CN103396378B

CN103396378B - Stable febuxostat crystal

Info

Publication number: CN103396378B
Application number: CN201310323686.3A
Authority: CN
Inventors: 沈如杰; 李阅东; 唐建飞; 何海珍; 姚成娥; 赵福斌; 刘玉艳; 刘秋敏; 马雯霞
Original assignee: HANGZHOU ZHUYANGXIN PHARMACEUTICAL CO Ltd
Current assignee: HANGZHOU ZHUYANGXIN PHARMACEUTICAL CO Ltd
Priority date: 2013-07-29
Filing date: 2013-07-29
Publication date: 2015-06-10
Anticipated expiration: 2033-07-29
Also published as: CN103396378A

Abstract

The invention relates to a stable febuxostat crystal and particularly relates to a febuxostat compound represented by a formula (shown in the description). The febuxostat compound is radiated by Cu-Kalpha and has diffraction peaks at about 9.42 degrees and 12.54 degrees in a power X-ray diffraction pattern represented by an angle 2theta. The stable febuxostat crystal disclosed by the invention has good pharmaceutical properties.

Description

Febustat crystallization

Technical field

The present invention relates to medical art, relate to a kind of xanthine oxidase inhibitor Febustat, particularly relate to the stable crystalline of Febustat, also relate to by the pharmaceutical composition of this Febustat crystalline, and the preparation method of this this Febustat crystallization.Febustat result provided by the invention has excellent pharmaceutical properties.

Background technology

Hyperuricemia be due to uric acid produce increase and/or kidney uric acid secretion reduce caused by, it is the most dangerous factor of bringing out gout.Using medicine to reduce uric acid concentration in blood is one of common method of occurring of prevention gout, and this kind of medicine comprises can block the uricosuric and XOD/xanthine dehydrogenase inhibitor that uriniferous tubules chamber film absorbs uric acid.But uricosuric is forbidden in renal tubal dysfunction patient, the patient with normal renal function then can cause urine alkalization with this type of medicine; Allopurinol is then the XOD/xanthine dehydrogenase inhibitor of unique listing at present, but it is only for following 3 kinds of patients: uricosuric medicine can not make uric acid concentration in its blood lower than 70mg/L patient, cause gout simultaneously with the patient of renal tubal dysfunction to the not tolerant patient of uricosuric medicine and because uric acid produces to increase, and allopurinol has obvious untoward reaction, as hepatitis, ephrosis and anaphylaxis etc.

In view of being the mechanism that prevention gout occurs to the suppression of XOD, thus researchist has targeted effective drug development safer compared with allopurinol.Look back nearly 2 years gout treatment medicine market, be not difficult to find out that being difficult to see new product in this field goes on the market, market is still based on Zyloric and benzbromarone.These two kinds of medicines are all catabasis medications, and the former is to suppress uricogenesis, and the latter is to promote excretion.

Febustat (febuxostat), also known as Febuxostat, chemical name: 2-[3-cyano group-4-(2-methyl propoxy-) phenyl]-4-methylthiazol-5-formic acid, English name: 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, its molecular formula is: C ₁₆h ₁₆n ₂o ₃s, molecular weight is 316.38, and chemical structural formula is:

Febustat is the anti-gout drugs of new generation of Supreme Being people (Teijin) company synthesis, and demonstrate fabulous activity, it is a kind of selectivity XOD/xanthine dehydrogenase inhibitor, has a good application prospect.Di Ren company has submitted the application of Febustat sheet 20 ~ 40mg dosage in April, 2004 in Japan, and Febustat compound is developed by the SK Chemical company that special permission gives European Ipsen company and Korea S.Febustat (Adenuric) listing of in May, 2008 European Union's approval Ipsen company, is used for the treatment of the chronic hyperuricemia of gout.In February, 2009, FDA ratified the Febustat (ULORIC) of TAKEDA company in U.S.'s listing, specification 40mg, 80mg.

The current kind of antigout drug is few, and clinical treatment is mainly based on colchicine, non-steroidal anti-inflammatory drugs, hormone, promotion uric acid excretion medicine (as probenecid, sulfinpyrazone and benzbromarone) and suppression uric acid synthetic drug (Zyloric).These medicines are all defectiveness in treatment.Weak curative effect, side effect become greatly the bottleneck of its clinical application.And the validity of Febustat and specificity are all better than the standard drug allopurinol for the treatment of gout at present, it is the new drug of first treatment hyperuricemia over 40 years.

Febustat is a non-purines xanthine oxidase inhibitor, and its basic role mechanism is similar with allopurinol.But allopurinol is with obvious anaphylaxis, and Febustat does not but show and has cross reaction with allopurinol.And Febustat is used for Renal Failure Patients and has higher-security.In validity, Febustat 80mg/d display is better than allopurinol 300mg/d for the reduction of uric acid.

Multicenter, double blinding, randomized clinical the research evaluation security of Febustat and the curative effect to gout.Always have 136 male sex and 17 women's gout patients and accept placebo or this product (40,80 or 120mg/d) at random, discovery is detected after 4 weeks, this product each dosage group patients serum uric acid (sUA) concentration all significantly reduces before comparatively treating, according to dosage each group is average respectively from low to high reduces by 37%, 44% and 59%, and placebo patients sUA concentration reduced by only 2%; And the patient that in placebo and from low to high each dosage group, sUA concentration drops to below 60mg/L accounts for 0%, 56%, 76% and 94% respectively; Most humans adheres to completing test, and Febustat is close with placebo adverse reaction rate, is respectively 54% and 50%, and these untoward reactions are mostly slight, have self limiting.

The same with allopurinol, the formation of Febustat uric acid capable of blocking, and uric acid crystal is deposited on the joint of gout patients, causes painful swelling.But allopurinol can suppress the enzyme of a series of participation uric acid path, and Febustat then only suppresses XOD, thus its effect has more specificity.Doctor MacDonald of TAP company thinks, this difference between the effects makes Febustat more safer than allopurinol in theory.There is side effect in the patient that allopurinol can cause about 1% ~ 2%, wherein 25% or even fatal.Especially, this product, mainly at liver metabolism, may be more suitable for renal failure patient, and allopurinol is via renal excretion.

Febustat is that a kind of nonhygroscopic white crystals powder is easy, is dissolved in dimethyl formamide, is dissolved in dimethyl sulfoxide (DMSO); Be slightly soluble in ethanol; Slightly be dissolved in methyl alcohol and acetonitrile, substantially water insoluble.Melting range 205 DEG C to 208 DEG C.There is multiple crystal formation in Febustat, and there is the possibility turning crystalline substance between each crystal formation.

