CN101684107A - New febuxostat crystal form and preparing method thereof - Google Patents
New febuxostat crystal form and preparing method thereof Download PDFInfo
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- CN101684107A CN101684107A CN200810200565A CN200810200565A CN101684107A CN 101684107 A CN101684107 A CN 101684107A CN 200810200565 A CN200810200565 A CN 200810200565A CN 200810200565 A CN200810200565 A CN 200810200565A CN 101684107 A CN101684107 A CN 101684107A
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Abstract
The invention discloses a new crystal form X, Y and Z of 2-(3-cyanogroup-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid (febuxostat for short) with the formula of I and a preparing method thereof, and is confirmed by a melting point and a powder X diffraction pattern. The febuxostat prepared with the method is stable in temperature, illumination and humidity and is favourable for storage fora long term; adopted solvent is safe and easy to remove, and the method has easy operation, is suitable for industrial production and is suitable for directly producing preparation.
Description
Technical field
The present invention relates to pharmaceutical chemistry, be specifically related to 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid crystal form X, crystal formation Y, the crystal formation Z and preparation method thereof of (being called for short " Febuxostat ")
Background technology
The Febuxostat general by name or the Febustat of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid are mainly used in the treatment of hyperuricemia.
EP513379 has reported the synthetic method of Febuxostat, has mentioned with ethyl alcohol recrystallization in the literary composition and has obtained the finished product, does not still tell about the problem of crystal formation.Put down in writing Febuxostat and have five kinds of crystal form As, B, C, D, G and a kind of amorphousness in Chinese patent CN1275126, wherein the A crystalline substance is wherein relative stable crystal formation, and the D crystalline substance is a methylate, and the G crystalline substance is a hydrate.This piece patent all adopts the mixed solvent system of methanol or isopropanol to carry out crystallization, and can carry out the crystal formation conversion according to different drying meanss.
Summary of the invention
The object of the present invention is to provide the crystal formation of new Febuxostat, i.e. crystal form X, crystal formation Y and crystal formation Z.Another kind of purpose of the present invention is to provide the simple industrialized method for preparing the above-mentioned new crystal of Febuxostat that is fit to.
Wherein, the feature of Febuxostat crystal form X:
Its X-ray powder diffraction pattern is about at reflection angle 2 θ: 4.08,4.77,5.73,6.80,7.17,7.91,8.27,9.62,9.99,11.66,12.70,13.70,14.30,15.42,15.90,16.80,17.51,18.06,18.42,20.48,20.95,23.27,23.72,24.78,25.18,25.82,26.10,26.64,26.96,27.90,28.85,29.70,31.08,34.18, its X-ray powder diffraction pattern is seen Fig. 1.
The feature of Febuxostat crystal formation Y:
Its X-ray powder diffraction pattern is about at reflection angle 2 θ: 6.60,7.18,11.68,12.8,13.26,14.4,16.1,16.46,17.46,18.98,19.58,20.96,21.92,22.68,23.76,24.69,25.16,25.83,26.65,27.88,36.70, its X-ray powder diffraction pattern is seen Fig. 2.
The feature of Febuxostat crystal formation Z:
Its X-ray powder diffraction pattern is about at reflection angle 2 θ: 4.81,5.84,6.68,8.08,9.20,9.66,11.66,13.32,13.82,14.64,16.22,17.38,18.12,21.36,23.18,24.84,25.24,25.80,26.62,27.92, its X-ray powder diffraction pattern is seen Fig. 3.
Crystal form X is with after Febuxostat and the butanone heating for dissolving, and the cooling recrystallization obtains.The butanone consumption is that the 1-20 of Febuxostat doubly measures w/v, the solvent w/v that preferred 2-8 doubly measures; Heating required temperature is 0-100 ℃, is preferably 50-80 ℃.
Crystal formation Y is dissolved in Febuxostat in the acetone, stirs dropping acetonitrile down then, and cooling crystallization filters, and oven dry obtains.In the said process consumption of acetone be Febuxostat weight 1-10 doubly, preferred 2-5 doubly, the consumption of acetonitrile be Febuxostat weight 1-20 doubly, preferred 2-5 is doubly; Heating temperature is 40-100 ℃, preferred 40-60 ℃; Acetonitrile wherein: the preferred 1-10 of the ratio of acetone doubly, more preferably 2-5 times of v/v.
Crystal formation Z is with after Febuxostat and the Virahol heating for dissolving, and the cooling recrystallization obtains.The Virahol consumption is that the 1-20 of Febuxostat doubly measures w/v, the solvent w/v that preferred 3-8 doubly measures;
The used solvent of Chinese patent CN1275126 crystallization is the first alcohol and water, operates loaded down with trivial detailsly, is difficult to reappear.And generally adopt single solvent such as butanone or Virahol among the present invention, or the mixed solvent of fixed proportion such as acetone and acetonitrile be as solvent, and solvent for use is removed easily, and simple to operate, is easy to industrialization, but and gained stable crystal form standing storage.
