CN101891702B - Crystal of febuxostat, preparation method and application in medicaments - Google Patents
Crystal of febuxostat, preparation method and application in medicaments Download PDFInfo
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- CN101891702B CN101891702B CN2009100593716A CN200910059371A CN101891702B CN 101891702 B CN101891702 B CN 101891702B CN 2009100593716 A CN2009100593716 A CN 2009100593716A CN 200910059371 A CN200910059371 A CN 200910059371A CN 101891702 B CN101891702 B CN 101891702B
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- 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 35
- 239000013078 crystal Substances 0.000 title claims abstract description 30
- 239000003814 drug Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229960005101 febuxostat Drugs 0.000 title abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000002245 particle Substances 0.000 claims abstract description 13
- 238000010521 absorption reaction Methods 0.000 claims abstract description 10
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 7
- 238000009826 distribution Methods 0.000 claims description 11
- 229940079593 drug Drugs 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000008363 phosphate buffer Substances 0.000 claims description 3
- 238000011287 therapeutic dose Methods 0.000 claims description 3
- 238000002050 diffraction method Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 6
- 238000002329 infrared spectrum Methods 0.000 abstract 1
- 238000007561 laser diffraction method Methods 0.000 abstract 1
- 239000008055 phosphate buffer solution Substances 0.000 abstract 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 11
- 239000003826 tablet Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000005755 formation reaction Methods 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 206010013786 Dry skin Diseases 0.000 description 2
- 239000004278 EU approved seasoning Substances 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- -1 TMX-67 compound Chemical class 0.000 description 2
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 2
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 239000007919 dispersible tablet Substances 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 235000011194 food seasoning agent Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229920003109 sodium starch glycolate Polymers 0.000 description 2
- 239000011122 softwood Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229940116269 uric acid Drugs 0.000 description 2
- 235000020985 whole grains Nutrition 0.000 description 2
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 1
- CUXYLFPMQMFGPL-UHFFFAOYSA-N (9Z,11E,13E)-9,11,13-Octadecatrienoic acid Natural products CCCCC=CC=CC=CCCCCCCCC(O)=O CUXYLFPMQMFGPL-UHFFFAOYSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- CUXYLFPMQMFGPL-SUTYWZMXSA-N all-trans-octadeca-9,11,13-trienoic acid Chemical compound CCCC\C=C\C=C\C=C\CCCCCCCC(O)=O CUXYLFPMQMFGPL-SUTYWZMXSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- PZZYQPZGQPZBDN-UHFFFAOYSA-N aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 1
- 229910000323 aluminium silicate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 229940046011 buccal tablet Drugs 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000004703 cross-linked polyethylene Substances 0.000 description 1
- 229920003020 cross-linked polyethylene Polymers 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 229940100242 glycol stearate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000009702 powder compression Methods 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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Abstract
The invention relates to a crystal (type M) of febuxostat, a preparation method and an application in medicaments. The reflected angle 2theta of the crystal X-ray powder diffraction pattern has characteristic absorption peak at about 2.95 degrees, 5.84 degrees, 11.19 degrees, 14.04 degrees, 14.54 degrees, 16.75 degrees, 18.47 degrees, 20.81 degrees, 22.72 degrees, 24.34 degrees and 25.62 degrees,wherein the reflected angle 2theta has three strongest peaks at 11.19 degrees, 2.98 degrees and 5.84 degrees; in an infrared spectrum pattern, the characteristic absorption peak occurs at about 3425cm<1>, 2964cm<1>, 2873cm<1>, 1689cm<1>, 835cm<1>, 815cm<1>, 765cm<1> and 729cm<1>; the particle diameter measured with a laser diffraction method ranges from 0.5 mu m to 50 mu m, the counting particle diameter D90 is less than 40 mu m and the average particle diameter is less than 20 mu m. The crystal can be obtained by recrystalling the febuxostat with toluene; the crystal and pharmaceutically acceptable auxiliary parts can form the useable corresponding medicinal preparation with satisfactory dissolving rate; the dissolution of a tablet in phosphate buffer solution medium with the pH value of7.2 is greater than or equal to 45% within five minutes and greater than or equal to 95% within 35 minutes.
