CN103588724B - Febuxostat crystal form A and preparation method thereof - Google Patents
Febuxostat crystal form A and preparation method thereof Download PDFInfo
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- CN103588724B CN103588724B CN201310409096.2A CN201310409096A CN103588724B CN 103588724 B CN103588724 B CN 103588724B CN 201310409096 A CN201310409096 A CN 201310409096A CN 103588724 B CN103588724 B CN 103588724B
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- 239000013078 crystal Substances 0.000 title claims abstract description 120
- 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 50
- 229960005101 febuxostat Drugs 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 58
- 239000002904 solvent Substances 0.000 claims abstract description 23
- 238000009826 distribution Methods 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims description 40
- 238000003756 stirring Methods 0.000 claims description 24
- 238000001816 cooling Methods 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 20
- 230000011218 segmentation Effects 0.000 claims description 19
- 229960004756 ethanol Drugs 0.000 claims description 16
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 13
- 238000002425 crystallisation Methods 0.000 abstract description 12
- 230000008025 crystallization Effects 0.000 abstract description 12
- 238000004090 dissolution Methods 0.000 abstract description 7
- 238000005516 engineering process Methods 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 4
- 239000007864 aqueous solution Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 238000011084 recovery Methods 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 2
- 238000010276 construction Methods 0.000 abstract 1
- 239000000843 powder Substances 0.000 description 24
- 239000002245 particle Substances 0.000 description 23
- 239000007787 solid Substances 0.000 description 22
- 238000000634 powder X-ray diffraction Methods 0.000 description 19
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000005755 formation reaction Methods 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 12
- 238000000967 suction filtration Methods 0.000 description 9
- 238000002411 thermogravimetry Methods 0.000 description 9
- 238000007605 air drying Methods 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000010298 pulverizing process Methods 0.000 description 4
- 239000012267 brine Substances 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- FPVGTPBMTFTMRT-NSKUCRDLSA-L fast yellow Chemical compound [Na+].[Na+].C1=C(S([O-])(=O)=O)C(N)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 FPVGTPBMTFTMRT-NSKUCRDLSA-L 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- 229940124186 Dehydrogenase inhibitor Drugs 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-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
- 238000002441 X-ray diffraction Methods 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 238000002288 cocrystallisation Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 229940045136 urea Drugs 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention belongs to the field of chemical crystallization technologies for drugs and particularly relates to a novel single febuxostat crystal form A and a preparation method thereof. According to the crystal form A provided by the invention, the grain size D50 is 16-25 microns, the grain size distribution curve of the crystal form A is of normal unimodal distribution, a preparation of the crystal form A has good dissolubility and a zero-deflection dissolution curve, and the bioavailability is high. The invention further provides the preparation method which can be used for preparing the single febuxostat crystal form A, and the yield reaches up over 86%; meanwhile, the preparation process is stable, the crystallization conditions are mild, and the volume of a consumed solvent is small, so that during industrial large-scale production, the production cost is reduced greatly, and the recovery and mechanical applying of the solvent are facilitated; the solvent is an aqueous solution containing ethanol and is non-toxic and harmless, so that the construction of an environmental-friendly and safe production environment is facilitated, and the preparation method is very suitable for industrial large-scale production.
Description
Technical field
The invention belongs to pharmaceutical chemistry crystallization technique field, be specifically related to a kind of single Febuxostat crystal form A and preparation method thereof.
Technical background
Febustat, is gone on the market through FDA approval in the U.S. in February, 2009 in April, 2004 in European Union's approval listing.
Febustat is the yellow fast cry of certain animals oxydase/yellow fast cry of certain animals dehydrogenase inhibitor of a kind of non-fast cry of certain animals class selectivity, can suppress the oxidasic oxidized and reduced of yellow fast cry of certain animals, be used for the treatment of relevant disease too high with uric acid.Febustat, mainly through liver metabolism, can be avoided HPPIsopurind because of renal metabolism preferably and drain the untoward reaction caused.
The chemical name of Febustat is Febuxostat, has chemical structural formula as follows:
Chinese invention patent CN1642546A describes the solid preparation containing single Febuxostat crystal form A invented by Japanese Di Ren company, provide stable and that stripping curve deviation is little solid preparation, the median size of its single crystal form preferably more than 3 μm less than 50 μm.When median size is less than 3 μm, easily disperse during weighing, in the shortcoming weighed and should be noted that when feeding intake.
When particle diameter is greater than 50 μm, stripping curve when making solid preparation can produce deviation.But it meets median size be more than 3 μm less than 50 μm is beat powder by the pulverizer of different model just can meet the demands, table 1 specific as follows, preparation process relative complex.
