CN101671314B - A crystal form of febuxostat and its preparation method - Google Patents
A crystal form of febuxostat and its preparation method Download PDFInfo
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- CN101671314B CN101671314B CN2009100353727A CN200910035372A CN101671314B CN 101671314 B CN101671314 B CN 101671314B CN 2009100353727 A CN2009100353727 A CN 2009100353727A CN 200910035372 A CN200910035372 A CN 200910035372A CN 101671314 B CN101671314 B CN 101671314B
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- 239000013078 crystal Substances 0.000 title claims abstract description 51
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 229960005101 febuxostat Drugs 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 10
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 5
- 238000010521 absorption reaction Methods 0.000 claims abstract 2
- 238000002441 X-ray diffraction Methods 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000007707 calorimetry Methods 0.000 claims 1
- 238000001914 filtration Methods 0.000 claims 1
- 238000002329 infrared spectrum Methods 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 5
- 239000007787 solid Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 description 16
- 238000005755 formation reaction Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000003556 assay Methods 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 229920003081 Povidone K 30 Polymers 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 238000002798 spectrophotometry method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 206010061623 Adverse drug reaction Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007613 slurry method Methods 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 239000011122 softwood Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
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- Saccharide Compounds (AREA)
Abstract
本发明涉及药物化学领域，具体涉及一种非布索坦的晶型体及其制备方法。其特征是：其x-射线粉末衍射特征吸收峰(2θ)值在接近6.70，7.26，9.40，12.86，13.42，16.48，19.70，22.10，23.16，23.86，25.02，25.92，26.74，28.34和40.48°处具有特征峰。本发明的非布索坦α晶型的工艺操作简单，成本低廉。只需将非布索坦溶解于单一溶剂乙二醇单甲醚中，避免了溶剂化结晶形态的出现，晶形稳定，重现性好。并且，本发明的非布索坦α晶型溶解度好，在固体制剂中的溶出度均好于A晶。The invention relates to the field of medicinal chemistry, in particular to a crystal form of febuxostat and a preparation method thereof. It is characterized in that its X-ray powder diffraction characteristic absorption peak (2θ) values are close to 6.70, 7.26, 9.40, 12.86, 13.42, 16.48, 19.70, 22.10, 23.16, 23.86, 25.02, 25.92, 26.74, 28.34 and 40.48° have characteristic peaks. The process of the febuxostat α crystal form of the present invention is simple in operation and low in cost. Only need to dissolve febuxostat in a single solvent ethylene glycol monomethyl ether, avoiding the appearance of solvated crystal form, stable crystal form and good reproducibility. Moreover, the α crystal form of febuxostat of the present invention has good solubility, and the dissolution rate in solid preparations is better than that of A crystal.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to alpha-crystal form of a kind of Febuxostat and preparation method thereof.
Background technology
Febuxostat is a specific specificity xanthine oxidase inhibitor, compares with allopurinol, and the curative effect of Febuxostat prevention gout outbreak and the incidence of adverse drug reaction are similar, but it is higher to suppress uricogenesis intensity.Its chemistry 2-(3-cyano-4-isobutoxy phenyl) by name-4-methyl-5-thiazole formic acid has the activity that suppresses XOD.
Same substance has two or more spatial disposition and unit cell parameters, and the phenomenon that forms multiple crystal formation is called heteromorphism, and all there is heteromorphism in many crystalline drugs.The different crystal forms of same medicine may have remarkable difference at aspects such as outward appearance, solubleness, fusing point, dissolution rate, biological effectivenesses, thereby has influenced stability of drug, bioavailability and curative effect.The medicine heteromorphism is one of important factor that influences drug quality and clinical efficacy.In the patent of invention CN1275126A of Japanese Supreme Being people company, six kinds of crystal formations of relevant Febuxostat have been mentioned.Wherein the A crystal formation is metastable crystal formation, and D is brilliant and G is brilliant in containing the pseudo-polymorphic of solvent, and B is brilliant to be obtained by drying under reduced pressure for hydrate G, and the C crystalline substance is converted to by the solvent mediation.The Chinese patent CN1642546A of Supreme Being people company application has announced the brilliant method for preparing solid preparation of A.Chinese patent CN1970547A discloses in addition three kinds of crystal habit H, I and the J of relevant Febuxostat.
