CN100546985C - Febuxotat microcrystal and composition thereof - Google Patents
Febuxotat microcrystal and composition thereof Download PDFInfo
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- CN100546985C CN100546985C CNB2007100431784A CN200710043178A CN100546985C CN 100546985 C CN100546985 C CN 100546985C CN B2007100431784 A CNB2007100431784 A CN B2007100431784A CN 200710043178 A CN200710043178 A CN 200710043178A CN 100546985 C CN100546985 C CN 100546985C
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Abstract
The invention discloses a kind of natural fine particle size that has, have the Febuxotat microcrystal and the composition thereof of good dissolution rate.This crystallite adopts the preparation of solvent crystallization method, only needs nontoxic a kind of solvent of ethyl acetate to get final product.The product that makes is safer, and the preparation method is friendly more to environment.This crystallite is because the granularity that itself possesses makes it have good dissolution rate in aqueous systems, in preparation medical solid preparation and suspensoid process, do not need micronization processing or other extra processing, make conventional manufacturing process can make the good preparation of dissolution rate.
Description
Technical field
The present invention relates to specific a kind of polymorphous medicinal compositions of Fei Butate (febuxotat), more specifically be meant a kind of crystal type of Fei Butate, this crystal type is natural to have fine particle size, be fit to form composition, be used to make oral solid formulation with good dissolution rate with conventional pharmaceutical excipient.
Background technology
The chemical structure of Fei Butate is 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole carboxylic acid, is a kind of xanthine oxidase inhibitor, is used for the treatment of gout.
Because the solubleness of Fei Butate in water is little, there is the problem of dissolution rate difference in the oral solid formulation that contains this activeconstituents.And the granularity of activeconstituents and polymorphic are the important factors that influences the solid preparation dissolution rate.As document 1[Chinese invention patent publication number CN 1275126A] disclosed, Fei Butate has polymorphic.Document 2[Chinese invention patent publication number CN 1642546A for another example] further specify Fei Butate different crystal types when being prepared into solid preparation such as tablet, the dissolution rate of crystal formation and granularity remarkably influenced preparation.This invention is pointed out, needs elite wherein a kind of crystal form A that crystallizes out from methyl alcohol, carries out the solid preparation that micronization processing just can be prepared into good dissolution rate afterwards.Perhaps as document 3[Chinese invention patent publication number CN 1785182A] take solid dispersion technology, with the polyvinylpyrrolidone vitreous state sosoloid of preparing carriers Fei Butate, be used to make solid preparation, to obtain suitable dissolution rate.
The present invention discloses a kind of natural Fei Butatexin crystalline form with fine particle size, do not need micronization processing during as the manufacturing oral solid formulation, do not need to be prepared into vitreous state sosoloid yet, but directly add auxiliary material routinely technology can make the match in excellence or beauty dissolution rate of document 2 defined micronization A crystalline substances of dissolution rate.Therefore the composition of this crystallite and pharmaceutical excipient composition has in the medicament manufacturing and is easy to the advantage of processing significantly.
Summary of the invention
The object of the invention provides a kind of natural fine particle size that has, and has the Fei Butate crystallization of good dissolution rate, is called Febuxotat microcrystal.This crystallite does not need micronization processing or other extra processing in preparation medical solid preparation and suspensoid process, make conventional manufacturing process can make the good preparation of dissolution rate.The present invention also provides the composition of being made up of above-mentioned Febuxotat microcrystal and conventional pharmaceutical excipient.
The preparation of solvent crystallization method is adopted in crystallization of the present invention, does not need to make solvent with toxic compounds such as methyl alcohol, only needs nontoxic a kind of solvent of ethyl acetate to get final product.The product that makes is safer, and the preparation method is friendly more to environment simultaneously.
Crystallization of the present invention by using the x-ray diffractogram of powder spectrum of Cu-K α radiation detection, when representing with reflection angle 2 θ, locates to have characteristic peak being about 5.78 °, 7.94 °, 11.60 °, 12.72 °, 20.50 °, 25.88 °.Reasonably can be characterized by: crystallization of the present invention, by using the x-ray diffractogram of powder spectrum of Cu-K α radiation detection, when representing, has characteristic peak at the powder X-ray RD spectrum place of the combination of 5.8 ° ± 0.1 °, 7.9 ° ± 0.1 °, 11.6 ° ± 0.1 °, 12.7 ° ± 0.1 °, 20.5 ° ± 0.1 °, 25.9 ° ± 0.1 ° and/or wherein any or they with reflection angle 2 θ.