Table 1:
Chinese invention patent CN1275126 describe invented by Japanese Di Ren company relate to Febuxostat crystal form A, B, C, D, G and unformed six kinds of crystal formations and preparation method thereof, bibliographical information crystal form A is relatively stable, and the stripping of tablet is better.The solvent that the method adopts is first alcohol and water, patent phasor known (the I district as Fig. 7) can obtain crystal form A, the forming of mixed solvent that these processing condition are formed by temperature and first alcohol and water is determined, and need to add a certain amount of crystal form A carrys out induced crystal precipitation as crystal seed, control very harsh to crystallization condition, can be very narrow and small between operational zone, very easily form Methanol Solvate, hydrate or stable crystal C, the circulation ratio obtaining single anhydrous crystal forms A is low, and do not mention the yield and purity of preparing crystal form A in this patent, be difficult to realize industrialized production, crystal formation D refines with ethanol, but crystal formation is unstable.
Chinese invention patent CN102267957A discloses the method preparing Febuxostat crystal form A, embodiment 2 utilizes the ethanol of 95%, and dissolving is placed on 25-40 DEG C and leaves standstill, when starting have crystal to separate out, stir 20-40 minute, then be placed in-15-0 DEG C and continue crystallization 8-10 hour, crystallization need in sub-zero zero, if industrialized production, cause production cost high, unfavorable industrialized production, this process recovery ratio is 94.6%, and purity is 99.96%.
Chinese invention patent CN101139325 discloses the method preparing crystal form II, first under alkaline heating condition, dissolves Febustat with ethanol, and then use hydrochloric acid conditioning solution pH value to neutral, stirring and crystallizing, this technique is more complicated, and yield is 80%.Also disclose and utilize ethanol heating for dissolving Febustat, then frozen water is cooled to 5 DEG C of stirrings 2 minutes, filters and obtains crystal D, and this technique is comparatively simple, but yield is 70%.
Chinese invention patent CN101525319 discloses a kind of oblique system, and (its spacer is P2 (1), unit cell parameters is: a=4.7179 (9), b=17.813 (4), c=10.690 (2), utilizes ethanol-water system to prepare, and concentration is 50 ~ 100%, the envelope-bulk to weight ratio of Febustat and aqueous ethanolic solution is 1:20 ~ 80, cooling, natural crystallization, obtains Febustat and ethanol association body with the peculiar monocrystalline of 1:1 form.
Chinese invention patent CN101805310A discloses δ-crystal formation and obtains the method for ethylate (δ-crystal formation) with anhydrous ethanol preparation.
CN101805310(δ-crystal formation), CN101926795A, CN101926794, WO2012020272A2 all disclose ethanol as solvent or aqueous ethanol makes solvent preparation, but its crystal formation is alcohol solvent compound;
World patent WO2011139886A2 discloses the mixed solvent adopting alcohols, and that it obtains is not anhydrous crystal forms A; World patent WO2012140632A1 reports a kind of method adopting spray-drying process to prepare amorphous solid dispersion agent, and Febustat and polymer carrier are dissolved in alcohols equal solvent by it, by spray-drying process by obtained after solvent removing; World patent WO2012098501A1 discloses and adopts ethanol or acetone etc. to be solvent, adopts decrease temperature crystalline mode to prepare the cocrystallization thing of Febustat and urea, niacinamide or caffeine.
At present, the bibliographical information preparing this single crystal form of Febuxostat crystal form A is less, and mostly disclosed preparation technology is containing other crystal formations of Febustat as crystal form B, and preparation technology is unstable, and yield is low, and condition is harsh, is difficult to realize suitability for industrialized production.
At present, the Febuxostat crystal form of report is a lot, and wherein crystal form A is relatively stable, and the dissolution rate of tablet is better.Therefore, this area need to develop a kind ofly obtain single Febuxostat crystal form A, its size distribution curve is normal state unimodal distribution, process stabilizing, crystallization condition gentle, cost is low, the preparation method that is very suitable for the Febuxostat crystal form A of the large production of industrialization.
Code interpreter:
D
50: particle diameter corresponding when the cumulative particle sizes percentile of a sample reaches 50%.Its physical significance is that the particle that particle diameter is greater than it accounts for 50%, and the particle being less than it also accounts for 50%, D
50also meso-position radius or median particle diameter is.D
50be commonly used to the mean particle size representing powder.
Summary of the invention
Object of the present invention is exactly to overcome the deficiencies in the prior art, provides the Febuxostat crystal form A being beneficial to preparation.
The invention discloses a kind of single Febuxostat crystal form A, its D
50be 16 ~ 25 μm, and size distribution curve is normal state unimodal distribution.Single described in the application, refers to only containing a kind of crystal formation, instead of the mixed crystal of two or more crystal formation or without mixture that is fixed and crystal formation.
