CN102988326A - Febuxostat tablets and preparation method and detection method thereof - Google Patents
Febuxostat tablets and preparation method and detection method thereof Download PDFInfo
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- CN102988326A CN102988326A CN2012105440901A CN201210544090A CN102988326A CN 102988326 A CN102988326 A CN 102988326A CN 2012105440901 A CN2012105440901 A CN 2012105440901A CN 201210544090 A CN201210544090 A CN 201210544090A CN 102988326 A CN102988326 A CN 102988326A
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- febuxostat
- methanol
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- measuring bottle
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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 145
- 229960005101 febuxostat Drugs 0.000 title claims abstract description 145
- 238000002360 preparation method Methods 0.000 title claims abstract description 94
- 238000001514 detection method Methods 0.000 title claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 38
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 32
- 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 claims abstract description 25
- 239000008101 lactose Substances 0.000 claims abstract description 25
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 16
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 16
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 16
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 16
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 16
- 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 claims abstract description 11
- 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 303
- 239000000243 solution Substances 0.000 claims description 137
- 238000012360 testing method Methods 0.000 claims description 95
- 239000011248 coating agent Substances 0.000 claims description 51
- 238000000576 coating method Methods 0.000 claims description 51
- 239000013558 reference substance Substances 0.000 claims description 44
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 39
- 238000005303 weighing Methods 0.000 claims description 38
- 239000003826 tablet Substances 0.000 claims description 37
- 239000000843 powder Substances 0.000 claims description 35
- 239000000047 product Substances 0.000 claims description 35
- 239000000706 filtrate Substances 0.000 claims description 33
- 238000004090 dissolution Methods 0.000 claims description 29
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 27
- 239000012535 impurity Substances 0.000 claims description 22
- 239000002609 medium Substances 0.000 claims description 22
- 238000003556 assay Methods 0.000 claims description 20
- 239000002671 adjuvant Substances 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000000945 filler Substances 0.000 claims description 15
- 238000010521 absorption reaction Methods 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 14
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 13
- 239000000377 silicon dioxide Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000004132 cross linking Methods 0.000 claims description 12
- 230000014759 maintenance of location Effects 0.000 claims description 12
- 239000008213 purified water Substances 0.000 claims description 12
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 12
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 12
- 238000012546 transfer Methods 0.000 claims description 12
- 239000012738 dissolution medium Substances 0.000 claims description 11
- 239000012071 phase Substances 0.000 claims description 11
- 238000005070 sampling Methods 0.000 claims description 11
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 10
- 238000011978 dissolution method Methods 0.000 claims description 10
- 239000008187 granular material Substances 0.000 claims description 10
- 239000008363 phosphate buffer Substances 0.000 claims description 10
- 239000007921 spray Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 238000002347 injection Methods 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 9
- 238000004811 liquid chromatography Methods 0.000 claims description 9
- 239000012467 final product Substances 0.000 claims description 8
- 238000007689 inspection Methods 0.000 claims description 8
- 230000000813 microbial effect Effects 0.000 claims description 7
- 238000000870 ultraviolet spectroscopy Methods 0.000 claims description 7
- 101100515520 Arabidopsis thaliana XI-J gene Proteins 0.000 claims description 6
- 230000033228 biological regulation Effects 0.000 claims description 6
- 238000010812 external standard method Methods 0.000 claims description 6
- 238000005429 filling process Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 5
- 206010013786 Dry skin Diseases 0.000 claims description 5
- 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 claims description 5
- 238000007605 air drying Methods 0.000 claims description 5
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000000428 dust Substances 0.000 claims description 5
- 239000000835 fiber Substances 0.000 claims description 5
- 239000007941 film coated tablet Substances 0.000 claims description 5
- 239000007791 liquid phase Substances 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000007779 soft material Substances 0.000 claims description 5
- 239000007888 film coating Substances 0.000 claims description 3
- 238000009501 film coating Methods 0.000 claims description 3
- 230000002087 whitening effect Effects 0.000 claims description 3
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims description 2
- 238000012850 discrimination method Methods 0.000 claims description 2
- 229960001375 lactose Drugs 0.000 claims description 2
- 230000036961 partial effect Effects 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 23
- 201000005569 Gout Diseases 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 9
- 201000001431 Hyperuricemia Diseases 0.000 abstract description 6
- 201000010099 disease Diseases 0.000 abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- 229960001681 croscarmellose sodium Drugs 0.000 abstract 1
- 230000009897 systematic effect Effects 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000005755 formation reaction Methods 0.000 description 8
- 239000011230 binding agent Substances 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 238000011835 investigation Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 229960003459 allopurinol Drugs 0.000 description 5
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000012856 packing Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- 238000004088 simulation Methods 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- 239000012490 blank solution Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000007542 hardness measurement Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 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 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 108010093894 Xanthine oxidase Proteins 0.000 description 1
- 102100033220 Xanthine oxidase Human genes 0.000 description 1
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
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- 238000013461 design Methods 0.000 description 1
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- 238000010586 diagram Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 238000005213 imbibition Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000008832 photodamage Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
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- 239000007787 solid Substances 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 229940126673 western medicines Drugs 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
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- G01N30/90—Plate chromatography, e.g. thin layer or paper chromatography
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
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Abstract
The invention provides Febuxostat tablets and a preparation method and a detection method thereof. The tablets are prepared from 40 to 120 parts of Febuxostat, 95 to 165 parts of microcrystalline cellulose, 20 to 60 parts of lactose, 10 to 27 parts of croscarmellose sodium and 1 to 3 parts of magnesium stearate according to parts by weight. Aiming at the shortcomings of the prior art, the formula and the preparation process of the Febuxostat tablets are optimized, so that the curative effects of the Febuxostat tablets for treating diseases such as hyperuricemia and gout are more remarkable, and the systematic, complete and effective component identification and content determination methods are established to effectively control the quality of the medicine, thereby ensuring the clinical curative effect.