Such as CN1275126A (CN99801366.8-Supreme Being people) and CN102020617A (CN201010562692.0-Supreme Being people) disclose a kind of method being prepared the various polymorphs bodies of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid by crystallization under the specified conditions limited by the methyl alcohol of temperature and mixed solvent used and the ratio of water, selectivity, and often kind of polymorphs body of 2-(3-the cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid that method is obtained thus; Additionally provide specific polymorphs body obtained other polymorphs body of above-mentioned acid or the method for its amorphous body thus by heating and the above-mentioned acid of vacuum-drying, and the polymorphs body of the described acid according to said method obtained or amorphous body; It is said and just may change into other crystal formation under certain conditions between several crystal formations that invention is recorded, the conversion of crystal formation for the dissolution rate of medicament character such as pharmaceutical preparation or stability etc. exist replace impact.Especially, this invention describes a kind of crystallization being referred to as A crystal formation, and its X-ray powder diffraction figure is about 6.62,7.18,12.80,13.26,16.48,19.58,21.92,22.68,25.84,26.70,29.16 and 36.70 ° of places at reflection angle 2 θ and has characteristic peak.

CN1970547A (CN200610095263.0, Chongqing medical professionals) disclose 3 kinds of new crystal H, I, J and preparation method thereof of a kind of 2-(3-cyano-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid (Febustat), further provide X-ray ray powder diffraction charateristic avsorption band and the infrared absorption peak of these 3 kinds of crystal formations; Especially, reflection angle 2 θ of the X-ray powder diffraction figure of disclosed crystal formation I has charateristic avsorption band being about 3.28,6.58,12.70,13.34,19.97,24.26 and 25.43 ° of places.

CN101684107A (CN200810200565.9, Shanghai is excellent opens up) disclose 2-(3-cyano-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid (abbreviation " Febuxostat ", formula I) new crystal form X, Y and Z and preparation method thereof, and by fusing point and powder X-ray diffractogram confirmation, the Febuxostat prepared the method is extremely stable to temperature, illumination and humidity, be beneficial to long-term storage, use solvent safety and be easy to remove, simple to operately be suitable for suitability for industrialized production, and be suitable for and be directly used in preparation and produce.The X-ray powder diffraction pattern of the polymorphic Y wherein recorded 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, there is charateristic avsorption band at 36.70 places.

Other crystal formation of Febustat such as has: crystal form A, B, C, D, G, amorphous (their preparation example is as being recorded in CN1275126A), crystal formation H, I, J (their preparation example is as being recorded in CN1970547A), crystal form K, L (their preparation example is as being recorded in CN101759656A), crystal form M (their preparation example is as being recorded in CN101891702A), crystal formation N (their preparation example is as being recorded in CN101891703A), crystal form P (their preparation example is as being recorded in CN101824006A), crystal form Q (their preparation example is as being recorded in CN101824005A), crystal formation R, S, T (their preparation example is as being recorded in CN101928260A), crystal form X, Y, Z (their preparation example is as being recorded in CN101684107A).

Well-known, there is unstable situation in various crystal formation itself, such as, may occur to turn brilliant phenomenon in long-term preservation process.But the problem that another kind be can not ignore is, medicament prepared by different crystal forms is particularly because of body pharmaceutical preparation such as tablet, they may affect the performance of tablet in Long-term Storage process due to the instability of crystal formation, such as affect the dissolving out capability of tablet, the consequence caused thus is that preparation bioavailability changes, and this does not allow clinically to occur.

Therefore, those skilled in the art's expect have a kind of new method to prepare Febustat crystallization that the Febustat with Good Pharmacy feature such as has invariant feature.

Summary of the invention

The object of the invention is to for the clinical Febustat crystallization providing a kind of novelty, expect that crystallization has satisfactory stability, such as crystal formation itself is stablized, and/or the tablet be prepared into by this crystal formation has satisfactory stability.The present inventor finds that the Febustat with specific crystal formation not only itself has stability, and tablet prepared therefrom has satisfactory stability performance equally.The present invention is based on this find and be accomplished.

For this reason, first aspect present invention provides following formula: compound:

It uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, has diffraction peak at about 9.42 ° and about 12.54 ° of places.

Compound according to a first aspect of the present invention, it uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, has diffraction peak at about 9.42 °, about 12.54 °, about 19.12 ° and about 19.94 ° of places.

Compound according to a first aspect of the present invention, it uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, there is diffraction peak at about 6.64 °, about 7.18 °, about 9.42 °, about 12.54 °, about 12.81 °, about 16.39 °, about 19.12 ° and about 19.94 ° of places.

Compound according to a first aspect of the present invention, it uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, there is diffraction peak at about 6.64 °, about 7.18 °, about 9.42 °, about 12.54 °, about 12.81 °, about 16.39 °, about 19.12 °, about 19.60 °, about 19.94 °, about 20.86 °, about 21.25 °, about 23.82 °, about 25.30 °, about 25.88 °, about 26.71 ° places.

Compound according to a first aspect of the present invention, it uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 9.42 ° and 12.54 ° each angle places ± 0.20 °, the scope of ± 0.10 ° or ± 0.05 ° has diffraction peak.In one embodiment, described compound uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, has diffraction peak at 9.42 ° ± 0.10 ° and 12.54 ° ± 0.10 ° place.

Compound according to a first aspect of the present invention, it uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 9.42 °, 12.54 °, 19.12 ° and 19.94 ° each angle places ± 0.20 °, the scope of ± 0.10 ° or ± 0.05 ° has diffraction peak.In one embodiment, described compound uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, there is diffraction peak at 9.42 ° ± 0.10 °, 12.54 ° ± 0.10 °, 19.12 ° ± 0.10 ° and 19.94 ° ± 0.10 ° place.

Compound according to a first aspect of the present invention, it uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 6.64 °, 7.18 °, 9.42 °, 12.54 °, 12.81 °, 16.39 °, 19.12 ° and 19.94 ° each angle places ± 0.20 °, the scope of ± 0.10 ° or ± 0.05 ° has diffraction peak.In one embodiment, described compound uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, there is diffraction peak at 6.64 ° ± 0.10 °, 7.18 ° ± 0.10 °, 9.42 ° ± 0.10 °, 12.54 ° ± 0.10 °, 12.81 ° ± 0.10 °, 16.39 ° ± 0.10 °, 19.12 ° ± 0.10 ° and 19.94 ° ± 0.10 ° place.