Reflection angle 2 θ of the X-ray powder diffraction of described single Febuxostat crystal form A is disclosed consistent with prior art: have charateristic avsorption band being about 6.62,7.18,12.80,13.26,16.48,19.58,21.92,22.68,25.84,26.70,29.16,36.70 ± 0.02 ° of places.Its X-ray powder diffraction pattern is shown in Fig. 1.
Present invention also offers a kind of method preparing single Febuxostat crystal form A, comprise the steps:
1. Febustat heated and stirred is dissolved in the solvent containing ethanol;
2. add crystal seed, equal time segmentation is lowered the temperature;
3. be separated, wash, dry.
Wherein, step 1. described in be dehydrated alcohol, dehydrated alcohol and water mixed solvent containing the solvent of ethanol, preferred dehydrated alcohol and water mixed solvent.Wherein, dehydrated alcohol and water volume ratio are 15:1 ~ 1:1, preferred 12:1 ~ 5:1, more preferably 9:1 ~ 7:1.
Wherein, step 1. described in Febustat and dehydrated alcohol weightmeasurement ratio be 30 ~ 150:1(mg/ml), preferably 100 ~ 130:1(mg/ml), more preferably 110 ~ 125:1(mg/ml).
Wherein, step 2. in add crystal seed, be Febuxostat crystal form A, granularity D
50be 3 ~ 15 μm, preferably 5 ~ 10 μm; By weight, add that crystal seed amount accounts for Febustat charging capacity 0.3 ~ 2.0%, preferably 0.5 ~ 1.5%, more preferably 0.5 ~ 1.0%.
Wherein, step 2. described equal time segmentation cooling refers to after the dissolving of Febustat sample heated and stirred, keep stirring 10min under solvent temperature, be then cooled to 62 DEG C, temperature fall time overall length used at the end of from 62 DEG C to crystallization is 0.5 ~ 3 hour, preferably 1.0 ~ 2.5 hours, more preferably 1.5 ~ 2 hours, above-mentioned temperature fall time was divided into 3 sections, and such as temperature fall time is 1 hour, be divided into 3 sections, every section is 20 minutes.
Wherein, step 2. in temperature final (at the end of crystallization) be down to 10 ~ 40 DEG C, preferably 20 ~ 35 DEG C, more preferably 25 ~ 30 DEG C.
This wherein, step 2. described equal time segmentation cooling adopts conventional cooling method cooling, constant-temperature circulating device cooling, cool brine Controlling System circulation temperature lowering etc.This wherein, constant-temperature circulating device utilizes to be realized cooling by the refrigerator of microcomputerized control and well heater, heated up and constant temperature, time variable control constant-temperature circulating device JULABO Presto LH50 can be selected, time variable control constant-temperature circulating device PCC-7000S(EYELA), NCB-3300 cold cycle tank (EYELA), consider cooling-down effect, automatic control level, preferred time variable control constant-temperature circulating device JULABO Presto LH50 in the present invention; Cool brine Controlling System selects sky, Nanjing to add heavy industry refrigerating apparatus company limited, model TES370.1J.
Wherein, step 2. described equal time segmentation rate of temperature fall is 7.2 ~ 60 DEG C/h, it is 7.2 ~ 24 DEG C/h at first paragraph rate of temperature fall, second segment rate of temperature fall is 9.6 ~ 48 DEG C/h, final stage rate of temperature fall is 15.6 ~ 60 DEG C/h, and its rate of temperature fall is in first slow rear fast non-linear cooling.
Wherein, step controls stirring velocity when 2. prepared by described segmentation cooling is 300 ~ 900 turns/min.
After preparation process of the present invention completes, by the crystal of precipitation and solution separating.Described separation can adopt the separation method of any routine known in the art, such as filtration or centrifugal.Then by being separated the solids wash obtained, solvent for use ethanol and water mixed solvent in described method, is washed, dry afterwards, preferred vacuum-drying or forced air drying, drying temperature is 60 ~ 120 DEG C, preferred 90-100 DEG C, can obtain single Febustat anhydrous crystal forms A.
Febustat raw material, no matter be which kind of crystal habit or amorphous, all can obtain single Febuxostat crystal form A by above-mentioned preparation process.
Wherein, the Febustat sample that 1. step is mentioned in described Febustat or the embodiment of the present invention, the method that to refer to disclosed in document WO2010142653A1 prepares or market is bought and obtained.
Wherein, the 2. described crystal seed of step is not adding according to the present invention the single Febuxostat crystal form A obtained under crystal seed condition, adopts BFM-6A prototype version Baily pulverizing mill (Jinan Billionpowder Tech& Eng Co., Ltd) to play powder acquisition.
Adopt preparation method of the present invention, under described solvent system and operating procedure, can operate by Simplified flowsheet, obtain crystal form A granularity D
50be the single Febuxostat crystal form A within the scope of the specified particle size of 16 ~ 25 μm.
Single Febuxostat crystal form A prepared by the present invention is stable in conditions of the present invention, and the mutual conversion between crystal formation can not occur.