Description
Technical field
The present invention relates to a kind of Febuxostat tablet and preparation method thereof and detection method, belong to technical field of western medicines.
Background technology
Gout be purine metabolic disturbance and (or) one group of different substantiality disease of hyperuricemia due to the sour acatharsia.After the World War II, along with the raising of various countries' economic level, the change of dietary structure, population aging, life, hyperuricemia has become old people's height morbidity.
Gout is exactly the commonly encountered diseases of the developed country such as American-European from ancient times.Over nearly 20 years, the prevalence of Asia hyperuricemia and gout has the trend that significantly increases.
Allopurinol is a unique medicine that be used for to suppress uricopoiesis clinically, and be widely used in clinical as the gold medicine of gout, but because allopurinol only has inhibitory action to the XOR of reduced form, need to repeat heavy dose of administration and keep higher levels of drugs.Many patients maybe can not tolerate allopurinol is irritated, invalid.But not Bu Suotan (febuxostat) then is a species specificity xanthine oxidase inhibitor.Compare with allopurinol, the curative effect of Febuxostat prevention gout outbreak and the incidence rate of adverse effect are similar, but it is higher to suppress uricopoiesis intensity.Existing European Union and FDA all ratify its application for quotation, are used for the treatment of the too high disease gout of chronic uric acid.Clinical research is the result show: the Clinical efficacy of Febuxostat and safety all have satisfactory result.
But, because Febuxostat is purine analogue, inevitably causes the impact that relates to purine and other enzymatic activitys of pyridine metabolism, so in the allopurinol treatment, need to repeat heavy dose of administration and keep higher levels of drugs, affect the treatment curative effect of Febuxostat.
In addition, at present the Febuxostat medicine also there is not the strict reliably quality inspection standard of a cover.If there is not strict quality standard, the product that obtains can not be guaranteed its quality, and the result will affect the clinical efficacy of this medicine; Think the therapeutical effect that improves the Febuxostat medicine, guarantee medication safe, effectively reach the stable of product quality, formulating a strict reliable quality standard becomes the basic demand of ensuring drug quality.Along with the development of Modern Instrument Analytical Technique, the analytical methods such as high performance liquid chromatography have obtained using more and more widely in the quality control of medicine.
Summary of the invention
The object of the invention is to, a kind of Febuxostat tablet and preparation method thereof and detection method are provided.The present invention is directed to the deficiencies in the prior art, prescription and preparation technology to the Febuxostat tablet are optimized, make its curative effect to diseases such as hyperuricemia and gouts more remarkable, and set up system, complete, effective composition and differentiated and content assaying method, can effectively control the quality of this medicine, thereby guarantee its clinical efficacy.
Technical scheme of the present invention: a kind of Febuxostat tablet, calculate by weight, made by 40～120 parts of Febuxostats, 95～165 parts of microcrystalline Cellulose, 20～60 parts of lactose, 10～27 parts of cross-linking sodium carboxymethyl celluloses and 1～3 part of magnesium stearate.
Preferred Febuxostat tablet is made by 80g Febuxostat, 110g microcrystalline Cellulose, 40g lactose, 18g cross-linking sodium carboxymethyl cellulose and 2g magnesium stearate.