Crystallization of the present invention has basically the infrared spectrophotometric determination absorption spectrum of Fourier Tranform as shown in Figure 2.Adopt the KBr compressing tablet during mensuration.
Crystallization of the present invention is measured size-grade distribution with laser diffractometry, and each is added up particle diameter and has following feature: average diameter is less than 20 μ m, D
90Less than 40 μ m.
The hot analytical characteristic of crystalline of the present invention, when the differential scanning calorimetry, can characterize by near near two endothermic transition peaks that are characterized as 201 ℃ and 210 ℃, shown in the heat culvert-temperature variation curve of differential scanning calorimetry in the accompanying drawing 3, two endotherm(ic)peaks of 201.4 ℃ and 210.3 ℃.Weight-temperature variation curve is measured when carrying out thermogravimetric analysis in the accompanying drawing 3, and showing does not have recrystallisation solvent to exist.
Crystalline preparation method of the present invention: any crystal formation or armorphous Fei Butate, with ethyl acetate is solvent, heating makes dissolving, naturally cool to room temperature, or the temperature that reduces solution rapidly to room temperature or lower temperature such as 0 ℃, promptly separate out crystallization, filter, drying promptly gets the crystal type that the present invention discloses.Crystalline preparation method characteristic of the present invention is to use ethyl acetate to be solvent.
The conventional required pharmaceutical excipient of solid preparation is added in crystallization of the present invention, is prepared into tablet, pill, powder, capsule or dry suspensoid, and containing crystalline amount of the present invention in the unit preparation is 40mg, 80mg or 120mg.With the weight percent meter of crystallization of the present invention in unit formulation, be 1～50%, be 10～30% more specifically.Auxiliary material can be weighting agent lactose, N.F,USP MANNITOL, starch etc., disintegrating agent low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose, sodium starch glycolate, polyvinylpolypyrrolidone, croscarmellose sodium, dry starch etc., tamanori polyvidone, Vltra tears, being prepared into the aqueous solution and using, also can be water; Lubricant is a Magnesium Stearate.
Because the granularity that this crystallite possesses itself makes it have good dissolution rate in aqueous systems.
Description of drawings
The crystalline x-ray diffractogram of powder spectrum of Fig. 1, embodiment 1 preparation.
The infrared IR collection of illustrative plates of the crystalline Fourier Tranform of Fig. 2, embodiment 1 preparation.
The crystalline thermogravimetric analysis and the differential scanning calorimetry figure of Fig. 3, embodiment 1 preparation.
The size distribution curve that the crystallization of Fig. 4, embodiment 1 preparation is measured with laser diffractometry.
The size distribution curve that the crystallization of Fig. 5, embodiment 2 preparations is measured with laser diffractometry.
Embodiment
Only the present invention will be described for example of the present invention, do not limit the invention.
Embodiment 1:
The extraordinarily thick product 100g of Fei Buta, ethyl acetate 1400ml are added in the 3L round-bottomed flask, be warming up to backflow, be stirred to complete molten after, filtered while hot, filtrate placement naturally cools to room temperature, crystallization filters, and filter cake washs with a spot of ethyl acetate, in 80 ℃ of vacuum-dryings 4 hours, get solid 82.6g, mp198.7～201.4 ℃ (differential thermal analysis is measured, and sees Fig. 3).
Powder x-ray diffraction analysis: collection of illustrative plates is seen Fig. 1; Locate to have characteristic peak at 5.78 °, 7.94 °, 11.60 °, 12.72 °, 20.50 °, 25.88 °.
IR analyzes: the infrared IR collection of illustrative plates of Fourier Tranform is seen Fig. 2.
Sreen analysis: particle size distribution figure is seen Fig. 4; Statistics particle diameter D
102.779 μ m, D
5011.24 μ m, D
9038.14 μ m, average diameter 16.73 μ m.