Summary of the invention
The invention discloses a kind of polymorphs body of Febuxostat.
The crystal formation of Febuxostat of the present invention is named the type into α, and its x-ray powder diffraction charateristic avsorption band (2 θ) value is near 6.70,7.26, and 9.40,12.86,13.42,16.48,19.70,22.10,23.16,23.86, locate to have characteristic peak for 25.02,25.92,26.74,28.34 and 40.48 °.Its x-ray diffraction pattern is seen Fig. 1.
The Febuxostat alpha-crystal form through infrared analysis (KBr compressing tablet) near 1683,1296cm
-1The place has the charateristic avsorption band that itself and other crystal formation can be made a distinction, and sees Fig. 2.
Differential heat scanning demonstration Febuxostat alpha-crystal form is being located endotherm(ic)peak near 200 ℃.
Among the present invention, the mensuration of 2 θ values is used CuK
aLight source, precision is ± 0.2 °, and therefore, " approaching " in above-mentioned " x-ray powder diffraction charateristic avsorption band (2 θ) value is approaching " should be defined as 2 θ ± 0.2 °, represent above-mentioned obtained 2 θ values to allow certain reasonably limit of error, its limit of error is ± 0.2 °.
Febuxostat alpha-crystal form preparation of the present invention is simple, and the preparation method comprises: Febuxostat is dissolved in the ethylene glycol monomethyl ether, and heating for dissolving, decompression is extracted solvent out to crystallization down, filters, drying, promptly.
Wherein the weightmeasurement ratio of Febuxostat and ethylene glycol monomethyl ether preferred 1: 40～1: 100g/ml.Further preferred 1: 70g/ml.
Wherein the temperature of decompression extraction solvent is preferred 40～80 ℃.Further preferred 60 ℃.
Animal experiment proves that the crystal formation α of Febuxostat of the present invention has the stronger activity of falling uric acid in the interior blood of body.
The advantage of Febuxostat alpha-crystal form of the present invention is that technological operation is simple, and is with low cost.Only need Febuxostat is dissolved in the single solvent ethylene glycol monomethyl ether, avoided the appearance of solvation crystal habit, stable crystal formation, favorable reproducibility.And Febuxostat alpha-crystal form solubleness of the present invention is good, and the dissolution rate in solid preparation all is better than the A crystalline substance.
Description of drawings
Fig. 1 is the alpha-crystal form x-ray diffraction pattern of Febuxostat of the present invention.
Fig. 2 is the alpha-crystal form infrared absorpting light spectra of Febuxostat of the present invention.
Fig. 3 is the differential heat scintigram of the alpha-crystal form of Febuxostat of the present invention.
Fig. 4 is the thermal multigraph of the alpha-crystal form of Febuxostat of the present invention.
Embodiment
The preparation of Febuxostat alpha-crystal form:
The 1g Febuxostat is placed the single neck flask of 100ml, add ethylene glycol monomethyl ether 70ml, in the dissolving extremely fully of 60 ℃ of oil bath heated and stirred.60 ℃ down decompression extract the solvent crystallizatioies out, washing is filtered, and in 60 ℃ of following drying under reduced pressure 8 hours, obtains crystalline powder.Measure its powder diagram and see Fig. 1, infrared spectrogram is seen Fig. 2, and according to powder diagram and infrared spectrogram, that obviously generate is crystal formation α.Yield: 90%, mp:198-200 ℃.
Embodiment 2
The stability test of Febuxostat alpha-crystal form
The alpha-crystal of the Febuxostat of embodiment 1 preparation is placed respectively under the condition of 4500LX, 60 ℃ and RH92.5%, in sampling in 0 day, 5 days, 10 days, carry out assay, relevant room mensuration, draw X-powder diagram and infrared absorpting light spectra, the results are shown in Table 1.