Febustat anhydrous crystal forms A prepared by the present invention can adopt the crystal formation detection method of this area routine to detect, such as, adopt the methods such as X-ray powder diffraction, thermogravimetric analysis (TGA analysis), differential scanning calorimetric analysis (dsc analysis) to detect.
Described " single Febuxostat crystal form A " refers to through X-ray powder diffraction, TGA analyzes and dsc analysis detection is single Febuxostat crystal form A.
Compared with prior art, the useful technique effect that brings of the present invention is as follows:
For insoluble drug Febustat, single Febuxostat crystal form A, its D provided by the invention
50be 16 ~ 25 μm, and size distribution curve is normal state unimodal distribution, dissolution rate is good, and the preparation prepared with original formulation and technology solubility rate in 15 minutes all reaches more than 85%, contributes to the raising of its preparation bioavailability.
Single crystal form A provided by the invention, particle diameter is less, carries out pulverizing and beats powder, thus simplify technique, improve efficiency, saved cost without the need to finishing operations to raw material.
The present invention is to provide single Febuxostat crystal form A, and non-hydrate, solvate, crystal form B, crystal C or mixing crystal formation.For hydrate, the effective ingredient content of anhydrous crystal forms is higher; For mixing crystal formation, single crystal form is more conducive to the control of quality product and the foundation of quality standard.
Stable preparation process of the present invention, circulation ratio is high, and crystal formation prepared by revision test is single Febuxostat crystal form A.In preparation process, Febustat and ethanol weightmeasurement ratio are 30 ~ 150:1(mg/ml), preferably 100 ~ 130:1(mg/ml), more preferably 110 ~ 125:1(mg/ml), solvent amount used is few, in industrialized production, greatly reduce production cost, be conducive to solvent recuperation and apply mechanically, and solvent of the present invention is the aqueous solution containing ethanol, have nontoxic, be conducive to building green safety production environment.
Present invention process adopts low temperature crystallization, reaction conditions is gentle, without the need to temperature of reaction being increased to close to solvent boiling point temperature, without the need to reacting the long period under the high temperature conditions, shorten reaction time, reduce energy consumption, improve production capacity, be more conducive to industrialized production, and gained stable crystal form, purity is higher, can prolonged storage.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction that the present invention prepares single Febuxostat crystal form A.
Fig. 2 is thermogravimetric analysis (TGA) collection of illustrative plates that the present invention prepares single Febuxostat crystal form A.
Fig. 3 is dsc (DSC) spectrogram that the present invention prepares single Febuxostat crystal form A.
Fig. 4 is the X-ray powder diffraction that the present invention prepares that single Febuxostat crystal form A adopts delayed sweep.
Fig. 5 is the particle size distribution figure (PSD) that the present invention prepares single Febuxostat crystal form A.
Fig. 6 is the Dissolution of Tablet curve that the present invention prepares the different median sizes of single Febuxostat crystal form A.
Use Cu-K α radiation, the experimental error of X-ray powder diffraction pattern depends on the preparation of the condition of instrument, sample and the purity of sample.Particularly, as well known to those skilled in the art, X-ray diffractogram can change along with the condition of instrument usually to some extent.Special needs to be pointed out is, the relative intensity of X-ray diffractogram also may change along with the change of experiment condition, so the order of peak intensity can not as unique or deciding factor.In addition, the experimental error of peak angle is usually 5% or less, and the error of these angles also should be considered into, and usual reflection angle 2 θ allows ± error of 0.02 °.In addition, due to the impact of the empirical factors such as height of specimen, the overall offset of peak angle can be caused, usually allow certain skew.Thus, it will be understood by those skilled in the art that, the single crystal form x-ray diffraction pattern that the different preparation method of the present invention obtains need not be identical with spectrogram shown in Fig. 1, as long as its reflection angle 2 θ allow ± limit of error of 0.02 ° in, be consistent X-ray powder diffraction.Any have crystal formation that is identical with the characteristic peak in these collection of illustrative plates or characteristic peak in limit of error and all belong within category of the present invention.
Fig. 7 is the crystallization condition figure of polymorphs body disclosed in Chinese invention patent CN1275126 in methanol/water solvent.
Embodiment
Below by some embodiments, some explanations are done to the present invention.Should understand these embodiments only for the object of illustration, not limit the scope of the invention, meanwhile, the apparent change that those skilled in the art make the present invention and modification are also contained within the scope of the invention.
Below in conjunction with embodiment, the present invention is further elaborated, but these embodiments do not form any restriction to the present invention.