Compound according to a first aspect of the present invention, it uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 6.64 °, 7.18 °, 9.42 °, 12.54 °, 12.81 °, 16.39 °, 19.12 °, 19.60 °, 19.94 °, 20.86 °, 21.25 °, 23.82 °, 25.30 °, 25.88 °, 26.71 ° each angle places ± 0.20 °, the scope of ± 0.10 ° or ± 0.05 ° has diffraction peak.In one embodiment, described compound uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, there is diffraction peak at 6.64 ° ± 0.10 °, 7.18 ° ± 0.10 °, 9.42 ° ± 0.10 °, 12.54 ° ± 0.10 °, 12.81 ° ± 0.10 °, 16.39 ° ± 0.10 °, 19.12 ° ± 0.10 °, 19.60 ° ± 0.10 °, 19.94 ° ± 0.10 °, 20.86 ° ± 0.10 °, 21.25 ° ± 0.10 °, 23.82 ° ± 0.10 °, 25.30 ° ± 0.10 °, 25.88 ° ± 0.10 °, 26.71 ° ± 0.10 ° place.

Compound according to a first aspect of the present invention, it uses Cu-K α radiation, has powder x-ray diffraction collection of illustrative plates as shown in Figure 1 substantially.

As well known to those skilled in the art, when representing the intensity of diffraction peak, all can represent by diffraction relative intensity or relative intensity (it is abbreviated as I/Io), and usually the I/Io of highest peak is expressed as 100, the ratio of the intensity of other diffraction peak and the intensity of highest peak is multiplied by 100 and can be regarded as to obtain the relative intensity of other diffraction peak.Or for a certain diffracting spectrum, defining its relative intensity I/Io value for a certain stronger diffraction peak is wherein 100, the intensity of other diffraction peak and the ratio of the intensity at most peak are multiplied by 100 and can be regarded as to obtain the relative intensity of other diffraction peak.

Compound according to a first aspect of the present invention, it uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, have diffraction peak at about 19.94 ° of places, and the I/Io value of this diffraction peak is in 100, the I/Io value of the diffraction peak at 2 θ about 12.81 ° place is greater than 65, be preferably greater than 70, such as between 70 ~ 120, such as, between 70 ~ 110, such as, between 70 ~ 100.

Compound according to a first aspect of the present invention, it is the Febustat crystallization substantially with diffractive features of the present invention.

Further, second aspect present invention provides the method preparing Febustat crystallization of the present invention, it comprises the steps: Febustat to add in the mixing solutions of propyl carbinol and acetonitrile, be heated to reflux under stirring and make dissolving, under agitation to mixed solution and dripping glacial acetic acid, being then slowly cooled to about 5 DEG C (5-8 hour can be left standstill at this temperature) to separate out precipitation, leach precipitation, with propyl carbinol washing, 40 DEG C of vacuum-dryings, to obtain final product.

Method according to a second aspect of the present invention, wherein said propyl carbinol and the volume ratio both acetonitrile are 100:(30 ~ 50), preferred volume ratio is 100:(35 ~ 45).

Method according to a second aspect of the present invention, the dripping quantity of wherein said glacial acetic acid is: make its concentration in the solution reach the amount of 2 ~ 5% (v/v).

Method according to a second aspect of the present invention, wherein the amount of the mixing solutions of propyl carbinol and acetonitrile is the minimum quantity making medicine dissolution, and such as every 100ml propyl carbinol usage quantity can be used for process 5 ~ 15g active medicine.

Further, third aspect present invention provides a kind of pharmaceutical composition, wherein comprises Febustat crystallization mentioned above and pharmaceutically acceptable carrier.

Pharmaceutical composition according to a third aspect of the present invention, it is oral preparations or injection formulations.

Pharmaceutical composition according to a third aspect of the present invention, it is tablet, capsule, granule, injection (comprising injection liquid and lyophilize powder injection), suspensoid, pill.

Pharmaceutical composition according to a third aspect of the present invention, it is tablet, wherein comprise Febustat crystallization described in the arbitrary embodiment of first aspect present invention, and Spherolac 100, Microcrystalline Cellulose, hydroxy propyl cellulose, croscarmellose sodium, silicon-dioxide and Magnesium Stearate.

Pharmaceutical composition according to a third aspect of the present invention, it is tablet, wherein comprise Febustat crystallization 40 weight part described in the arbitrary embodiment of first aspect present invention, and Spherolac 100 20 ~ 60 weight part, Microcrystalline Cellulose 20 ~ 60 weight part, hydroxypropylcellulose 3-30 weight part, croscarmellose sodium 2-15 weight part, silicon-dioxide 0.5-2 weight part and Magnesium Stearate 0.5-2 weight part.

Pharmaceutical composition according to a third aspect of the present invention, it is tablet, wherein comprises Febustat crystallization described in the arbitrary embodiment of first aspect present invention, and Microcrystalline Cellulose, pregelatinized Starch, carboxymethylstach sodium, PVP K30, Magnesium Stearate.

Pharmaceutical composition according to a third aspect of the present invention, it is tablet, wherein comprise Febustat crystallization 40 weight part described in the arbitrary embodiment of first aspect present invention, and Microcrystalline Cellulose 60 ~ 120 weight part, pregelatinized Starch 30 ~ 50 weight part, carboxymethylstach sodium 5 ~ 15 weight part, the PVP K30 of 2 ~ 6 weight parts, Magnesium Stearate 0.5 ~ 2 weight part.

Pharmaceutical composition according to a third aspect of the present invention, it is tablet, and it is further by dressing.Exemplary coating material is such as purchased from the Opadry II of the happy Kanggong department of card.Clothing layer is heavy can be the 1-4% accounting for greatly tablet total weight.

Due to above-mentioned auxiliary material, this can not show typical diffraction peak in time testing X-ray diffraction, and when these auxiliary materials mix with the activeconstituents such as Febustat of the present invention with typical diffractive peak, prepare tablet time, if the crystal formation of activeconstituents can keep stable in preparation process, the tablet be then pressed into still has the diffraction spectra suitable with bulk drug substantially, particularly comprises the typical diffractive peak of bulk drug.

Arbitrary embodiment of either side of the present invention, can combine with other embodiment, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characteristic goes for this technical characteristic in other embodiment, as long as they there will not be contradiction.

