CN102070558B - New crystal form of febuxostat and preparation method thereof - Google Patents
New crystal form of febuxostat and preparation method thereof Download PDFInfo
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- CN102070558B CN102070558B CN2009101992484A CN200910199248A CN102070558B CN 102070558 B CN102070558 B CN 102070558B CN 2009101992484 A CN2009101992484 A CN 2009101992484A CN 200910199248 A CN200910199248 A CN 200910199248A CN 102070558 B CN102070558 B CN 102070558B
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Abstract
The invention discloses an L-shaped crystal of a compound shown as a molecular formula 1 and a preparation method thereof.
Description
Technical field
The present invention relates to compound crystal, relate in particular to new crystal of Febuxostat and preparation method thereof.
Background technology
Febuxostat (Febuxostat), chemical name 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid.Structural formula is suc as formula shown in 1:
Febuxostat has obtained the approval of U.S. FDA in February, 2009, is used for treatment and the too high diseases associated of uric acid.Febuxostat has multiple crystal formation.Chinese patent CN1275126 discloses five kinds of crystal form As of Febuxostat, B, C, D, G and a kind of amorphousness, and this patent adopts the solvent system of methanol or isopropanol to carry out crystallization, and wherein, crystal form A exists with the metastable state form; Crystal formation D is a methylate, and crystal formation G is a hydrate.Patent CN1970547 has put down in writing H, I, three kinds of crystal formations of J, adopts acetonitrile/propionitrile crystallization to obtain.Patent CN101386605 is 1, and the mixed solvent system of a kind of solvent in 4-dioxane or it and normal hexane, sherwood oil and the hexanaphthene has obtained the K crystal formation.In patent CN101139325, disclosed crystal formation I, II adopt ETHYLE ACETATE, ethanol to obtain.Patent CN101412700 discloses the crystal form II I that obtains with ETHYLE ACETATE.
This area also need provide a kind of good stability, and water absorbability is low, is suitable for processing the crystal formation of various stabilised pharmaceutical and standing storage.
Summary of the invention
The present invention aims to provide the L N-type waferN of a kind of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid.
Another object of the present invention provides the preparation method of said L N-type waferN.
The pharmaceutical composition that it is activeconstituents that a further object of the present invention provides with said L N-type waferN.
The 4th purpose of the present invention provides the purposes of said L N-type waferN.
In first aspect of the present invention, a kind of L N-type waferN of the compound shown in molecular formula 1 is provided:
Said crystalline X-ray powder diffraction figure is 3.12,4.85, and 6.81,7.38,11.62,14.77,16.75,24.81,25.18 and 26.03 ± 0.2 ° diffraction angle (2 θ) has characteristic peak.
In another preference, said crystalline X-ray powder diffraction figure is as shown in Figure 1.
In second aspect of the present invention, a kind of preparation method of aforesaid L N-type waferN provided by the invention is provided, described method comprises step:
(1) with 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid and solvent RCOOH 80-120 ℃ of mixing, obtain solution 1; With
(2) solution 1 is cooled to-20 ℃-40 ℃, filters and obtain aforesaid L N-type waferN provided by the invention;
Wherein R representes the alkyl of H or C1-C9.
In another preference, (milliliter: be 5-20 gram): 1 mixes said solvent RCOOH and 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid with envelope-bulk to weight ratio.
In another preference, in step (2), carry out drying at 60-120 ℃ after filtering and obtain aforesaid L N-type waferN provided by the invention.
In another preference, R representes methyl, ethyl or propyl group.
In the third aspect of the invention, a kind of pharmaceutical composition is provided, described compsn comprises aforesaid L N-type waferN provided by the invention as its activeconstituents and pharmaceutically acceptable carrier.
In fourth aspect of the present invention, a kind of purposes of aforesaid L N-type waferN provided by the invention is provided, described L N-type waferN is used to prepare the medicine of treatment and the too high diseases associated of uric acid.
In view of the above, the invention provides a kind of good stability, water absorbability is low, is suitable for processing the crystal formation of various stabilised pharmaceutical and standing storage.
Description of drawings
Fig. 1 is the X-ray powder diffraction spectrum of Febuxostat crystal formation L.
Fig. 2 is the infrared absorpting light spectra of Febuxostat crystal formation L.
Embodiment
The contriver attempts using a large amount of different solvents and their combination, unexpectedly finds that Febuxostat also has other a kind of new crystal, and this crystal formation is different from any in the disclosed crystal formation of prior art.This stable crystal form property is good, and water absorbability is low, is suitable for processing various stabilised pharmaceutical and standing storage.
