CN101671314B - Uloric crystal and preparation method thereof - Google Patents
Uloric crystal and preparation method thereof 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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Abstract
The invention relates to the field of medicinal chemistry, in particular to an Uloric crystal and a preparation method thereof. The Uloric crystal is characterized in that x-ray powder diffraction feature absorption peak (2theta) values have feature peaks at the parts of 6.70 degrees, 7.26 degrees, 9.40 degrees, 12.86 degrees, 13.42 degrees, 16.48 degrees, 19.70 degrees, 22.10 degrees, 23.16 degrees, 23.86 degrees, 25.02 degrees, 25.92 degrees, 26.74 degrees, 28.34 degrees and 40.48 degrees. An Uloric alpha crystal form of the invention has simple process operation and low cost. Only Uloric needs to be dissolved in a single solvent of ethylene glycol monomethyl ether so as to avoid solvation crystal habit, and the crystal form is stable and has good reproducibility. Moreover, the Uloric alpha crystal form has good solubility and better dissolution rate than A crystals in a solid preparation.
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)
1. the alpha-crystal form of a Febuxostat is characterized in that: reflection angle 2 θ of this crystalline X-ray powder diffraction figure are near 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, locate to have characteristic peak, its x-ray diffraction pattern such as Fig. 1 for 28.34 and 40.48 °.
2. the alpha-crystal form of claim 1, its differential heat scanning is being located endotherm(ic)peak near 200 ℃.
3. the alpha-crystal form of claim 1, its infrared spectrum be near 1683,1296cm
-1There is charateristic avsorption band at the place.
4. the preparation method of the alpha-crystal form of the Febuxostat of a claim 1, comprise: Febuxostat is dissolved in the ethylene glycol monomethyl ether, heating for dissolving, decompression is extracted solvent out to crystallization down, filter, drying, promptly, wherein the weightmeasurement ratio of Febuxostat and ethylene glycol monomethyl ether is 1: 40～1: 100g/ml, the temperature that solvent is extracted in decompression out is 40～80 ℃.
5. the preparation method of claim 4, wherein the weightmeasurement ratio of Febuxostat and ethylene glycol monomethyl ether is 1: 70g/ml.
6. the preparation method of claim 4, wherein to extract the temperature of solvent out be 60 ℃ in decompression.
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP5215505B2 (en) | 2009-06-10 | 2013-06-19 | 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 |
| 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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