In the present invention, the implication of " % " can be determined according to concrete environment for use, and particularly it has as implication as described in Article 28 (4) money under " metering " item in version Chinese Pharmacopoeia in 2010 two notes on the use.

In the present invention, determine various material (the such as bulk drug of various crystal formation, pharmaceutical composition etc.) in the content of Febustat or other impurity time, and when determining in these materials chromatographic purity, certain methods below can be adopted to measure, " content determination " such as, " Related substances separation method ", " dissolution method ", " powder x-ray diffraction analysis method ", in the present invention's embodiment part hereinafter, the content of some material is measured as needed, related substance, dissolution rate, powder x-ray diffraction, if not otherwise indicated, all carry out according to following method.

content determination (this law can be used for the content, dissolution rate etc. that measure Febustat in bulk drug, pharmaceutical composition):

High performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD) is adopted to measure:

Chromatographic condition and system suitability: be weighting agent with octadecylsilane chemically bonded silica; Be moving phase with acetonitrile-phosphate buffer soln (get disodium hydrogen phosphate,anhydrous 5.8g, be dissolved in water, add 16.7g citric acid, and be diluted to 1000ml, regulate pH to 3.0)=36:64; Determined wavelength is 284nm.Number of theoretical plate calculates should be not less than 4000 by peak Febuxostat;

The preparation of reference substance solution: get Febustat reference substance and be about 40mg, accurately weighed, put in 200ml measuring bottle, add acetonitrile: water (36:64) is appropriate, ultrasonic make dissolving after be diluted to scale, shake up, precision measures 10ml and puts in 100ml measuring bottle, add acetonitrile: water (36:64) is diluted to scale, shakes up, in contrast product solution.

Prepared by need testing solution: get the sample to be tested being about equivalent to Febustat 40mg, accurately weighed, put in 200ml measuring bottle, add acetonitrile: water (36:64) is appropriate, ultrasonic make dissolving after be diluted to scale, shake up, precision measures 10ml and puts in 100ml measuring bottle, add acetonitrile: water (36:64) is diluted to scale, shakes up, as need testing solution; Dissolution rate sample can directly after filtration measure with after above-mentioned solvent cut to suitable concentration;

Assay method: precision measures reference substance solution and each 50ul of need testing solution.Injection liquid chromatography respectively, record color atlas, by external standard method with calculated by peak area, to obtain final product.

related substances separation method (this law can be used for the content measuring single contaminant or total impurities in bulk drug or composition):

Sample thief is appropriate, adds acetonitrile-water (36:64) and makes in every 1ml the solution containing 0.2mg (in containing Febuxostat), as need testing solution;

Get need testing solution more appropriate, be diluted to the solution of 2 μ g/ml with acetonitrile-water (36:64), solution in contrast;

High performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD) is adopted to measure, be weighting agent with octadecylsilane chemically bonded silica, (disodium hydrogen phosphate,anhydrous 5.8g is got with acetonitrile-phosphate buffer soln, be dissolved in water, add 16.7g citric acid, and be diluted to 1000ml, regulate pH to 3.0) be moving phase, adopt linear gradient elution, 0 to 7 minute, acetonitrile ratio is 5%, 7 to 20 minutes, acetonitrile rose to 20% from 5%, maintained 5 minutes, 20 to 30 minutes, acetonitrile ratio rose to 30% from 20%; Determined wavelength is 284nm, flow velocity: 0.5ml/min, sample size: 20 μ l, and number of theoretical plate (n) calculates should be not less than 3000 by Febuxostat chromatographic peak;

Column temperature is under the chromatographic condition of 40 DEG C, gets contrast solution 20 μ l and injects high performance liquid chromatograph, record color atlas; Adjustment instrumental sensitivity, makes principal constituent peak height be about 15 ~ 20% of full range, then gets need testing solution 20 μ l injection liquid chromatography, 4 times that record the principal constituent peak retention time of color atlas;

Calculate the peak area of each impurity in need testing solution color atlas; By well known to a person skilled in the art method, compare with main peak area in contrast solution color atlas the content calculating this impurity in trial-product by the peak area of each impurity peaks; Such as, in contrast solution color atlas, main peak area was 1000 (they are equivalent to 1% of need testing solution concentration), if the peak area of certain impurity is 500 in need testing solution color atlas, the content of this impurity in trial-product is 0.5%, if the peak area of certain impurity is 2000 in need testing solution color atlas, the content of this impurity in trial-product is 2%; These calculating can obtain the content of the maximum single contaminant in this trial-product; The content of all dirt adds and can obtain total impurities content.Above in mensuration haveduring related substance, for the pharmaceutical composition comprising pharmaceutical excipient, the chromatographic peak of auxiliary material in subtractive color spectrogram when calculating.

powder x-ray diffraction analysis method:

INSTRUMENT MODEL: powder X-ray diffractometer, Rigaku Dmax/2400

Experiment condition: CuK α radiation, graphite monochromator, 40KV, 100MA, 2 θ sweep limit: 0.0-50 °, sweep velocity 4 °/point, step-length: 0.01 °

Scan mode: continuous sweep

Slit is arranged: outgoing slit DS:1/2 ° of anti-scatter slit:SS 1/2 °; RS:0.3mm.

" pharmaceutically acceptable carrier " that use in pharmaceutical composition of the present invention can be the carrier of any routine in field of pharmaceutical preparations.The selection of specific support will depend on the administering mode or disease type and state that are used for the treatment of particular patient.For the preparation method of the said synthetic processes of specific administration pattern completely in the ken of pharmaceutical field technician.Such as, the thinner of pharmaceutical field routine, carrier, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier and lubricant etc. can be comprised as pharmaceutically acceptable carrier.If desired, flavouring agent, preservative and sweetener etc. can also be added in pharmaceutical composition.

Pharmaceutical composition of the present invention can make the various ways such as tablet, pulvis, granule, capsule, oral liquid, paste, creme, injectable emulsion (aseptic powder needle for injection).The medicine of above-mentioned various formulation all can be prepared according to the ordinary method of pharmaceutical field.

Again further, the invention provides the purposes of Febustat crystallization of the present invention in the medicine for the preparation of gout and complication such as hyperuricemia thereof.

The Febustat medicament (such as tablet etc.) of now list marketing, it can be used for treatment gout and complication such as hyperuricemia thereof.The invention provides a kind of new Febustat crystallization, its solubility property and oral after body in there is excellent feature in behavior, the Febustat crystallization that therefore the present invention is new can be used for treatment gout and complication such as hyperuricemia thereof equally.