The instrument that X-ray powder diffraction detection (X-PRD) spectrogram uses is Bruker D8Advance.Testing process is: employing Cu target wavelength is the Ka X-ray of 1.54nm, 3-40 ° of 2 θ, step-length: 0.02 ° of 2 θ, speed: 0.2s. walks-1, or is 4-14 ° of 2 θ, step-length: 0.02 ° of 2 θ, speed: 1s. walks-1, is usually placed on no reflection events plate by sample during detection.
The instrument that differential scanning calorimetric analysis (dsc analysis) uses is TA-Q200DSC.Differential scanning calorimetric analysis data acquisition is certainly in TA Instruments Q200MDSC.Testing process is: be usually positioned in aluminium crucible by the sample of 1 ~ 10mg; 170 DEG C of balances; under the protection of the dry N2 of 30 ~ 50mL/min, sample is risen to 220 DEG C from room temperature with the heat-up rate of 2 DEG C/min again, record the thermal change of sample in temperature-rise period simultaneously.
The instrument that thermogravimetric analysis (TGA analysis) uses is TA-Q500-1503-TGA.Thermogravimetric analysis data picks up from TAInstruments Q500TGA His-Res.Testing process is: be usually positioned in platinum crucible by the sample of 5 ~ 15mg; after 30 DEG C of balances, under the protection of the dry N2 of 30 ~ 50mL/min, sample is risen to 250 DEG C from room temperature with the heat-up rate of 10 DEG C/min, record the changes in weight of sample in temperature-rise period simultaneously.
The instrument that particle size analyzer (PSD analysis) uses is 7Microtrac FLEX S3500 laser particle size instrument.Detect parameters: dispersion agent is water; Dispersion agent flow velocity 55%, sample specific refractory power: 1.58, dispersion agent specific refractory power: 1.33, integral way: volume, laser source wavelength: 780nm (nanometer).
In following examples 1 or 2, equal time segmentation cooling employing equipment is: time variable control constant-temperature circulating device JULABO Presto LH50.Working temperature-50 ~ 250 degrees Celsius, maximum pump pressure 2.2bar, flow velocity 16 ~ 30L/min, flow volume 13.5L, liquid storage volume 4.9L.
In embodiment 3 ~ 9, equal time segmentation cooling employing equipment is: sky, Nanjing adds the cool brine Controlling System of heavy industry refrigerating apparatus company limited, model TES370.1J.
Embodiment 1
To in the there-necked flask that 3g sample is housed, add 100ml dehydrated alcohol and 6.67ml purified water, stir, stir speed (S.S.) is 600r/min, and be heated to 70 DEG C, system is clearly molten, in pistac, keep 10min at this temperature, be then cooled to 62 DEG C, add the crystal seed that 0.009g median is 3 μm.Adopt equal time segmentation cooling method temperature in 0.5 hour to be down to 40 DEG C by 62 DEG C afterwards, first in 10 minutes, temperature is down to 58 DEG C by 62 DEG C, and secondly in 10 minutes, temperature is down to 50 DEG C by 58 DEG C, and finally in 10 minutes, temperature is down to 40 DEG C by 50 DEG C, suction filtration.Wet sample weighs to obtain white powder solid for more than 6 hours 60 DEG C of vacuum-dryings, yield 86.2%.The X-ray powder diffraction of this white powder solid being checked is shown in Fig. 1, and be single Febuxostat crystal form A, its particle size distribution figure is shown in Fig. 5, its D
50be 24.4 μm, Fig. 2 is shown in by its TGA collection of illustrative plates, and Fig. 3 is shown in by its DSC collection of illustrative plates, and the X-ray powder diffraction of its delayed sweep is shown in Fig. 4.
Embodiment 2
To in the jacketed reaction bottle that 30g sample is housed, add 333.3mL dehydrated alcohol and 27.8ml purified water, stir, stir speed (S.S.) is 400r/min, be heated to 70 DEG C, system is clearly molten, keep 10min at this temperature, then be cooled to 62 DEG C, add the crystal seed that 0.15g median is 5 μm, adopt equal time segmentation cooling method temperature in 1 hour to be down to 15 DEG C by 62 DEG C afterwards, first in 20 minutes, temperature is down to 52 DEG C by 62 DEG C, secondly in 20 minutes, temperature is down to 37 DEG C by 52 DEG C, and finally in 20 minutes, temperature is down to 15 DEG C by 37 DEG C, suction filtration.Wet sample weighs to obtain white powder solid for more than 6 hours 60 DEG C of forced air dryings, yield 86.8%.The X-ray powder diffraction of this white powder solid being checked is consistent with Fig. 1, and be single Febuxostat crystal form A, its particle size distribution figure is similar to Fig. 5, its D
50be 21.6 μm, consistent with embodiment 1 of other spectrograms.
