

In some embodiments, in step S3, the volume ratio of the second volume of water to the methanol is 1: 1.16.

In some embodiments, the time for thermal crystallization in step S4 is 50-80 min.

In some embodiments, the crystals obtained in step S4 are collected and then dried under vacuum.

In some preferred embodiments, the preparation method of the present invention comprises the steps of:

s1: dissolving 225g of febuxostat in 2750mL of methanol to obtain a methanol solution;

s2: controlling the temperature of the methanol solution obtained in the step S1 to be 60-65 ℃, dropwise adding 385mL of water into the methanol solution, and separating out needle crystals after the dropwise adding is finished, wherein the dropwise adding speed is 17-20 mL/min;

s3: controlling the temperature of the feed liquid obtained in the step S2 to be 60-65 ℃, and dripping 2365mL of water into the feed liquid at a dripping speed of 25 mL/min; and

s4: and after the dropwise addition of water is finished, cooling to 20-25 ℃, preserving heat and crystallizing, collecting obtained crystals and drying to obtain the febuxostat crystal form A.

The febuxostat A crystal form preparation method provided by the invention effectively inhibits the generation of crystal transformation phenomenon by accurately controlling the dripping speed and the dripping volume of a poor solvent before crystallization and in the crystallization process, and the prepared febuxostat crystal is a single crystal form A, has good purity and high yield.

Drawings

FIG. 1 is an X-ray powder diffraction pattern of the febuxostat crystal prepared in example 3;

FIG. 2 is an X-ray powder diffraction pattern of the febuxostat crystal prepared in example 1;

FIG. 3 is an X-ray powder diffraction pattern of the febuxostat crystal obtained in example 4;

FIG. 4 is an X-ray powder diffraction pattern of the febuxostat crystals prepared in example 5.

Detailed Description

The technical solution of the present invention is further described in detail with reference to the following specific examples.

Febuxostat used in the examples of the present invention was prepared by a synthetic method disclosed in patent US 5614520.

The X-ray Powder diffraction pattern of the embodiment of the invention is measured by an X' pert Powder X-ray diffractometer in the family Pasnaureae, and the diffraction pattern of copper, palladium, incident wavelength is as follows: 1.54 angstroms.

In the examples of the present invention, other reagents used in the examples are commercially available products unless otherwise specified, and the devices or methods used in the examples are those commonly used in the art unless otherwise specified.

Example 1

Adding 225g of febuxostat and 2750mL of methanol into a four-mouth bottle, starting stirring, heating to 65-70 ℃, preserving heat for 30 minutes, dissolving the feed liquid clearly, controlling the temperature of the feed liquid to be 60-65 ℃, dripping 385mL of deionized water into the four-mouth bottle through a metering pump, controlling the dripping speed to be 17mL/min, preserving heat and stirring for 30 minutes after dripping is finished, and separating out needle crystals. And continuously controlling the temperature of the feed liquid to be 60-65 ℃, dripping 2365mL of deionized water into a four-mouth bottle through a metering pump, controlling the dripping speed to be 25mL/min, keeping the temperature and stirring for 30 minutes after dripping, cooling to the temperature of the feed liquid to be 20-25 ℃, and keeping the temperature for 1 hour. Filtering to obtain white needle crystal, putting the obtained solid into a vacuum drying oven, controlling the temperature at 75-80 ℃ and the vacuum degree at more than 0.095MPa, and vacuum-drying for 24 hours to obtain 191g of febuxostat with the yield of 85%.

The XRPD pattern of the obtained crystal is shown in figure 2, and is confirmed to be febuxostat crystal form A by comparing with the crystal form data disclosed in WO 99/65885.

Examples 2 to 6

Examples 2-6 following the procedure of example 1, only the rate of water addition was varied before crystal precipitation, keeping the remaining crystallization process parameters constant.

The water drop acceleration of each example and the obtained crystal form detection results are shown in table 1.

TABLE 1

The XRPD patterns of the febuxostat crystals obtained in examples 3, 1, 4 and 5 were compared with the pattern of crystal form A, B, G disclosed in WO 99/65885 for the major 2 θ diffraction angles, and the results are shown in table 2.

TABLE 2

As can be seen from the results in Table 2, when the dropping rate of water before crystal precipitation is too slow (as in example 3) or too fast (as in example 5), both the precipitated crystals are mixed crystals; and when the dropping speed is 17-20 mL/min (examples 1 and 4), the crystal transformation phenomenon can be avoided, and a single crystal form A can be obtained.

Industrial applicability

From the examples 1-6, it can be seen that the preparation method provided by the invention effectively inhibits the phenomenon of crystal transformation in the crystallization process by controlling the process parameters such as the water adding speed and the like, and conveniently prepares the single febuxostat crystal form a without adding seed crystals, and the obtained product has high purity and high yield. The preparation process of the embodiment 1 is repeated for a plurality of times, the single crystal form A can be prepared, and the scale-up production is not affected, so that the preparation method disclosed by the invention is simple, convenient, stable and reliable in process, excellent in effect and suitable for industrial scale production.

Unless otherwise defined, all terms used herein have the meanings commonly understood by those skilled in the art.

The described embodiments of the present invention are for illustrative purposes only and are not intended to limit the scope of the present invention, and those skilled in the art may make various other substitutions, alterations, and modifications within the scope of the present invention, and thus, the present invention is not limited to the above-described embodiments but only by the claims.

Claims

1. A preparation method of febuxostat crystal form A is characterized by comprising the following steps:

s1: dissolving febuxostat in methanol to obtain a methanol solution;

2. The method according to claim 1, wherein in step S1, the febuxostat and the methanol are used in a ratio of 1: 12.0-12.5 (g/mL).

3. The method according to claim 2, wherein the febuxostat is used in an amount ratio of 1:12.22(g/mL) to the methanol.

4. The method according to any one of claims 1 to 3, wherein in the step S2, the volume ratio of the first volume of water to the methanol is 1: 7.14.

5. The method of any one of claims 1-4, wherein the first volume of water is added dropwise at a constant rate.

6. The method according to any one of claims 1 to 5, wherein in the step S3, the volume ratio of the second volume of water to the methanol is 1: 1.16.

7. The method according to any one of claims 1 to 6, wherein the time for the thermal crystallization in step S4 is 50 to 80 min.