Term used herein " base peak ", refers to the peak that in a certain X-ray diffractogram, intensity is maximum, and its relative intensity (I/Io) is 100, and other peak directly calculates its I/Io value by diffractometer.

In this article, when describing the occurrence of 2 θ angles, the concrete angle value of drawing with " about " represent allow this angle place ± 0.20 °, in the scope of ± 0.10 ° or ± 0.05 °.In other situation of the present invention, when modifying a certain numerical value with term " about ", such as when for modifying a certain numerical value or numerical range, refer to the acceptable limit of error of the those skilled in the art comprising this numerical value or numerical range and this numerical value or numerical range, such as this limit of error is ± 10%, ± 5%, ± 2%, ± 1%, ± 0.5% etc.

Accompanying drawing explanation

Fig. 1: the x-ray diffractogram of powder of Febustat crystallization prepared by the embodiment of the present invention, in figure, X-coordinate is 2 θ, to spend (°) for unit, ordinate zou is the intensity (cps) at peak, what in figure, each peak indicated is its 2 θ angle, and such as 2 θ angles are the peak of 19.94 ° is highest peak (can be described as base peak).

Embodiment

Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible at this.

The Febustat bulk drug used when preparing crystal formation of the present invention can obtain with reference to art methods, such as, with reference to the method preparation described in WO92/90279.They measure through powder x-ray diffraction, all do not show be similar to characteristic diffraction peak of the present invention at about 6.64 °, about 7.18 °, about 9.42 °, about 12.54 °, about 12.81 °, about 16.39 °, about 19.12 ° and about 19.94 ° of places.

embodiment 1: preparation Febustat crystallization

Febustat raw material (hereafter also with a collection of) 10g is added in the mixing solutions of 100ml propyl carbinol and 40ml acetonitrile, be heated to reflux under stirring and make dissolving, under agitation to mixed solution and dripping glacial acetic acid (add-on is: make glacial acetic acid concentration in the solution reach the amount of 4% (v/v)), then about 5 DEG C (leaving standstill 6 hours) are slowly cooled to separate out precipitation, leach precipitation, wash with propyl carbinol, 40 DEG C of vacuum-dryings, obtain, yield 95.7%.

Content and impurity is measured respectively according to mensuration content method mentioned above and related substance detection method.

Content is 99.7% (HPLC), wherein total impurities 0.176%, maximum single contaminant 0.033%.

Measure powder x-ray diffraction, result is as Fig. 1.

Powder x-ray diffraction result shows, and in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, has diffraction peak at about 9.42 ° and about 12.54 ° of places; Especially, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, this crystallization has diffraction peak at about 9.42 °, about 12.54 °, about 19.12 ° and about 19.94 ° of places; Especially, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, this crystallization has diffraction peak at about 6.64 °, about 7.18 °, about 9.42 °, about 12.54 °, about 12.81 °, about 16.39 °, about 19.12 ° and about 19.94 ° of places; Especially, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, this crystallization has diffraction peak at about 6.64 °, about 7.18 °, about 9.42 °, about 12.54 °, about 12.81 °, about 16.39 °, about 19.12 °, about 19.60 °, about 19.94 °, about 20.86 °, about 21.25 °, about 23.82 °, about 25.30 °, about 25.88 °, about 26.71 ° places.

In addition, powder x-ray diffraction result also shows, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, there iing diffraction peak at about 6.64 °, about 7.18 °, about 9.42 °, about 12.54 °, about 12.81 °, about 16.39 °, about 19.12 ° and about 19.94 ° of places; In the relative intensity (I/Io value) of about 19.94 ° of place's diffraction peaks for 100, the I/Io value of about 12.81 ° of place's diffraction peaks is greater than 65, is preferably greater than 70, such as, between 70 ~ 120, such as, between 70 ~ 110, such as, between 70 ~ 100.

In Fig. 1, the I/Io value of about 12.81 ° of place's diffraction peaks is about 86.In addition, this embodiment 1 sample is measured diffractogram on other three different brands powder x-ray diffractions, the I/Io value of result about 12.81 ° place diffraction peak is in 79 ~ 91 scopes.

embodiment 2: preparation Febustat crystallization

Febustat raw material 10g is added in the mixing solutions of 100ml propyl carbinol and 35ml acetonitrile, be heated to reflux under stirring and make dissolving, under agitation to mixed solution and dripping glacial acetic acid (add-on is: make glacial acetic acid concentration in the solution reach the amount of 5% (v/v)), then about 5 DEG C (leaving standstill 8 hours) are slowly cooled to separate out precipitation, leach precipitation, with propyl carbinol washing, 40 DEG C of vacuum-dryings, obtain, yield 95.1%.

Content is 99.7% (HPLC), wherein total impurities 0.182%, maximum single contaminant 0.037%.

Measure powder x-ray diffraction, result is substantially consistent with Fig. 1, and specifically: basically identical with the 2 θ values at 15 peaks in Fig. 1, each peak differs all in the scope of ± 0.10 ° with 2 θ values of Fig. 1 respective peaks.

Altogether on four different brands powder x-ray diffractions, measure diffractogram, in the relative intensity (I/Io value) of about 19.94 ° of place's diffraction peaks for 100, the I/Io value of about 12.81 ° of place's diffraction peaks is between 71 ~ 83.

embodiment 3: preparation Febustat crystallization

Febustat raw material 14g is added in the mixing solutions of 100ml propyl carbinol and 45ml acetonitrile, be heated to reflux under stirring and make dissolving, under agitation to mixed solution and dripping glacial acetic acid (add-on is: make glacial acetic acid concentration in the solution reach the amount of 2% (v/v)), then about 5 DEG C (leaving standstill 5 hours) are slowly cooled to separate out precipitation, leach precipitation, with propyl carbinol washing, 40 DEG C of vacuum-dryings, obtain, yield 94.6%.

Content is 99.7% (HPLC), wherein total impurities 0.221%, maximum single contaminant 0.034%.