The present invention provides a kind of new crystal of Febuxostat, names the type into L.The characteristic of this crystal formation is that its X-ray ray powder diffraction (XRPD) charateristic avsorption band 2 θ values are about: 3.12,4.85,6.81,7.38,11.62,14.77,16.75,24.81,25.18,26.03 °, see Fig. 1.
Among the present invention; The mensuration of 2 θ values is used CuK α light source; Precision is ± 0.2 °, and therefore, " pact " in above-mentioned " its X-ray ray powder diffraction charateristic avsorption band 2 θ values are about " should be defined as 2 θ ± 0.2 °; Represent above-mentioned 2 θ that get to allow certain reasonably limit of error, its limit of error is ± 0.2 °.
Its infrared signature absorption peak is about: 1702 ± 5,1683 ± 5,1297 ± 5 and 1012 ± 5cm
-1, see Fig. 2.(wherein, " ± 5 " measuring error scope) for allowing
The present invention also provides the preparation method of said L N-type waferN, and this method comprises: after Febuxostat and solvent RCOOH heating for dissolving, obtain through recrystallization.The consumption of acid is 5-20 a times of Febuxostat, preferred 5 times; Heat required temperature and be about 80-120 ℃.When crystallisation by cooling, promptly separate out aspect the temperature at crystal, can select-20-40 ℃ preferred 25 ℃.After crystal is separated out, dry under 60-120 ℃ of temperature, dry under preferred 80 ℃ of temperature.Wherein, R representes H, alkyl C1-C9, and like methyl, ethyl, concrete solvent can be formic acid, acetate and propionic acid etc., and preferred solvent is formic acid, acetate or their mixture.
The term " room temperature " that uses in the present invention is meant 15-25 ℃, preferred 20-25 ℃.
The represented L N-type waferN of molecular formula of the present invention 1 can be used for treatment and the too high diseases associated of uric acid as the pharmaceutical composition of activeconstituents; For example: the too high gout that causes of blood uric acid; The high blood uric acid that cancer patients's chemicotherapy causes, and the too high illness of other blood uric acid.
When the pharmaceutical composition that contains the L N-type waferN in use carries out medical treatment; The same with the method for use of relevant 2-well known in the art (3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid; Use its different dosage forms; Comprise that tablet, capsule, pill, lozenge, granule, fine granule, suspension-s, powder, lozenge, elixir, injection, liquor, salve, suppository, emplastrum etc. can supply per os or parenteral to use respectively.Wherein preferred tablet, capsule, pill, lozenge, suspension-s, powder, lozenge or elixir.
The compound method of various pharmaceutical compositions; Can be the same with the compound method of relevant 2-well known in the art (3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid, will mix with acceptable carrier pharmaceutically or on the food as the L N-type waferN provided by the invention of activeconstituents.Carrier can be solid-state or liquid, generally selects type according to the used mode that gives.Activeconstituents can powder, particle, and a form or any other solid form perhaps give with liquid form together.The example of solid-state carrier comprises (but being not limited to): lactose, sucrose, gelatin and agar.Capsule or tablet can easily prepare, and are convenient to swallow or chew; Other solid form comprises particle.Tablet can contain suitable adhesive, lubricant, thinner, disintegrating agent, tinting material, seasonings etc.The example of liquid dosage form comprises: solution in water, pharmaceutically acceptable fat or oil, alcohol or other organic solvents (comprising ester) or suspension-s, emulsion, syrup, elixir, with non-effervescent granule regenerated solution and/or suspension-s and with effervescent granule regenerated effervescent formulation.Such liquid dosage form can contain, for example, and appropriate solvent, sanitas, emulsifying agent, suspension agent, thinner, sweeting agent, thickening material and solubility promoter.Oral dosage form can contain seasonings and tinting material.The formulation that parenteral and intravenously give also can contain mineral substance and other materials, so that make them and injection or selected type of release system compatible.
When using pharmaceutical composition of the present invention to carry out medical treatment; Can be the same with the method for use of relevant 2-well known in the art (3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid; According to the factors such as actual conditions that age, sex, body weight, severity extent, the palpus of individual patients are handled, correspondingly confirm the dosage of the L N-type waferN shown in the molecular formula 1.Supply the standard dose scope of grownup's oral administration.Above-mentioned dosage can be used once a day, perhaps is divided into 1 to using for several times.The optimum route of administration of L N-type waferN is oral.
Major advantage of the present invention is:
1, the L N-type waferN good stability of Febuxostat is difficult for taking place to change brilliant phenomenon in depositing process.