Embodiment 3
To in the jacketed reaction bottle that 10kg sample is housed, add 80L dehydrated alcohol and 11.4L purified water, stir, stir speed (S.S.) is 900r/min, be heated to 75 DEG C, system is clearly molten, keep 10min at this temperature, be cooled to 62 DEG C, add the crystal seed that 0.1kg median is 10.0 μm, adopt equal time segmentation cooling method temperature in 1.5 hours to be down to 30 DEG C by 62 DEG C afterwards, first in 30 minutes, temperature is down to 54 DEG C by 62 DEG C, secondly in 30 minutes, temperature is down to 44 DEG C by 54 DEG C, and finally in 30 minutes, temperature is down to 30 DEG C by 44 DEG C, suction filtration.Wet sample weighs to obtain white powder solid for more than 6 hours 60 DEG C of vacuum-dryings, yield 86.2%.The X-ray powder diffraction of this white powder solid being checked is consistent with Fig. 1, and be single Febuxostat crystal form A, its particle size distribution figure is similar to Fig. 5, its D
50be 16.8 μm, consistent with embodiment 1 of other spectrograms.
Embodiment 4
To in the jacketed reaction bottle that 1.0kg sample is housed, add 10L dehydrated alcohol and 1.1L purified water, stir, stir speed (S.S.) is 600r/min, be heated to 70 DEG C, system is clearly molten, keep 10min at this temperature, then be cooled to 62 DEG C, add the crystal seed that 0.1kg median is 7.5 μm, adopt equal time segmentation cooling method temperature in 1.5 hours to be down to 20 DEG C by 62 DEG C afterwards, first in 30 minutes, temperature is down to 52 DEG C by 62 DEG C, secondly in 30 minutes, temperature is down to 38 DEG C by 52 DEG C, and finally in 30 minutes, temperature is down to 20 DEG C by 38 DEG C, suction filtration.Wet sample weighs to obtain white powder solid for more than 6 hours 60 DEG C of forced air dryings, yield 87.0%.The X-ray powder diffraction of this white powder solid being checked is consistent with Fig. 1, and be single Febuxostat crystal form A, its particle size distribution figure is similar to Fig. 5, its D
50be 20.0 μm, consistent with embodiment 1 of other spectrograms.
Embodiment 5
To in the jacketed reaction bottle that 10kg sample is housed, add 90.9L dehydrated alcohol and 11.4L purified water, stir, stir speed (S.S.) is 500r/min, be heated to 70 DEG C, system is clearly molten, keep 10min at this temperature, the crystal seed that 0.15kg median is 10 μm is added when being cooled to 62 DEG C, adopt equal time segmentation cooling method temperature in 2 hours to be down to 25 DEG C by 62 DEG C afterwards, first in 40 minutes, temperature is down to 54 DEG C by 62 DEG C, and secondly in 40 minutes, temperature is down to 42 DEG C by 54 DEG C, finally in 40 minutes, temperature is down to 25 DEG C by 42 DEG C, suction filtration.Wet sample weighs to obtain white powder solid for more than 6 hours 75 DEG C of forced air dryings, yield 87.5%.The X-ray powder diffraction of this white powder solid being checked is consistent with Fig. 1, and be single Febuxostat crystal form A, its particle size distribution figure is similar to Fig. 5, its D
50be 16.4 μm, consistent with embodiment 1 of other spectrograms.
Embodiment 6
To in the jacketed reaction bottle that 10kg sample is housed, add 87.0L dehydrated alcohol, stir, stir speed (S.S.) is 700r/min, be heated to 70 DEG C, system is clearly molten, keep 10min at this temperature, the crystal seed that 0.1kg median is 10 μm is added when being cooled to 62 DEG C, adopt equal time segmentation cooling method temperature in 1.5 hours to be down to 30 DEG C by 62 DEG C afterwards, first in 30 minutes, temperature is down to 54 DEG C by 62 DEG C, and secondly in 30 minutes, temperature is down to 44 DEG C by 54 DEG C, in last 30 minutes, temperature is down to 30 DEG C by 42 DEG C, suction filtration.Wet sample weighs to obtain white powder solid for more than 6 hours 60 DEG C of forced air dryings, yield 86.3%.The X-ray powder diffraction of this white powder solid being checked is consistent with Fig. 1, and be single Febuxostat crystal form A, its particle size distribution figure is similar to Fig. 5, its D
50be 16.7 μm, consistent with embodiment 1 of other spectrograms.
Embodiment 7
To in the jacketed reaction bottle that 10kg sample is housed, add 83.3L Virahol and 10.4L purified water, stir, stir speed (S.S.) is 600r/min, be heated to 70 DEG C, system is clearly molten, keep 10min at this temperature, the crystal seed that 0.1kg median is 7.5 μm is added when being cooled to 62 DEG C, adopt equal time segmentation cooling method temperature in 2 hours to be down to 25 DEG C by 62 DEG C afterwards, first in 40 minutes, temperature is down to 52 DEG C by 62 DEG C, and secondly in 40 minutes, temperature is down to 40 DEG C by 52 DEG C, in last 40 minutes, temperature is down to 25 DEG C by 40 DEG C, suction filtration.Wet sample weighs to obtain white powder solid for more than 6 hours 90 DEG C of forced air dryings, yield 87.7%.The X-ray powder diffraction of this white powder solid being checked is consistent with Fig. 1, and be single Febuxostat crystal form A, its particle size distribution figure is similar to Fig. 5, its D
50be 16.0 μm, consistent with embodiment 1 of other spectrograms.