Altogether on four different brands powder x-ray diffractions, measure diffractogram, in the relative intensity (I/Io value) of about 19.94 ° of place's diffraction peaks for 100, the I/Io value of about 12.81 ° of place's diffraction peaks is between 89 ~ 98.

embodiment 4: preparation Febustat crystallization

Febustat raw material 6g is added in the mixing solutions of 100ml propyl carbinol and 40ml acetonitrile, be heated to reflux under stirring and make dissolving, under agitation to mixed solution and dripping glacial acetic acid (add-on is: make glacial acetic acid concentration in the solution reach the amount of 3% (v/v)), then about 5 DEG C (leaving standstill 7 hours) are slowly cooled to separate out precipitation, leach precipitation, with propyl carbinol washing, 40 DEG C of vacuum-dryings, obtain, yield 96.3%.

Content is 99.5% (HPLC), wherein total impurities 0.331%, maximum single contaminant 0.031%.

Altogether on four different brands powder x-ray diffractions, measure diffractogram, in the relative intensity (I/Io value) of about 19.94 ° of place's diffraction peaks for 100, the I/Io value of about 12.81 ° of place's diffraction peaks is between 97 ~ 108.

reference examples 1: preparation Febustat crystallization

The method of reference example 1, but do not use glacial acetic acid.Result at about 9.42 ° of places, about 12.54 ° of places, about 19.12 ° of places, about 19.94 ° of places all do not show as typical diffractive peak of the present invention.

reference examples 2: preparation Febustat crystallization

The method of reference example 1, but the add-on of glacial acetic acid is: make glacial acetic acid concentration in the solution reach the amount of 1% (v/v).Result at about 9.42 ° of places, about 12.54 ° of places, about 19.12 ° of places all do not show as typical diffractive peak of the present invention, in the relative intensity (I/Io value) of about 19.94 ° of place's diffraction peaks for 100, about 12.81 ° of I/Io values locating diffraction peaks reach 420.In supplementary test, the method for reference example 1, but the add-on of glacial acetic acid is: make glacial acetic acid concentration in the solution reach the amount of 10% (v/v) or 20%, result yield drops to less than less than 70% and 50% respectively.

reference examples 3: preparation Febustat crystallization

Method according to CN102020617A (CN201010562692.0-Supreme Being people) embodiment 1 is carried out, obtain A crystal formation, through the X-ray diffraction analysis display collection of illustrative plates identical with [0014] section with the Fig. 2 in CN102020617A and data, such as, at the salt free ligands peaks, place such as about 9.42 °, about 12.54 °, about 19.12 °.

Content is 99.6% (HPLC), wherein total impurities 0.263%, maximum single contaminant 0.027%.

reference examples 4: preparation Febustat crystallization

According to CN1970547A (CN200610095263.0, Chongqing medical professionals) method of embodiment 2 carries out, obtain I crystal, through the X-ray diffraction analysis display collection of illustrative plates identical with claim 3 with the Fig. 3 in CN1970547A and data, such as, at the salt free ligands peaks, place such as about 7.18 °, about 9.42 °, about 12.54 °, about 19.12 °.

Content is 99.4% (HPLC), wherein total impurities 0.334%, maximum single contaminant 0.023%.

reference examples 5: preparation Febustat crystallization

According to CN101684107A (CN200810200565.9, Shanghai is excellent opens up) method of embodiment 3 carries out, obtain Y crystal formation, through the X-ray diffraction analysis display collection of illustrative plates identical with claim 3 with the Fig. 2 in CN101684107A and data, such as, at the salt free ligands peaks, place such as about 7.18 °, about 9.42 °, about 12.54 °, about 19.94 °.

Content is 99.6% (HPLC), wherein total impurities 0.312%, maximum single contaminant 0.039%.

Provide the method that preparation comprises Febustat composition particularly tablet below in each composition example, fed batch amount is 10000/batches, with every sheet gauge when representing prescription.Followingly prepare in the example of tablet, if not otherwise indicated, tablet is all suppressed with the tabletting machine of same model.And various tablet is when suppressing, the hardness of tablet is all controlled in the scope of 5-6kgf (i.e. 49 ~ 59N), (use the tablet hardness tester of same model to measure tablet hardness).

composition example 1: preparation Febustat tablet

The Febustat crystallization using foregoing embodiments 1 to prepare is bulk drug.

Formula: Febustat 40mg, Spherolac 100 45mg, Microcrystalline Cellulose 45mg, hydroxypropylcellulose 20mg, croscarmellose sodium 10mg, silica 1 mg and Magnesium Stearate 1mg; 50% ethanol is used to prepare tablet with conventional wet lay method of granulating for wetting agent.

composition example 2: preparation Febustat tablet

The Febustat crystallization using foregoing embodiments 2 to prepare is bulk drug.

Formula: Febustat 40mg, Spherolac 100 60mg, Microcrystalline Cellulose 20mg, hydroxypropylcellulose 3mg, croscarmellose sodium 15mg, silicon-dioxide 2mg and Magnesium Stearate 0.5mg; Water is used to prepare tablet with conventional wet lay method of granulating for wetting agent.

composition example 3: preparation Febustat tablet

The Febustat crystallization using foregoing embodiments 3 to prepare is bulk drug.

Formula: Febustat 40mg, Spherolac 100 20mg, Microcrystalline Cellulose 60mg, hydroxypropylcellulose 30mg, croscarmellose sodium 2mg, silicon-dioxide 0.5mg and Magnesium Stearate 2mg; Conventional dry granulation method is used to prepare tablet.

composition example 4: preparation Febustat tablet

The Febustat crystallization using foregoing embodiments 1 to prepare is bulk drug.Formula: Febustat 40mg, Microcrystalline Cellulose 85mg, pregelatinized Starch 40mg, carboxymethylstach sodium 10mg, 4mg PVP K30, Magnesium Stearate 1mg; The aqueous solution of PVP preparation is used to prepare tablet with conventional wet lay method of granulating for tackiness agent.Use the Opadry II film coating purchased from the happy Kanggong department of card, covering is great accounts for 3% of tablet total weight.

composition example 5: preparation Febustat tablet

The Febustat crystallization using foregoing embodiments 2 to prepare is bulk drug.Formula: Febustat 40mg, Microcrystalline Cellulose 60mg, pregelatinized Starch 50mg, carboxymethylstach sodium 15mg, 2mg PVP K30, Magnesium Stearate 2mg; 50% ethanolic soln of PVP preparation is used to prepare tablet with conventional wet lay method of granulating for tackiness agent.Use the Opadry purchased from the happy Kanggong department of card 85G62756 film coating, covering is great accounts for 3% of tablet total weight.