2, used solvent among the present invention does not almost have toxicity, and is safe.Solvent for use dissolving power when high temperature is big, and consumption is few during recrystallization.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in the restriction scope of the present invention.The experimental technique of unreceipted actual conditions in the following example is usually according to the normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio, ratio, ratio or umber by weight.
Unit in the percent weight in volume among the present invention is well-known to those skilled in the art, for example is meant the weight of solute in 100 milliliters solution.
Only if definition separately, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any with the institute similar content of putting down in writing or the equalization method and material all can be applicable in the inventive method.The usefulness that preferable implementation method described in the literary composition and material only present a demonstration.
Embodiment 1
The preparation of Febuxostat crystal formation L crystalline
The acetic acid of 10ml is added in the 1.0g Febuxostat, be heated to 100 ℃ of dissolvings.Be cooled to room temperature, 2 hours after-filtration under stirring.80 ℃ of dryings.Obtain sample 0.9g.
The result:
X-ray powder diffraction (XRD) collection of illustrative plates (Fig. 1): the diffraction angle (2 θ degree) being about 3.12,4.85,6.81,7.38,11.62,14.77,16.75,24.81,25.18 and 26.03 degree has characteristic peak (instrument: CuK-ALPHA1/40kV/60mA);
Infared spectrum detects (instrument: NICOLET NEXUS 470 FT-IR SPECTROMETER type IRs, KBr compressing tablet) result and sees Fig. 2.
The result shows, what prepare with the method for embodiment 1 is the L N-type waferN.
The preparation of Febuxostat crystal formation L crystalline
The acetic acid of 5ml is added in the 1.0g Febuxostat, be heated to 120 ℃ of dissolvings.Be cooled to room temperature, 2 hours after-filtration under stirring.120 ℃ of dryings.Obtain sample 0.95g.
The result is with embodiment 1.
The preparation of Febuxostat crystal formation L crystalline
The formic acid of 20ml is added in the 1.0g Febuxostat, be heated to 80 ℃ of dissolvings.Be cooled to-20 ℃, 2 hours after-filtration under stirring.80 ℃ of dryings.Obtain sample 0.85g.
The result is with embodiment 1.
Embodiment 4
The preparation of Febuxostat crystal formation L crystalline
With the 20ml ratio of mixture is in the acetic acid and propionic acid adding 1.0g Febuxostat of 1: 1 (volume ratio), is heated to 120 ℃ of dissolvings.Be cooled to 40 ℃, 2 hours after-filtration under stirring.120 ℃ of dryings.Obtain sample 0.8g.
The result is with embodiment 1.
Embodiment 5
L N-type waferN stability experiment
Febuxostat L type body got place the plate kind that is numbered L1, L2, L3 in right amount, carry out stability experiment under the illumination that is placed in (intensity 4500lx), high temperature (60 ℃), the high humidity (relative humidity 92.5).
The result sees table 1:
Table 1. strong illumination, high temperature, high humidity experiment study on the stability
With compare before the experiment beginning, L N-type waferN total impurities does not increase, crystal formation changes.Prove this stable crystal form, be fit to long storage and process preparation.
Embodiment 6
L N-type waferN water absorbability is analyzed
Be under 75% and 92.5% the condition, crystal formation L of the present invention and crystal form A to be placed 24 hours in humidity, measure its moisture absorption weightening finish (%).
The result:
Through the comparison of wettability test, Febuxostat L type body is stable under super-humid conditions, and is lower than crystal form A water absorbability, and concrete data are seen table 2.
Table 2 is 75% and 92.5% condition held 24 hours in humidity, water absorbability
The result shows that the L N-type waferN is relatively stable under the higher environment of humidity, and water absorbability is lower, is suitable for processing stabilised pharmaceutical.
Embodiment 7
Pharmaceutical compositions (tablet)
| The L N-type waferN (g) that embodiment 1 makes | 40g |
| Lactose | 60g |
| Starch | 88g |
| Crosslinked carboxymethyl fecula sodium | 10g |
| Magnesium Stearate | 1g |
| Colloidal silica | 1g |
| Add up to | 200g |
Above-mentioned materials is mixed, and wet granulation makes 1000 tablets of tablets.
Embodiment 8
Pharmaceutical compositions (capsule)
| The L N-type waferN (g) that |
80g |
| Precoking starch | 108g |
| Microcrystalline Cellulose | 60g |
| Magnesium Stearate | 2g |
| Add up to | 250g |
Above-mentioned materials is mixed, and non-slurry pelletizing makes 1000 capsules.