The condition and the method for assay are: high performance liquid chromatography is moving phase with methyl alcohol-0.01mol/L potassium dihydrogen phosphate (75: 25) with 5% phosphorus acid for adjusting pH value to 5.4 ± 0.1; Detect wavelength X=315nm; The preparation of need testing solution and reference substance solution: accurate claim random sample product fine powder about 30mg, put in the 100ml measuring bottle, add that moving phase is ultrasonic to make dissolving, add moving phase to scale, shake up, precision is measured 10ml, puts in the 100ml measuring bottle, adds moving phase to scale, shakes up.Precision is measured reference substance solution and each 20 μ l of need testing solution respectively, injects liquid chromatograph, and the record color atlas is by the content of external standard method with Febuxostat in the calculated by peak area trial-product.
Determination of related substances adopts high performance liquid phase-Self-control method.The same assay of condition determination.
Through X-ray powder diffraction and Infrared spectroscopy, crystal formation does not change; Content and impurity level do not have considerable change, prove that alpha-crystal form is highly stable.
The study on the stability result of table 1 alpha-crystal
Embodiment 3
The solubility test of Febuxostat alpha-crystal form and A crystal formation
Brilliant and the brilliant abundant porphyrize respectively of A with Febuxostat α, the difference water, 0.1NHCl, PH5.0 phosphate buffer soln and PH6.8 phosphate buffer soln preparation saturated solution (ultrasonic 30 minutes, still have the white solid thing to exist in the solution), content with Febuxostat in the determined by ultraviolet spectrophotometry saturated solution the results are shown in Table 2.As can be seen from Table 2: about the solubleness of alpha-crystal form is doubled than A crystal formation.
Table 2 alpha-crystal form and A crystal formation solubility test result
Embodiment 4
The dissolution rate test of Febuxostat alpha-crystal form and A crystal formation
The brilliant 80mg of Febuxostat α crystalline substance/A
Microcrystalline Cellulose 35mg
HPMC E15 5mg
Lactose 30mg
Sodium starch glycolate 8mg
4% 30 POVIDONE K 30 BP/USP, 30 aqueous solution are an amount of
Magnesium Stearate 1mg
Preparation technology:
Get the brilliant and above-mentioned various auxiliary material of Febuxostat α crystalline substance or A and cross 100 mesh sieves respectively, mix, with 4% 30 POVIDONE K 30 BP/USP, 30 aqueous solution system softwoods, mistake 20 mesh sieve system wet granulars, 60 ℃ of dryings 5 hours, whole of 20 mesh sieves add the Magnesium Stearate mixing, compressing tablet.
Measure the dissolution rate of two kinds of tablets.Condition determination and method: dissolution medium pH6.8 phosphate buffered saline buffer; The slurry method, 100 rev/mins; Ultraviolet spectrophotometry is measured wavelength X=314nm; The concentration of reference substance solution is 7.5 μ g/ml; Calculate the stripping quantity of each time point by absorbancy.The results are shown in Table 3.The result shows: the tablet of alpha-crystal form compacting reached full stripping in 20 minutes, and the agent of A wafer needed 45 minutes to reach full stripping, and the stripping of α wafer is better than the A wafer.
The dissolution rate test-results of two kinds of crystal formation tablets of table 3 (n=6, %)
Claims (6)
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| CN2009100353727A CN101671314B (en) | 2009-09-17 | 2009-09-17 | A crystal form of febuxostat and its preparation method |
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2395381T3 (en) | 2009-06-10 | 2013-02-12 | Teva Pharmaceutical Industries Ltd. | Crystal forms of Febuxostat |
| 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 |
| 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 |
| CN102127033A (en) * | 2011-01-21 | 2011-07-20 | 北京虹湾医药技术有限公司 | Febuxostat crystal form and industrial preparation method thereof |
| WO2013088449A1 (en) | 2011-12-16 | 2013-06-20 | Natco Pharma Limited | Stable crystal form of febuxostat and process for the preparation thereof |
| CN105372372B (en) * | 2012-12-14 | 2018-05-01 | 贵州信邦制药股份有限公司 | A kind of detection method of febuxostat tablet |
| CN103396378B (en) * | 2013-07-29 | 2015-06-10 | 杭州朱养心药业有限公司 | Stable febuxostat crystal |
| CN107540630A (en) * | 2016-06-29 | 2018-01-05 | 康普药业股份有限公司 | A kind of Febustat compound and preparation method |
| 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 |
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