composition example 6: preparation Febustat tablet

The Febustat crystallization using foregoing embodiments 3 to prepare is bulk drug.Formula: Microcrystalline Cellulose 120mg, pregelatinized Starch 30mg, carboxymethylstach sodium 5mg, 6mg PVP K30, Magnesium Stearate 0.5mg; Conventional dry granulation method is used to prepare tablet.

composition example 7: preparation Febustat tablet

The Febustat crystallization using foregoing embodiments 4 to prepare is bulk drug.Tablet is prepared according to the formula of composition example 1 above and method.

composition example 8: preparation Febustat tablet

The Febustat crystallization using reference examples 1 above to prepare is bulk drug.Tablet is prepared according to the formula of composition example 3 above and method.

composition example 9: preparation Febustat tablet

The Febustat crystallization using reference examples 2 above to prepare is bulk drug.Tablet is prepared according to the formula of composition example 3 above and method.

composition example 10: preparation Febustat tablet

The Febustat crystallization using reference examples 3 above to prepare is bulk drug.Tablet is prepared according to the formula of composition example 3 above and method.

composition example 11: preparation Febustat tablet

The Febustat crystallization using reference examples 4 above to prepare is bulk drug.Tablet is prepared according to the formula of composition example 3 above and method.

composition example 12: preparation Febustat tablet

The Febustat crystallization using reference examples 5 above to prepare is bulk drug.Tablet is prepared according to the formula of composition example 3 above and method.

Test the X-ray diffractogram of above composition example 1 to composition example 12 tablet, the diffracting spectrum that the crystal formation of their Febustat raw materials used with it respectively of result display is identical, show these different crystallizations, after experiencing different tablet making technology, do not show the change of crystal formation.

test example 1: stability test

By above each embodiment 1 ~ embodiment 4, the crystallization of reference examples 1 ~ reference examples 5 gained Febustat, above composition example 1 ~ composition example 12 gained tablet totally 21 samples, as sample, carries out study on the stability.

Above-mentioned each bulk drug or tablet are packed with aluminium foil bag respectively, be placed in 45 DEG C of thermostat containers and place May, measure content and its related substances (representing with maximum single contaminant and total impurities) of each sample activeconstituents when 0 month (namely before setting-out) and May.

For each sample, with May active component content divided by the percentage value of 0 month active component content gained, as the activeconstituents relative content (%) after high-temperature treatment May, namely calculating formula is as follows:

Activeconstituents relative content (%)=(content ÷ in May 0 month content) × 100%

In addition, for each sample, with the percentage value of the maximum single contaminant content in May divided by the maximum single contaminant content gained be somebody's turn to do when 0 month, as the relative content (%) of maximum single contaminant after high-temperature treatment May, namely calculating formula is as follows:

Maximum single contaminant relative content (%)=

(maximum single contaminant content ÷ in May 0 month maximum single contaminant content) × 100%

In addition, for each sample, with the percentage value of the total impurities content in May divided by total impurities content gained when 0 month, as the relative content (%) of total impurities after high-temperature treatment May, namely calculating formula is as follows:

Total impurities relative content (%)=(total impurities content ÷ in May 0 month total impurities content) × 100%

Have been surprisingly found that, Febustat crystallization of the present invention and prepared troche medical composition thereof have satisfactory stability, and the content of activeconstituents is little, and impurity change is also less, and after high-temperature treatment May, concrete outcome is as shown in table 1.

Table 1:

	Activeconstituents relative content	Maximum single contaminant relative content	Total impurities relative content
				Embodiment 1 crystallization	99.1％	132.5％	153.3％
Embodiment 2 crystallization	99.3％	126.4％	161.6％
				Embodiment 3 crystallization	99.5％	128.2％	158.5％
Embodiment 4 crystallization	99.2％	126.3％	154.8％
				Reference examples 1 crystallization	96.4％	183.4％	232.3％
Reference examples 2 crystallization	95.5％	203.6％	251.5％
				Reference examples 3 crystallization	97.2％	194.6％	244.8％
Reference examples 4 crystallization	97.7％	205.6％	264.2％
				Reference examples 5 crystallization	96.8％	189.9％	257.8％
Composition example 1	98.5％	153.3％	197.6％
				Composition example 2	98.3％	148.6％	179.2％
Composition example 3	98.5％	149.4％	202.7％
				Composition example 4	98.6％	144.5％	183.5％
Composition example 5	98.4％	137.8％	179.8％

Composition example 6	99.1％	151.2％	189.4％
				Composition example 7	98.3％	140.2％	181.2％
Composition example 8	89.3％	253.5％	293.4％
				Composition example 9	91.2％	241.2％	311.3％
Composition example 10	93.4％	188.4％	273.5％
				Composition example 11	94.3％	198.5％	331.5％
Composition example 12	92.7％	213.7％	306.8％

Result from table, crystallization of the present invention all have under bulk drug or formulated state than the better chemical stability of the result prepared in prior art.

test example 2: the measuring method of Dissolution of Tablet

The tablet (all getting the plain sheet of non-dressing) getting each composition example preparation above measures dissolution rate, according to dissolution method (Pharmacopoeia of People's Republic of China version in 2010 two annex XC second methods), 0.25% sodium dodecyl sulfate solution 900ml is dissolution medium, and rotating speed is per minute 50 turns, operates in accordance with the law, through 45 minutes time, get solution appropriate, filter, it is appropriate that precision measures subsequent filtrate, quantitatively dilute with dissolution medium, measure by HPLC method.Result shows, the dissolution rate of each tablet of composition example 1 ~ composition example 12 all reaches the scope of 87 ~ 95%, and the dissolution rate of tablet 45 minutes time of such as composition example 1 is 91.2%.Wherein, the stripping quantity of Febustat adopts document (foundation of Febustat sheet determination of related substances method, Chinese Journal of New Drugs, the 22nd phase in the 2011) method of Zhang Xiaoyan etc. to measure.Visible, various tablet all shows and has good dissolution rate.

The each tablet of above-mentioned composition example 1 ~ composition example 12 is packed with aluminium foil bag respectively, is placed in 45 DEG C of thermostat containers and places May, measure each sample dissolution rate of (after high-temperature treatment) when 0 month (namely before high-temperature treatment) and May.For same tablet, calculate it through the forward and backward dissolution rate percent change (%) of high-temperature treatment with following formula:

Dissolution rate percent change=[(0 month dissolution rate-May dissolution rate) ÷ 0 month dissolution rate] × 100%

This dissolution rate percent change (%) is more better with the tablet stability of dissolution rate sign close to 0%.