In addition, through comparison shows that of water absorbability experiment, Febuxostat crystal form X, Y and Z are stable under super-humid conditions, and the illumination experiment shows its good stability, and concrete data see the following form 1.
| Crystal formation | 92.5% humidity moisture |
10 days related substances of illumination change | 10 days related substances of high temperature change |
| ??X | ??3.42％ | No considerable change | No considerable change |
| ??Y | ??4.68 | No considerable change | No considerable change |
| ??Z | ??5.36 | No considerable change | No considerable change |
Table 1: the stability experiment result of study of crystal X, Y and Z
Experiment shows that Febuxostat crystal form X, Y and Z are under high humidity, high temperature and illumination condition, and related substance does not have considerable change.Be suitable for prolonged preservation and be used for preparation processing.
Description of drawings
The accompanying drawing that comprises among the application is a part that constitutes specification sheets, and accompanying drawing and specification sheets and claim item one are used from explanation flesh and blood of the present invention, are used for understanding better the present invention.
Fig. 1 is the X-ray powder diffraction spectrum of Febuxostat crystal form X;
Fig. 2 is the X-ray powder diffraction spectrum of Febuxostat crystal formation Y;
Fig. 3 is the X-ray powder diffraction spectrum of Febuxostat crystal formation Z;
Embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment do not constitute any restriction to the present invention.
Embodiment 1
The preparation method of Febuxostat crystal form X:
With Febuxostat 1g, add among the butanone 6ml, the reflux dissolving is chilled to room temperature under stirring then, stirs after 2 hours, filters.60 ℃ of oven dry.Obtain crystal form X sample 0.7 gram, fusing point is 201-204 ℃.
The preparation method of Febuxostat crystal form X:
With Febuxostat 5g, add among the butanone 20ml, the reflux dissolving is chilled to room temperature under stirring then, stirs after 2 hours, filters.60 ℃ of oven dry.Obtain crystal form X sample 4.1 grams, fusing point is 201-204 ℃.
Crystal form X powder x-ray diffraction 20 is: 4.08,4.77,5.73,6.80,7.17,7.91,8.27,9.62,9.99,11.66,12.70,13.70,14.30,15.42,15.90,16.80,17.51,18.06,18.42,20.48,20.95,23.27,23.72,24.78,25.18,25.82,26.10,26.64,26.96,27.90,28.85,29.70,31.08,34.18
The preparation method of Febuxostat crystal formation Y:
Febuxostat 2g is added 5 milliliters of backflow dissolvings of acetone, drip acetonitrile 10ml then under the stirring and refluxing, finish and be cooled to room temperature, stir after 1 hour, filter.60 ℃ of oven dry.Obtain Febuxostat crystal formation Y sample 1.4 grams, fusing point 202-204 ℃
Embodiment 4
The preparation method of Febuxostat crystal formation Y:
Febuxostat 6g is added 18 milliliters of backflow dissolvings of acetone, drip acetonitrile 60ml then under the stirring and refluxing, finish and be cooled to room temperature, stir after 1 hour, filter.60 ℃ of oven dry.Obtain Febuxostat crystal formation Y sample 4.8 grams, fusing point 202-204 ℃
Crystal formation Y powder x-ray diffraction 20 is: 6.60,7.18,11.68,12.8,13.26,14.4,16.1,16.46,17.46,18.98,19.58,20.96,21.92,22.68,23.76,24.69,25.16,25.83,26.65,27.88,36.70,
Embodiment 5
The preparation method of Febuxostat crystal formation Z:
With Febuxostat 1g, add among the Virahol 3ml, the reflux dissolving is chilled to room temperature under stirring then, stirs after 1 hour, filters.60 ℃ of oven dry.Obtain crystal form X sample 0.76 gram, fusing point is 198～201 ℃.
The preparation method of Febuxostat crystal formation Z:
With Febuxostat 5g, add among the Virahol 40ml, the reflux dissolving is chilled to room temperature under stirring then, stirs after 2 hours, filters.60 ℃ of oven dry.Obtain crystal form X sample 4.3 grams, fusing point is 198～201 ℃.
Crystal formation Z powder x-ray diffraction 20 is: 4.81,5.84,6.68,8.08,9.20,9.66,11.66,13.32,13.82,14.64,16.22,17.38,18.12,21.36,23.18,24.84,25.24,25.80,26.62,27.92,
Embodiment 7
Carry out the stability experiment of crystal X, Y and Z in following condition:
| Crystal formation | 92.5% humidity moisture |
10 days related substances of illumination change | 10 days related substances of high temperature change |
| ??X | ??3.42％ | No considerable change | No considerable change |
| ??Y | ??4.68％ | No considerable change | No considerable change |
| ??Z | ??5.36％ | No considerable change | No considerable change |
Experiment shows that Febuxostat crystal form X, Y and Z are under high humidity, high temperature and illumination condition, and related substance does not have considerable change.Be suitable for prolonged preservation and be used for preparation processing.