Embodiment 2:
The extraordinarily thick product 100g of Fei Buta, ethyl acetate 2000ml are added in the 5L round-bottomed flask, be warming up to backflow, be stirred to complete molten after, filtered while hot, filtrate are positioned in 0 ℃ the ice-water bath cools off crystallization, filter, filter cake washs with a spot of ethyl acetate, in 80 ℃ of vacuum-dryings 4 hours, gets solid 88.4g.
Sreen analysis: adopt laser diffractometry to measure particle size distribution figure and see Fig. 5; Statistics particle diameter D
101.160 μ m, D
5010.36 μ m, D
9036.03 μ m, average diameter 15.07 μ m.
Embodiment 3:
The capsule preparation.
The crystallite 40g of embodiment 1 preparation
Pharmaceutical lactose 90g
Pregelatinized Starch 30g
Carboxymethylstach sodium 12g
Magnesium Stearate 1g
Make 1000 altogether
Preparation technology: the component in will writing out a prescription beyond the Magnesium Stearate mixes, with the aqueous solution that contains 3% (w/w) 30 POVIDONE K 30 BP/USP 29/31 in right amount is tackiness agent, make softwood, extruding becomes wet granular with crossing 14 mesh sieves, puts 80 ℃ of air seasonings 2 hours, and dried particle is by the whole grain of 14 mesh sieves, add remaining Magnesium Stearate, mix, be filled in gelatine capsule No. 2, promptly.
Embodiment 4:
The preparation of tablet.
The crystallite 40g of embodiment 2 preparations
Pharmaceutical lactose 160g
Microcrystalline Cellulose PH101 45g
Low-substituted hydroxypropyl methylcellulose 15g
Carboxymethylstach sodium 15g
Magnesium Stearate 2g
Make 500 altogether
Preparation technology: get carboxymethylstach sodium and Magnesium Stearate component in addition and mix, water is that tackiness agent is made softwood, promptly presses by 14 mesh sieves to become wet granular, put 80 ℃ of air seasonings 2 hours, make dried particle after, add carboxymethylstach sodium and Magnesium Stearate and mix, compressing tablet, promptly.Record hardness 5-7kg with tablet four-function instrument.
Embodiment 5:
Determination of dissolution rate: get each 6 or 6 of capsule that embodiment 3 and 4 makes and sheets respectively, measure respectively according to dissolution method [Chinese Pharmacopoeia version in 2005 two appendix X C (second method)].With pH5.5 McIlvaine buffered soln 1000ml is solvent (getting 0.1M citric acid solution 435.5ml mixes promptly with 0.2M disodium phosphate soln 564.5ml), and rotating speed is 50rpm, in accordance with the law operation.Respectively at 5,10,15,30,45, the 60min sampling, adopt ultraviolet spectrophotometry to measure at 317nm, the results are shown in following table:
The average stripping quantity of sheet and capsule (%) (N=6)
The result shows, reaches 80% through the solubility rate of 15 fens time-cards and capsule, through 45 minutes near all strippings.
Claims (6)
1, a kind of by using the Cu-Ka radiating to represent with reflection angle 2 θ, absorb feature as sign at 5.8 ° ± 0.1 °, 7.9 ° ± 0.1 °, 11.6 ° ± 0.1 °, 12.7 ° ± 0.1 °, 20.5 ° ± 0.1 °, 25.9 ° ± 0.1 ° powder X-ray RD spectrum place, adopt laser diffractometry to measure statistics particle diameter D
90＜40 microns, the Febuxotat microcrystal of average diameter＜20 micron sign.
2, Febuxotat microcrystal according to claim 1 is characterized in that described Febuxotat microcrystal is that solvent carries out recrystallization operation acquisition with the ethyl acetate.
3, a kind of composition of the Febuxotat microcrystal of forming by described Febuxotat microcrystal of claim 1 and conventional pharmaceutical excipient.
4, the composition of Febuxotat microcrystal according to claim 3 is characterized in that said composition is used to prepare oral solid formulation, tablet and capsule.
5, the composition of Febuxotat microcrystal according to claim 3, the prescription consumption that it is characterized in that Febuxotat microcrystal is 10～30% by weight.