Result shows, the dissolution rate percent change of composition example 1 ~ composition example 7 tablet is all in-4% to 5% scope, such as the dissolution rate percent change of composition example 3 tablet is 2.2%, shows that the tablet stability that these tablets characterize with dissolution rate in the process kept sample for a long time through simulation preparation is satisfactory; But surprisingly, the dissolution rate percent change of composition example 8 ~ composition example 12 tablet is all in 24% to 35% scope, such as the dissolution rate percent change of composition example 8 tablet is 31.2%, shows that the tablet stability that these tablets characterize with dissolution rate in the process kept sample for a long time through simulation preparation can not make us accepting.

test example 3: the crystalline stability of Febustat crystallization of the present invention and pharmaceutical composition thereof

Measure the crystallization of the present invention's above embodiment 1 ~ embodiment 4 gained Febustat, and the powder x-ray diffraction figure (as 0 month collection of illustrative plates) of above composition example 1 ~ composition example 7 gained tablet each sample.Then make these samples pack with aluminium foil bag respectively, be placed in 45 DEG C of thermostat containers and place May, measure each sample powder x-ray diffraction figure (as collection of illustrative plates in May) of (after high-temperature treatment) when May.For same sample, compare it through the forward and backward powder x-ray diffraction figure of high-temperature treatment.

Result shows, and these samples all have identical powder x-ray diffraction collection of illustrative plates in the forward and backward display of high-temperature treatment, particularly, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, about 9.42 ° and about 12.54 ° ± there is diffraction peak at 0.10 ° of place; Especially, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, this crystallization about 9.42 °, about 12.54 °, about 19.12 ° and about 19.94 ° ± there is diffraction peak at 0.10 ° of place; Especially, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, this crystallization about 6.64 °, about 7.18 °, about 9.42 °, about 12.54 °, about 12.81 °, about 16.39 °, about 19.12 ° and about 19.94 ° ± there is diffraction peak at 0.10 ° of place; Especially, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, this crystallization about 6.64 °, about 7.18 °, about 9.42 °, about 12.54 °, about 12.81 °, about 16.39 °, about 19.12 °, about 19.60 °, about 19.94 °, about 20.86 °, about 21.25 °, about 23.82 °, about 25.30 °, about 25.88 °, about 26.71 ° ± there is diffraction peak at 0.10 ° of place.

In addition, powder x-ray diffraction result also shows, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, these 0 month and May collection of illustrative plates all about 6.64 °, about 7.18 °, about 9.42 °, about 12.54 °, about 12.81 °, about 16.39 °, about 19.12 ° and about 19.94 ° ± there is diffraction peak at 0.10 ° of place; In the relative intensity (I/Io value) of about 19.94 ° of place's diffraction peaks for 100, the I/Io value of about 12.81 ° of place's diffraction peaks is all between 72 ~ 108.

Above disclosedly be only preferred embodiment of the present invention, certainly can not limit interest field of the present invention with this, therefore according to the equivalent variations that the present patent application the scope of the claims is done, still belong to the scope that the present invention is contained.

Claims

1. the crystallization of the compound of Febustat shown in following formula:

，

It uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 6.64 °, 7.18 °, 9.42 °, 12.54 °, 12.81 °, 16.39 °, 19.12 °, 19.60 °, 19.94 °, 20.86 °, 21.25 °, 23.82 °, 25.30 °, 25.88 °, 26.71 ° each angle places ± scope of 0.10 ° has diffraction peak.

2. crystallization according to claim 1, it uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 6.64 °, 7.18 °, 9.42 °, 12.54 °, 12.81 °, 16.39 °, 19.12 °, 19.60 °, 19.94 °, 20.86 °, 21.25 °, 23.82 °, 25.30 °, 25.88 °, 26.71 ° each angle places ± scope of 0.05 ° has diffraction peak.

3. crystallization according to claim 1, it uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, has diffraction peak at 19.94 ° of places, and the I/Io value of this diffraction peak is in 100,2 θ are greater than 65 in the I/Io value of the diffraction peak at 12.81 ° of places.

4. crystallization according to claim 1, it uses Cu-K α radiation, has powder x-ray diffraction collection of illustrative plates as shown in Figure 1.

5. prepare the method for any one of claim 1-4 crystallization, it comprises the steps: Febustat to add in the mixing solutions of propyl carbinol and acetonitrile, be heated to reflux under stirring and make dissolving, under agitation to mixed solution and dripping glacial acetic acid, then be slowly cooled to 5 ° of C to separate out precipitation, leach precipitation, wash with propyl carbinol, 40 ° of C vacuum-dryings, to obtain final product; The dripping quantity of described glacial acetic acid is: make its concentration expressed in percentage by volume in the solution reach the amount of 2 ~ 5%.

6. method according to claim 5, wherein after being slowly cooled to 5 ° of C, leaves standstill 5-8 hour at this temperature.

7. a pharmaceutical composition, wherein comprises crystallization and the pharmaceutically acceptable carrier of any one of claim 1-4.

8. pharmaceutical composition according to claim 7, it is tablet, wherein comprises Febustat crystallization, and Spherolac 100, Microcrystalline Cellulose, hydroxy propyl cellulose, croscarmellose sodium, silicon-dioxide and Magnesium Stearate.

9. pharmaceutical composition according to claim 8, wherein comprise Febustat crystallization 40 weight part, and Spherolac 100 20 ~ 60 weight part, Microcrystalline Cellulose 20 ~ 60 weight part, hydroxypropylcellulose 3-30 weight part, croscarmellose sodium 2-15 weight part, silicon-dioxide 0.5-2 weight part and Magnesium Stearate 0.5-2 weight part.

10. pharmaceutical composition according to claim 7, it is tablet, wherein comprises Febustat crystallization, and Microcrystalline Cellulose, pregelatinized Starch, carboxymethylstach sodium, PVP K30, Magnesium Stearate.

11. pharmaceutical compositions according to claim 10, wherein comprise Febustat crystallization 40 weight part, and Microcrystalline Cellulose 60 ~ 120 weight part, pregelatinized Starch 30 ~ 50 weight part, carboxymethylstach sodium 5 ~ 15 weight part, the PVP K30 of 2 ~ 6 weight parts, Magnesium Stearate 0.5 ~ 2 weight part.

The purposes of crystallization in the medicine for the preparation of gout and complication thereof described in 12. any one of claim 1-4.

13. purposes according to claim 12, wherein said complication is hyperuricemia.