Claims (13)
1, polymorphic X of the Febuxostat of a kind of formula (1) and preparation method thereof, the X-ray powder diffraction pattern of this crystal formation at 2 θ is: 4.08,4.77,5.73,6.80,7.17,7.91,8.27,9.62,9.99,11.66,12.70,13.70,14.30,15.42,15.90,16.80,17.51,18.06,18.42,20.48,20.95,23.27,23.72,24.78,25.18,25.82,26.10,26.64,26.96,27.90,28.85,29.70,31.08,34.18
2, a kind of polymorphic X of Febuxostat as claimed in claim 1 is characterized in that, the fusing point of described crystal formation is 201～204 ℃.
3, polymorphic Y of the Febuxostat of a kind of formula (1) and preparation method thereof, the X-ray powder diffraction pattern of this crystal formation at 2 θ is: 6.60,7.18,11.68,12.8,13.26,14.4,16.1,16.46,17.46,18.98,19.58,20.96,21.92,22.68,23.76,24.69,25.16,25.83,26.65,27.88,36.70.
4, a kind of polymorphic Y of Febuxostat as claimed in claim 3 is characterized in that, the fusing point of described crystal formation is 202～204 ℃.
5, polymorphic Z of the Febuxostat of a kind of formula (1) and preparation method thereof, the X-ray powder diffraction pattern of this crystal formation at 2 θ is: 4.81,5.84,6.68,8.08,9.20,9.66,11.66,13.32,13.82,14.64,16.22,17.38,18.12,21.36,23.18,24.84,25.24,25.80,26.62,27.92.
6, a kind of polymorphic Z of Febuxostat as claimed in claim 5 is characterized in that, the fusing point of described crystal formation is 198～201 ℃.
7, a kind of polymorphic X preparation method as claimed in claim 1 obtains product by crystalline method that described compound heating for dissolving is laid equal stress on, and it is characterized in that using butanone to make recrystallisation solvent.
8, the preparation method of a kind of polymorphic X as claim 1 and 7 described Febuxostats is characterized in that Febuxostat is dissolved in the butanone, heating for dissolving, and crystallisation by cooling progressively filters and collects formed crystal then.The butanone consumption is that the 1-20 of Febuxostat doubly measures w/v, the solvent w/v that preferred 2-8 doubly measures; Heating required temperature is 0-100 ℃, is preferably 50-80 ℃.
9, the preparation method of a kind of polymorphic Y of Febuxostat as claimed in claim 3 is characterized in that Febuxostat is dissolved in the acetone, and heating for dissolving stirs adding acetonitrile down then, and crystallisation by cooling filters and collects formed crystal then.
10. according to the preparation method of the polymorphic Y of claim 3 and 9 described Febuxostats, it is characterized in that heating for dissolving crystallization in acetone and acetonitrile, the acetone consumption is that the 1-10 of Febuxostat doubly measures w/v, the solvent w/v that preferred 2-5 doubly measures; The acetonitrile consumption is that the 3-20 of Febuxostat doubly measures w/v, the solvent w/v that preferred 3-5 doubly measures.
11. according to the preparation method of the polymorphic Y of the described Febuxostat of claim 3,9 and 10, recrystallisation solvent is with acetone and acetonitrile mixed solvent, wherein acetonitrile: the preferred 1-10 of the ratio of acetone doubly, more preferably 2-5 times of v/v.
12, the preparation method of a kind of polymorphic Z of Febuxostat as claimed in claim 1 is characterized in that Febuxostat is dissolved in the Virahol, heating for dissolving, and crystallisation by cooling filters and collects formed crystal then.
13. the preparation method according to the polymorphic Z of claim 4 and 12 described Febuxostats is characterized in that heating for dissolving crystallization in Virahol, the Virahol consumption is that the 1-20 of Febuxostat doubly measures w/v, the solvent w/v that preferred 3-8 doubly measures.