The above is merely preferred embodiment of the present invention; Be not in order to limit essence technology contents scope of the present invention; Essence technology contents of the present invention is broadly to be defined in the claim scope of application, and if any technological entity or method that other people accomplish are defined identical with the claim scope of application; Also or a kind of change of equivalence, all will be regarded as and be covered by among this claim scope.
Claims (5)
1. the L N-type waferN of the compound shown in molecular formula 1:
It is characterized in that said crystalline X-ray powder diffraction figure is as shown in Figure 1.
2. the preparation method of a L N-type waferN as claimed in claim 1 is characterized in that, it comprises step:
(1) with 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid and solvent RCOOH 80-120 ℃ of mixing, obtain solution 1;
(2) solution 1 is cooled to-20 ℃-40 ℃, filters and obtain L N-type waferN as claimed in claim 1;
Wherein R representes H, methyl, ethyl or propyl group;
(milliliter: be 5-20 gram): 1 mixes said solvent RCOOH and 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid with envelope-bulk to weight ratio.
3. preparation method as claimed in claim 2 is characterized in that, in step (2), carries out drying at 60-120 ℃ after filtering and obtains L N-type waferN according to claim 1 or claim 2.
4. a pharmaceutical composition is characterized in that, it comprises L N-type waferN as claimed in claim 1 as its activeconstituents and pharmaceutically acceptable carrier.
5. the purposes of a L N-type waferN as claimed in claim 1 is characterized in that, described L N-type waferN is used to prepare the medicine of treatment and the too high diseases associated of uric acid.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2009101992484A CN102070558B (en) | 2009-11-23 | 2009-11-23 | New crystal form of febuxostat and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2009101992484A CN102070558B (en) | 2009-11-23 | 2009-11-23 | New crystal form of febuxostat and preparation method thereof |
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| CN102070558A CN102070558A (en) | 2011-05-25 |
| CN102070558B true CN102070558B (en) | 2012-08-22 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103044353B (en) * | 2013-01-24 | 2014-06-11 | 吉林三善恩科技开发有限公司 | Febuxostat pharmaceutical co-crystal and preparation method thereof |
| CZ27857U1 (en) | 2014-12-12 | 2015-02-23 | Zentiva, K.S. | Formulation containing febuxostat solid solution |
| CN108530382A (en) * | 2018-03-20 | 2018-09-14 | 华南理工大学 | A kind of Febuxostat ligustrazine eutectic and its preparation method and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1642546A (en) * | 2002-03-28 | 2005-07-20 | 帝人株式会社 | Solid preparation containing single crystal form |
| CN101085761A (en) * | 2007-06-29 | 2007-12-12 | 上海华拓医药科技发展股份有限公司 | Febuxotat microcrystal and compositions thereof |
| CN101525319A (en) * | 2009-04-22 | 2009-09-09 | 天津泰普药品科技发展有限公司 | Febuxostat and drug combination thereof |
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2009
- 2009-11-23 CN CN2009101992484A patent/CN102070558B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1642546A (en) * | 2002-03-28 | 2005-07-20 | 帝人株式会社 | Solid preparation containing single crystal form |
| CN101085761A (en) * | 2007-06-29 | 2007-12-12 | 上海华拓医药科技发展股份有限公司 | Febuxotat microcrystal and compositions thereof |
| CN101525319A (en) * | 2009-04-22 | 2009-09-09 | 天津泰普药品科技发展有限公司 | Febuxostat and drug combination thereof |
Non-Patent Citations (1)
| Title |
|---|
| JP特开平10-45733A 1998.02.17 |
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Application publication date: 20110525 Assignee: Changzheng-Xinkai Pharmaceutical Co., Ltd., Suzhou Assignor: Xinkai Medical Chemical Intermediate (Shanghai) Co., Ltd. Contract record no.: 2014310000071 Denomination of invention: New febuxostat crystal form and preparing method thereof Granted publication date: 20120822 License type: Exclusive License Record date: 20140422 |
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Effective date of registration: 20201209 Address after: No. 567, Liufeng Road, Hedong Industrial Park, Wuzhong Economic Development Zone, Suzhou City, Jiangsu Province Patentee after: SUZHOU CHANGZHENG-XINKAI PHARMACEUTICAL Co.,Ltd. Address before: Room 2501, world trade building, 500 Guangdong Road, Shanghai Patentee before: CINKATE MEDICINE CHEMICAL INTERMEDIATE (SHANGHAI) Co.,Ltd. |