Description
Technical field
The present invention relates to use a kind of new crystal (M type), its preparation method of compound TMX-67, and the application in related drugs.
Background technology
TMX-67 (FEBUXOSTAT); Be that structure is suc as formula the 2-shown in (I) (3-cyano-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid; Be xanthine oxidase inhibitor of new generation, be mainly used at present treatment gout etc. clinically because of the illness of uric acid due to too high.
Publication number is to disclose TMX-67 in the Chinese patent document of CN1275126A multiple crystal formation (A, B, C, D, G) and amorphous compound are arranged, and mainly is to be that solvent prepares with methanol-water or Virahol-water.
For solving the low problem of TMX-67 solubleness in water; Publication number CN1970547A Chinese patent document has been reported H, I, three kinds of crystal formations of J of this compound and preparation method thereof again; This crystal formation is that solvent prepares with acetonitrile or propionitrile mainly; Its median size is 1～50 μ m, mainly is to investigate and improve its stability.
In addition; The Chinese patent document of publication number CN101085761A has reported that also a kind of is the crystallite and the compsn thereof of purpose to improve the TMX-67 dissulution; This crystallite is that solvent prepares by ETHYLE ACETATE; Show that but test its dissulution result still has satisfied inadequately and the part that has much room for improvement, fully to satisfy and raising effect needs.
Summary of the invention
To above-mentioned situation; The present invention at first will provide a kind of new crystal of TMX-67; This crystalline preparation method also will be provided, and further provide this crystal at related drugs, particularly be mainly used at present uric acid such as treatment gout etc. too high due to application in the illness medicine.
TMX-67 crystal of the present invention (abbreviating the M N-type waferN as) is that reflection angle 2 θ of its X-ray powder diffraction figure are being about 2.98 °, 5.84 °; 11.19 °, 14.04 °, 14.54 °; 16.75 °, 18.47 °, 20.81 °; 22.72 °, located charateristic avsorption band for 24.34 ° and 25.62 °, wherein about 11.19 °, 2.98 ° and 5.84 ° locate be respectively three the strongest absorption peaks.
In addition, in the infrared spectrogram of the above-mentioned TMX-67 M of the present invention N-type waferN at about 3425cm
-1, 2964cm
-1, 2873cm
-1, 1689cm
-1, 835cm
-1, 815cm
-1, 765cm
-1, 729cm
-1There is charateristic avsorption band at the place.
Further test shows, with the above-mentioned TMX-67 M of the present invention N-type waferN that laser diffractometry is measured, and its particle size distribution range 0.5～50 μ m, statistics particle diameter D
90＜40 μ m, median size＜20 μ m, and have the ideal dissolution rate, help the absorption of medicine and the raising of bioavailability.
The preparation of the above-mentioned TMX-67 M of the present invention N-type waferN is to be that solvent carries out recrystallization with toluene with the TMX-67 raw material, obtains said crystal.Reduce temperature during crystallization, crystalline is fully separated out normally favourable.Test shows, adopting the TMX-67 raw material generally speaking is 1 in the ratio of grams per milliliter: the amount of (2～50) with the toluene dissolving after, make crystal separate out and obtain this crystal through cooling, the result is comparatively satisfied.Particularly; The principle that goes out according to the heat of solution cold analysis; Preferred mode is to make the TMX-67 raw material in toluene, after being heated under the heating condition that is not higher than the refluxing toluene temperature (for example 60 ℃～110 ℃) dissolving, being cooled to-5～30 ℃ crystal is separated out very soon; Separate to obtain said crystal, can further reduce the consumption of toluene solvant and/or improve the yield of said M N-type waferN.