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Cited By (10)
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| CN101817801A (en) * | 2009-08-12 | 2010-09-01 | 北京红惠新医药科技有限公司 | Preparation method of new crystal form K of 2-(3-cyano-4-isobutoxy)-4-methyl-5-thiazole formic acid and other crystal forms |
| CN101824005A (en) * | 2010-04-27 | 2010-09-08 | 上海凯米侬医药科技有限公司 | New crystal form Q of Febuxostat and preparation method thereof |
| WO2010144685A1 (en) | 2009-06-10 | 2010-12-16 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of febuxostat |
| CN101928260A (en) * | 2010-06-13 | 2010-12-29 | 北京赛科药业有限责任公司 | Febuxostat new crystal form and preparation method thereof |
| WO2011007895A1 (en) * | 2009-07-15 | 2011-01-20 | 帝人ファーマ株式会社 | Process for producing crystals of polymorphic 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecaboxylic acid by poor-solvent addition method |
| CN102229581A (en) * | 2010-11-15 | 2011-11-02 | 邹巧根 | Preparation method for febuxostat intermediate |
| WO2012020272A2 (en) | 2010-08-13 | 2012-02-16 | EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság | New salts, polymorphs and solvates of a pharmaceutical active ingredient |
| WO2013088449A1 (en) | 2011-12-16 | 2013-06-20 | Natco Pharma Limited | Stable crystal form of febuxostat and process for the preparation thereof |
| CN103396378A (en) * | 2013-07-29 | 2013-11-20 | 杭州朱养心药业有限公司 | Stable febuxostat crystal |
| WO2016171254A1 (en) * | 2015-04-22 | 2016-10-27 | 日本ケミファ株式会社 | Crystals of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, method for producing same, and use thereof |
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| US8609856B2 (en) | 2009-06-10 | 2013-12-17 | Teva Pharmaceuticals Usa, Inc. | Crystalline forms of Febuxostat |
| DE202010017868U1 (en) | 2009-06-10 | 2012-11-28 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of febuxostat |
| US8415481B2 (en) | 2009-06-10 | 2013-04-09 | Teva Pharmaceuticals Usa, Inc. | Crystalline form of febuxostat |
| EP2532654A1 (en) | 2009-06-10 | 2012-12-12 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of febuxostat |
| US8742129B2 (en) | 2009-06-10 | 2014-06-03 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of febuxostat |
| WO2010144685A1 (en) | 2009-06-10 | 2010-12-16 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of febuxostat |
| US8735596B2 (en) | 2009-07-15 | 2014-05-27 | Teijin Pharma Limited | Process for producing crystals of polymorphic 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecaboxylic acid by poor-solvent addition method |
| WO2011007895A1 (en) * | 2009-07-15 | 2011-01-20 | 帝人ファーマ株式会社 | Process for producing crystals of polymorphic 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecaboxylic acid by poor-solvent addition method |
| CN101817801A (en) * | 2009-08-12 | 2010-09-01 | 北京红惠新医药科技有限公司 | Preparation method of new crystal form K of 2-(3-cyano-4-isobutoxy)-4-methyl-5-thiazole formic acid and other crystal forms |
| CN101824005A (en) * | 2010-04-27 | 2010-09-08 | 上海凯米侬医药科技有限公司 | New crystal form Q of Febuxostat and preparation method thereof |
| CN101824005B (en) * | 2010-04-27 | 2012-06-27 | 上海凯米侬医药科技有限公司 | New crystal form Q of Febuxostat and preparation method thereof |
| CN101928260A (en) * | 2010-06-13 | 2010-12-29 | 北京赛科药业有限责任公司 | Febuxostat new crystal form and preparation method thereof |
| CN101928260B (en) * | 2010-06-13 | 2012-09-05 | 华润赛科药业有限责任公司 | Febuxostat new crystal form R and preparation method thereof |
| WO2012020272A2 (en) | 2010-08-13 | 2012-02-16 | EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság | New salts, polymorphs and solvates of a pharmaceutical active ingredient |
| CN102229581B (en) * | 2010-11-15 | 2013-07-03 | 邹巧根 | Preparation method for febuxostat intermediate |
| CN102229581A (en) * | 2010-11-15 | 2011-11-02 | 邹巧根 | Preparation method for febuxostat intermediate |
| WO2013088449A1 (en) | 2011-12-16 | 2013-06-20 | Natco Pharma Limited | Stable crystal form of febuxostat and process for the preparation thereof |
| CN103396378A (en) * | 2013-07-29 | 2013-11-20 | 杭州朱养心药业有限公司 | Stable febuxostat crystal |
| CN103396378B (en) * | 2013-07-29 | 2015-06-10 | 杭州朱养心药业有限公司 | Stable febuxostat crystal |
| JP7164926B2 (en) | 2015-04-22 | 2022-11-02 | 日本ケミファ株式会社 | Crystal of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, method for producing the same, and use thereof |
| WO2016171254A1 (en) * | 2015-04-22 | 2016-10-27 | 日本ケミファ株式会社 | Crystals of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, method for producing same, and use thereof |
| JPWO2016171254A1 (en) * | 2015-04-22 | 2018-03-22 | 日本ケミファ株式会社 | Crystals of 2- [3-cyano-4- (2-methylpropoxy) phenyl] -4-methylthiazole-5-carboxylic acid, process for producing the same, and use thereof |
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