Embodiment 8
To in the jacketed reaction bottle that 10kg sample is housed, add 76.9L dehydrated alcohol and 15.4L purified water, stir, stir speed (S.S.) is 800r/min, be heated to 75 DEG C, system is clearly molten, keep 10min at this temperature, be cooled to 62 DEG C and add the crystal seed that 0.15kg median is 10 μm, adopt equal time segmentation cooling method temperature in 2.5 hours to be down to 35 DEG C by 62 DEG C afterwards, first in 50 minutes, temperature is down to 56 DEG C by 62 DEG C, and secondly in 50 minutes, temperature is down to 48 DEG C by 56 DEG C, in last 50 minutes, temperature is down to 35 DEG C by 48 DEG C, suction filtration.Wet sample weighs to obtain white powder solid for more than 6 hours 100 DEG C of forced air dryings, yield 87.4%.The X-ray powder diffraction of this white powder solid being checked is consistent with Fig. 1, and be single Febuxostat crystal form A, its particle size distribution figure is similar to Fig. 5, its D
50be 22.3 μm, consistent with embodiment 1 of other spectrograms.
Embodiment 9
To in the jacketed reaction bottle that 10kg sample is housed, add 66.7L dehydrated alcohol and 66.7L purified water, stir, stir speed (S.S.) is 300r/min, be heated to 75 DEG C, system is clearly molten, keep 10min at this temperature, be cooled to 62 DEG C and add the crystal seed that 0.2kg median is 15 μm, adopt equal time segmentation cooling method temperature in 3 hours to be down to 10 DEG C by 62 DEG C afterwards, first in 60 minutes, temperature is down to 52 DEG C by 62 DEG C, and secondly in 60 minutes, temperature is down to 35 DEG C by 52 DEG C, finally in 60 minutes, temperature is down to 10 DEG C by 35 DEG C, suction filtration.Wet sample weighs to obtain white powder solid for more than 6 hours 120 DEG C of forced air dryings, yield 87.5%.The X-ray powder diffraction of this white powder solid being checked is consistent with Fig. 1, and be single Febuxostat crystal form A, its particle size distribution figure is similar to Fig. 5, its D
50be 25.0 μm, consistent with embodiment 1 of other spectrograms.
Embodiment 10
Get single Febuxostat crystal form A prepared by 5mg the present invention to join in the centrifuge tube of 1.5mL, then centrifuge tube placed 97%RH(saltpetre saturated aqueous solution) air-tight bottle in, sample after 45 days.Its powder X-ray-Ray diffracting spectrum is consistent with Fig. 1, and DSC collection of illustrative plates is consistent with Fig. 3, is single Febuxostat crystal form A.
Embodiment 11
To the Febustat sheet that different-grain diameter raw material is made by the preparation process described in CN1642546 embodiment 1.Use the Mcllvaine damping fluid of pH5.5 as test dissolution medium, adopt paddle method to implement dissolution test.
Wherein D
50=3, D
50=50, D
50=do not control to be obtain Febuxostat crystal form A according to CN1275126 embodiment 1;
Wherein D
50=3 is adopt micronizer mill (Dalton, PJM-100SP), and pulverization conditions is: feed speed 5.0kg/ hour, pulverizes pressure 0.65MPa.
D
50=50 is adopt impact mill (Dalton, P-3), and pulverization conditions is screen cloth 2Hmm, 4000rpm.
D
50=do not control, referred to 80 mesh sieves, particle diameter is approximately 180um.
D
50=16, D
50=20, D
50=25 are selected from the embodiment of the present invention 7,4,9 respectively.
Table 2: different-grain diameter stripping situation, corresponding stripping curve figure is shown in Fig. 6:
Know from upper table: for insoluble drug Febustat, D
50=3, D
50=16, D
50=20, D
50=25, in its 15 minutes, dissolution rate all reaches more than 85%, all can meet the requirement of preparation about stripping, and D
50the dissolution rate of=3 is relative to D
50=16, D
50=20, D
50=25 do not have obvious advantage, and D
50the stripping of=50 is relatively poor, D
50=do not control stripping existing problems, be underproof formulation products.
It can thus be appreciated that single crystal form A provided by the present invention, can meet the requirements for pharmaceuticals of dissolution rate, simultaneously because preparation technology beats powder without the need to pulverizer, preparation technology is simple, reaches cost-saving object.