With the above-mentioned M N-type waferN of the present invention of effective therapeutic dose TMX-67 compound is the active drug composition; Cooperate with acceptable ancillary component in the pharmacy; Like vehicle, tackiness agent (Vltra tears, light propyl cellulose, Vilaterm adjoin in pyrrolidone, starch slurry, Z 150PH, Microcrystalline Cellulose, water, the ethanol-water solution etc. at least a), weighting agent (in lactose, N.F,USP MANNITOL, Xylitol, starch, pregelatinized Starch, W-Gum, Microcrystalline Cellulose, the sorbyl alcohol etc. at least a), thinner, tablet agent, lubricant (Triple Pressed Stearic Acid, Magnesium Stearate, calcium stearate, brown eleostearic acid, pure aluminium silicate, stearic phthalein amine, talcum powder; At least a in the silicon-dioxide etc.), disintegrating agent (low replace light propyl cellulose, crosslinked polyethylene adjoin pyrrolidone, Vilaterm adjoin at least a in pyrrolidone, starch, Microcrystalline Cellulose, the shuttle sodium carboxymethylcellulose pyce etc.), tinting material, seasonings, stablizer etc.; Routine processing, manufacture (for example at present existing widely used wet granule compression tablet according to corresponding formulation; Direct powder compression, the back of granulating are encapsulated etc.); Promptly can be prepared into the relative medicine compsn that can supply clinical use; Particularly multi-form oral preparation medicament; Like tablets (comprising slow releasing tablet, buccal tablet, orally disintegrating tablet, chewable tablet, effervescent tablet, dispersible tablet, control slow releasing tablet etc.) such as plain sheet commonly used or sugar-coat bag sheets; Capsule, dosage forms such as particle.
Said effective therapeutic dose generally can be 10～200mg every day, is preferably 40～120mg.Test shows; Said pharmaceutical composition preferably is adopted as the TMX-67 composition that contains 40mg, 80mg or 120mg in every preparation unit (sheet, grain etc.); Can have excellent dissolution characteristic; In the phosphate buffer soln medium of 900m milliliter pH 7.2, the solubility rate in 5 minutes and 35 minutes is respectively >=45% (w) and >=95% (w).
Below in conjunction with the embodiment of accompanying drawing illustrated embodiment, foregoing of the present invention is remake further detailed description.But should this be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following instance.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
Description of drawings
Fig. 1 is a TMX-67 M crystal form X x ray diffration pattern x of the present invention.
Fig. 2 is a TMX-67 M crystal formation infrared absorpting light spectra of the present invention.
Fig. 3 is TMX-67 M crystal formation size distribution curve figure of the present invention.
Embodiment
TMX-67 10g, toluene 500ml are added in the 1L round-bottomed flask, be stirred to solid under 90～100 ℃ of heating all after the dissolving, naturally cool to room temperature; Crystallization is separated out soon in a large number very much, and for improving yield, ice bath continues to be cooled to-5～0 ℃; Insulated and stirred crystallization 2 hours filters, and filter cake washs with small amount of toluene; 80 ℃ of dryings of vacuum 8 hours get light yellow crystalline powder 7.8g, purity >=99% (HPLC. normalization method).
The reflection angle 2 θ absorption peaks of its X-ray powder diffraction of sampling and measuring are as shown in Figure 1, and the data of absorption peak are as shown in table 1; Infrared spectrogram, crystal formation size distribution curve figure are respectively like Fig. 2～shown in Figure 3.Can find out that by Fig. 1 and table 1 reflection angle 2 θ of this crystal X-ray powder diffraction figure are being about 2.98 °, 5.84 °; 11.19 °, 14.04 °, 14.54 °; 16.75 °, 18.47 °, 20.81 °; 22.72 °, located charateristic avsorption band for 24.34 ° and 25.62 °, particularly wherein the 7th, 3, No. 5 peak is respectively three absorption peaks the strongest; In its infrared spectrogram at about 3425cm
-1, 2964cm
-1, 2873cm
-1, 1689cm
-1, 835cm
-1, 815cm
-1, 765cm
-1, 729cm
-1There is charateristic avsorption band at the place; In the sreen analysis, statistics particle diameter D
102.32 μ m, D
508.84 μ m, D
9020.71 μ m, average diameter 10.47 μ m, as shown in table 2, be shown as microcrystalline state.