6, the composition of Febuxotat microcrystal according to claim 3, the amount that it is characterized in that containing in the unit preparation of prescription of Febuxotat microcrystal Febuxotat microcrystal is 40mg, 80mg or 120mg.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010144685A1 (en) | 2009-06-10 | 2010-12-16 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of febuxostat |
| WO2012007487A1 (en) | 2010-07-13 | 2012-01-19 | Interquim, S.A. | Process for preparing the crystalline form ii of febuxostat |
| WO2013088449A1 (en) | 2011-12-16 | 2013-06-20 | Natco Pharma Limited | Stable crystal form of febuxostat and process for the preparation thereof |
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| CN101716132B (en) * | 2008-10-09 | 2012-01-11 | 北京方策方程医药科技有限公司 | Febuxostat enteric preparation |
| CN101781270B (en) * | 2009-01-20 | 2013-03-27 | 重庆医药工业研究院有限责任公司 | High-purity Febuxostat and preparation method thereof |
| CN101780073B (en) * | 2009-01-21 | 2013-07-03 | 重庆圣华曦药业股份有限公司 | Febuxostat dispersible tablet drug and preparing method thereof |
| CN103936689B (en) * | 2009-07-17 | 2016-08-17 | 北京利乐生制药科技有限公司 | 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid crystal forms and preparation method thereof |
| 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 |
| CN102070558B (en) * | 2009-11-23 | 2012-08-22 | 欣凯医药化工中间体（上海）有限公司 | New crystal form of febuxostat and preparation method thereof |
| WO2011080651A2 (en) | 2009-12-31 | 2011-07-07 | Ranbaxy Laboratories Limited | Polymorphic forms of febuxostat |
| EP2542540A1 (en) | 2010-03-04 | 2013-01-09 | Ranbaxy Laboratories Limited | Polymorph of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid |
| 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 |
| TW201217347A (en) * | 2010-07-13 | 2012-05-01 | Interquim Sa | Process for preparing the crystalline form a of febuxostat |
| WO2012038971A2 (en) | 2010-09-24 | 2012-03-29 | Hetero Research Foundation | Novel polymorphs of febuxostat |
| WO2012168948A2 (en) | 2011-06-06 | 2012-12-13 | Hetero Research Foundation | Process for febuxostat |
| JP2014533297A (en) * | 2011-11-15 | 2014-12-11 | マイラン ラボラトリーズ リミテッドＭｙｌａｎ Ｌａｂｏｒａｔｏｒｉｅｓ Ｌｉｍｉｔｅｄ | Process for the preparation of polymorphs of febuxostat |
| EP2692342A1 (en) | 2012-07-30 | 2014-02-05 | Interquim, S.A. | Process for the preparation of pharmaceutical compositions comprising febuxostat in the form of tablets |
| EP3153158A1 (en) | 2015-10-09 | 2017-04-12 | Stada Arzneimittel Ag | Oral febuxostat tablet |
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2007
- 2007-06-29 CN CNB2007100431784A patent/CN100546985C/en active Active
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010144685A1 (en) | 2009-06-10 | 2010-12-16 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of febuxostat |
| JP2012529537A (en) * | 2009-06-10 | 2012-11-22 | テバ ファーマシューティカル インダストリーズ リミティド | Crystal form of febuxostat |
| EP2532654A1 (en) | 2009-06-10 | 2012-12-12 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of febuxostat |
| US8415481B2 (en) | 2009-06-10 | 2013-04-09 | Teva Pharmaceuticals Usa, Inc. | Crystalline form of febuxostat |
| US8609856B2 (en) | 2009-06-10 | 2013-12-17 | Teva Pharmaceuticals Usa, Inc. | Crystalline forms of Febuxostat |
| US8742129B2 (en) | 2009-06-10 | 2014-06-03 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of febuxostat |
| WO2012007487A1 (en) | 2010-07-13 | 2012-01-19 | Interquim, S.A. | Process for preparing the crystalline form ii of febuxostat |
| WO2013088449A1 (en) | 2011-12-16 | 2013-06-20 | Natco Pharma Limited | Stable crystal form of febuxostat and process for the preparation thereof |
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| CN101085761A (en) | 2007-12-12 |
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Assignee: QIDONG HUATUO PHARMACEUTICAL CO., LTD. Assignor: Shanghai Huatuo Medical Science Co., Ltd. Contract record no.: 2011310000023 Denomination of invention: Febuxotat microcrystal and compositions thereof Granted publication date: 20091007 License type: Exclusive License Open date: 20071212 Record date: 20110323 |
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