Simultaneous test: Febuxostat crystal form A product property prepared by Different Preparation compares
Table 3: Febuxostat crystal form A product property prepared by Different Preparation compares
Claims (18)
1. a preparation method of single Febuxostat crystal form A, is characterized in that: the granularity D of described crystal form A
50be 16 ~ 25 μm, and size distribution curve is normal state unimodal distribution, comprises the steps:
1. Febustat heated and stirred is dissolved in the solvent containing ethanol;
2. add crystal seed, described crystal seed is Febuxostat crystal form A, granularity D
50it is 3 ~ 15 μm; Equal time segmentation is lowered the temperature, and described equal time segmentation cooling is temperature fall time overall length 0.5 ~ 3 hour; Temperature fall time is divided into 3 sections; Rate of temperature fall is 7.2 ~ 60 DEG C/h, and its rate of temperature fall is first slow rear fast non-linear cooling; Temperature is finally down to 10 ~ 40 DEG C;
3. be separated, wash, dry.
2. method according to claim 1, is characterized in that: step 1. described in be dehydrated alcohol containing the solvent of ethanol.
3. method according to claim 1, is characterized in that: step 1. described in be dehydrated alcohol and water mixed solvent containing the solvent of ethanol.
4. method according to claim 2, is characterized in that: step 1. described in Febustat and dehydrated alcohol weightmeasurement ratio be 30 ~ 150:1mg/ml.
5. method according to claim 2, is characterized in that: step 1. described in Febustat and dehydrated alcohol weightmeasurement ratio be 100 ~ 130:1mg/ml.
6. method according to claim 2, is characterized in that: step 1. described in Febustat and dehydrated alcohol weightmeasurement ratio be 110 ~ 125:1mg/ml.
7. method according to claim 3, is characterized in that: described dehydrated alcohol and water volume ratio are 15:1 ~ 1:1.
8. method according to claim 3, is characterized in that: described dehydrated alcohol and water volume ratio are 12:1 ~ 5:1.
9. method according to claim 3, is characterized in that: described dehydrated alcohol and water volume ratio are 9:1 ~ 7:1.
10., according to the method in claim 1 ~ 9 described in any one claim, it is characterized in that: step 2. described in crystal seed be Febuxostat crystal form A, granularity D
50it is 5 ~ 10 μm; By weight, add that crystal seed amount accounts for Febustat charging capacity 0.3 ~ 2.0%.
11., according to the method in claim 1 ~ 9 described in any one claim, is characterized in that: step 2. in by weight, add that crystal seed amount accounts for Febustat charging capacity 0.5 ~ 1.5%.
12., according to the method in claim 1 ~ 9 described in any one claim, is characterized in that: step 2. in by weight, add that crystal seed amount accounts for Febustat charging capacity 0.5 ~ 1.0%.
13. methods according to claim 1, is characterized in that: step 2. described in temperature fall time overall length be 1.0 ~ 2.5 hours; Temperature is finally down to 20 ~ 35 DEG C.
14. methods according to claim 1, is characterized in that: step 2. described in temperature fall time overall length be 1.5 ~ 2 hours; Temperature is finally down to 25 ~ 30 DEG C.
15. methods according to claim 1, it is characterized in that: step 2. described in equal time segmentation cooling be 7.2 ~ 24 DEG C/h at first paragraph rate of temperature fall, second segment rate of temperature fall is 9.6 ~ 48 DEG C/h, and final stage rate of temperature fall is 15.6 ~ 60 DEG C/h.
16. methods according to claim 1, is characterized in that: step 1. described in stirring velocity be 300 ~ 900 turns/min.
17. methods according to claim 1, is characterized in that: step 3. described in drying temperature be 60 ~ 120 DEG C.
18. methods according to claim 1, is characterized in that: step 3. described in drying temperature be 90 ~ 100 DEG C.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1275126A (en) * | 1998-06-19 | 2000-11-29 | 帝人株式会社 | Polymorphic modifications of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole-carboxylic acid and processes for the preparation thereof |
| CN1642546A (en) * | 2002-03-28 | 2005-07-20 | 帝人株式会社 | Solid preparation containing single crystal form |
| CN102267957A (en) * | 2011-08-24 | 2011-12-07 | 山东齐都药业有限公司 | Method for preparing Febuxostat crystal A |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1275126A (en) * | 1998-06-19 | 2000-11-29 | 帝人株式会社 | Polymorphic modifications of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole-carboxylic acid and processes for the preparation thereof |
| CN1642546A (en) * | 2002-03-28 | 2005-07-20 | 帝人株式会社 | Solid preparation containing single crystal form |
| CN102267957A (en) * | 2011-08-24 | 2011-12-07 | 山东齐都药业有限公司 | Method for preparing Febuxostat crystal A |
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