TMX-67 10g, toluene 20ml are added in the 250ml round-bottomed flask, stir and be warming up to backflow, treat that solid all after the dissolving, naturally cools to room temperature (15～30 ℃); In the temperature-fall period, crystallization is separated out soon in a large number very much, for improving yield; Insulated and stirred crystallization 2 hours filters, and filter cake washs with small amount of toluene; 80 ℃ of dryings of vacuum 8 hours get light yellow crystalline powder 8.8g, purity >=99% (HPLC. normalization method).Through detections such as corresponding X-ray powder diffraction figure, infrared spectrograms, show that it is the microcrystalline state that meets the said M N-type waferN of the present invention correlated characteristic equally.
Embodiment 3
The TMX-67 M type crystallite 406g of prescription: embodiment 1 preparation,
Pharmaceutical lactose 900g,
Pregelatinized Starch 300g,
Carboxymethylstach sodium 120g,
Magnesium Stearate 1g.
Each component except that Magnesium Stearate in the prescription raw material is mixed, use an amount of 75% ethanolic soln to be tackiness agent, process softwood; Be pressed through 14 mesh sieves and process wet granular, put 80 ℃ of air seasonings 2 hours, dried particle is through the whole grain of 14 mesh sieves; Add remaining Magnesium Stearate; Mix, be filled in gelatine capsule No. 2, process 1000 capsules medicines altogether.
The reflection angle 2 θ absorption peak data of table 1 crystal X-ray powder diffraction
The detected result of table 2 size-grade distribution
| Particle diameter (μ m) | Differential distribution (%) | Cumulative distribution (%) | Particle diameter (μ m) | Differential distribution (%) | Cumulative distribution (%) | Particle diameter (μ m) | Differential distribution (%) | Cumulative distribution (%) |
| 0.20 0.24 0.29 0.35 0.43 0.52 0.63 0.76 0.92 1.11 1.35 1.63 1.97 2.39 | ?0.10 0.13 0.17 0.25 0.30 0.40 0.50 0.66 0.84 1.13 1.41 1.81 2.35 | ?0.45 0.58 0.76 1.00 1.31 1.70 2.21 2.87 3.71 4.84 6.25 8.05 10.40 | 2.89 3.50 4.24 5.13 6.21 7.51 9.09 11.00 13.31 16.11 19.50 23.60 28.56 34.57 | 2.93 3.71 4.61 5.60 6.72 7.80 8.84 9.53 9.72 9.22 7.93 6.01 3.88 2.03 | 13.33 17.04 21.65 27.25 33.96 41.76 50.60 60.13 69.85 79.07 87.00 93.01 96.89 98.92 | 41.8 50.6 61.3 74.2 89.8 108.6 131.5 159.1 192.6 233.1 282.1 341.4 413.1 500.0 | 0.81 0.23 0.04 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 | 99.73 99.95 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 |
Embodiment 4
100.5 parts in the TMX-67 M type crystallite of prescription: embodiment 1 preparation,
0.2 part of Vinylpyrrolidone polymer K30,
13 parts of Icing Sugar,
10.8 parts of sodium starch glycolatees,
13.2 parts of cross-linked polyvinylpyrrolidones,
15 57.3 parts of polyethylene glycol stearates (28.7%),
5 parts of Magnesium Stearates,
75% ethanol is an amount of.
Vinylpyrrolidone polymer K30 and polyethylene glycol stearate 15 are dissolved in 75% an amount of ethanol, add TMX-67 crystallite, Icing Sugar, sodium starch glycolate and cross-linked polyvinylpyrrolidone, mix; Sieve system softwood, oven dry; Whole grain adds Magnesium Stearate, mixing again; Compressing tablet is processed every dispersible tablet drug that contains 120 milligrams of TMX-67s.
The mensuration of dissolution rate: get 6 of the above-mentioned tablet medicines of different batches preparation respectively, according to the dissolution method in two appendix XC first methods of Chinese Pharmacopoeia version in 2005, with pH 7.2 phosphate buffer solns (0.2mol/L potassium primary phosphate test solution 50ml and 0.2mol/ sodium hydroxide solution 35ml; Adding water to 200ml) 900ml is dissolution medium; Revolution Per Minute 50 changes, and operation in accordance with the law is respectively at got dissolution fluid 5ml (supplying total amount with dissolution medium of the same race after getting liquid) in 5 minutes, 15 minutes, 25 minutes, 35 minutes, 45 minutes, 55 minutes at every turn; Filter; Precision is measured subsequent filtrate 2ml, adds dissolution fluid and is diluted to 25ml, as sample solution.The stripping result of TMX-67 is as shown in table 3 in each time period.
Table 3 dissulution (w%) test-results
Claims (6)
1. the crystal of TMX-67, reflection angle 2 θ that it is characterized in that this crystal X-ray powder diffraction figure be at 2.98 °, 5.84 °; 11.19 ° 14.04 °, 14.54 °, 16.75 °; 18.47 °, 20.81 °, 22.72 °; 24.34 ° and 25.62 ° located charateristic avsorption band, wherein 11.19 °, 2.98 ° and 5.84 ° locate be respectively three the strongest absorption peaks, each absorption peak is following:
2. the crystal of TMX-67 as claimed in claim 1 is characterized in that in this crystalline infrared spectrogram at 3425cm
-1, 2964cm
-1, 2873cm
-1, 1689cm
-1, 835cm
-1, 815cm
-1, 765cm
-1, 729cm
-1There is charateristic avsorption band at the place.
3. the crystal of TMX-67 as claimed in claim 1 is characterized in that particle size distribution range 0.5～50 μ m that this crystalline is measured with laser diffractometry, statistics particle diameter D
90＜40 μ m, median size＜20 μ m.
4. prepare the said TMX-67 crystalline of claim 1 method; It is characterized in that with toluene being solvent; Is the amount of 1/ (2～50) with the TMX-67 raw material in the ratio of grams per milliliter; After dissolving under the heating condition that is not higher than the refluxing toluene temperature, in-5 ℃～30 ℃ with stir under separate out and obtain said crystal.
5. a pharmaceutical composition is characterized in that with the said TMX-67 crystal of the claim 1 of effective therapeutic dose be the active drug composition, forms jointly with acceptable ancillary component in the pharmacy.
6. pharmaceutical composition as claimed in claim 5; It is characterized in that this medicine for containing 40mg, 80mg or 120mg TMX-67 composition in each preparation unit, the oral prepns of solubility rate >=95% in solubility rate >=45%, 35 in the phosphate buffer soln medium of 900 milliliters of pH 7.2 in 5 minutes minute.
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| CA2764600A1 (en) | 2009-06-10 | 2010-12-16 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of febuxostat |
| CZ27857U1 (en) | 2014-12-12 | 2015-02-23 | Zentiva, K.S. | Formulation containing febuxostat solid solution |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1275126A (en) * | 1998-06-19 | 2000-11-29 | 帝人株式会社 | Polymorphic form of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid and preparation method thereof |
| CN1970547A (en) * | 2006-12-07 | 2007-05-30 | 重庆医药工业研究院有限责任公司 | New crystal form of febuxostat and preparation method thereof |
| CN101781270A (en) * | 2009-01-20 | 2010-07-21 | 重庆医药工业研究院有限责任公司 | High-purity Febuxostat and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1275126A (en) * | 1998-06-19 | 2000-11-29 | 帝人株式会社 | Polymorphic form of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid and preparation method thereof |
| CN1970547A (en) * | 2006-12-07 | 2007-05-30 | 重庆医药工业研究院有限责任公司 | New crystal form of febuxostat and preparation method thereof |
| CN101781270A (en) * | 2009-01-20 | 2010-07-21 | 重庆医药工业研究院有限责任公司 | High-purity Febuxostat and preparation method thereof |
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| Title |
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| 王瑊等.抗痛风药物febuxostat 的合成.《中国药物化学杂志》.2008,第18卷(第4期),259－262. * |
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