The preparation method of aforementioned Febuxostat tablet may further comprise the steps:
(1) preparation of label:
1. get Febuxostat, lactose, cross respectively 80 eye mesh screens, for subsequent use;
2. with Febuxostat and microcrystalline Cellulose, lactose, partial cross-linked sodium carboxymethyl cellulose mix homogeneously, add an amount of purified water soft material processed, 18 eye mesh screens are granulated, 70 ℃ of dryings, 18 mesh sieve granulate add surplus cross-linked carboxymethyl fiber sodium and magnesium stearate, mix homogeneously;
3. intermediate detects, and qualified rear tabletting gets plain sheet;
(2) film coating:
1. get ethanol, purified water places agitator, adds the premix coating powder in situation about constantly stirring, and continues to stir 1 hour, coating solution filters with 100 eye mesh screens, and is for subsequent use;
2. plain sheet is placed in the coating pan, open coating pan and start air draft and dust exhaust apparatus, use simultaneously 40 ℃～45 ℃ hot-air pre-heatings, plain sheet is heated evenly, and sops up the fine powder that is adsorbed on the plain sheet; Start coating pan, regulate coating solution granularity of spray and spray velocity, the coating solution for preparing is sparged on the label of rotation equably; After coating is complete, continue to use cold air drying 10 minutes, coating weightening finish 3%-5% gets final product.
In the preparation method of aforementioned Febuxostat tablet, in mixing and tabletting filling process, ambient humidity is controlled at below 50%.
The detection method of aforementioned Febuxostat tablet comprises character, discriminating, inspection and assay project; Wherein differentiate it is that the Febuxostat in the preparation is differentiated; Inspection is respectively this preparation to be carried out related substance, dissolution, microbial limit and weight differential to check; Assay is that Febuxostat is measured.
Concrete content assaying method is:
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Mobile phase is that methanol-transfer pH with triethylamine is 5.0 0.3% acetic acid=70:30, adopts UV to detect, and the detection wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed the Febuxostat peak and is calculated, and should be not less than 2000;
Algoscopy: get 20 in this preparation, accurately weighed, porphyrize, precision takes by weighing the fine powder that is equivalent to Febuxostat 10mg, put in the 50mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolving and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in the 25mL measuring bottle, add methanol and be diluted to scale, shake up, as need testing solution; In addition precision takes by weighing Febuxostat reference substance 10mg and puts in the 50mL measuring bottle, and it is an amount of to add methanol, ultrasonicly makes dissolving, adds methanol to scale, and precision is measured 5mL and put in the 25mL measuring bottle respectively, adds methanol and is diluted to scale, shakes up, in contrast product solution; Precision is measured above-mentioned reference substance solution and each 10 μ L of need testing solution, and the injection liquid chromatography records chromatogram respectively.
Concrete discrimination method is:
(1) liquid phase is differentiated: under the assay item, the retention time of the test sample main peak all retention time with the reference substance peak is consistent;
(2) ultraviolet is differentiated: get this preparation fine powder that is equivalent to Febuxostat 6mg, put in the 100mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolving and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in the 50mL measuring bottle, add methanol and be diluted to scale, shake up, with reference to " ultraviolet visible spectrophotometry of two appendix IV of Chinese pharmacopoeia version in 2010 A is measured, and at the wavelength place of 215nm and 315nm absorption maximum is arranged.
The particular exam method is:
(1) dissolution: concrete operations are as follows: get this preparation, with reference to " dissolution method of two appendix X of Chinese pharmacopoeia version in 2010 C the second method, take the 1000mL phosphate buffer of pH=6.8 as dissolution medium, rotating speed is that per minute 50 turns, in accordance with the law operation, and in 30 minutes sampling 10mL, filter, get subsequent filtrate 2mL, put in the 25mL measuring bottle, add the stripping medium to scale, shake up, as need testing solution; In addition precision takes by weighing Febuxostat reference substance 16mg, puts in the 50mL measuring bottle, adds dissolve with methanol and is diluted to scale, shakes up, and precision pipettes 2mL and puts in the 100mL measuring bottle again, adds the stripping medium to scale, shakes up, in contrast product solution; With reference to " spectrophotography of two records of Chinese pharmacopoeia version in 2010 IV A is measured trap at 317nm wavelength place; Calculate every stripping quantity;
(2) related substance:
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Mobile phase is that methanol-transfer pH with triethylamine is 5.0 0.3% acetic acid=70:30, adopts UV to detect, and the detection wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed the Febuxostat peak and is calculated, and should be not less than 2000;
Algoscopy: get this preparation sheet powder that is equivalent to contain Febuxostat 10mg, put in the 50mL measuring bottle, it is an amount of to add methanol, ultrasonicly makes dissolving, lets cool, and adds methanol and is diluted to scale, shakes up, and filters, and gets subsequent filtrate as need testing solution; Precision pipettes above-mentioned need testing solution 1mL again, is diluted to 1% own control product solution with methanol; Precision takes by weighing impurity A reference substance 10mg in addition, and the amount that is diluted to the impure A of every 1mL with methanol is 2 μ g, and product solution is got above-mentioned need testing solution, each 10 μ L injecting chromatograph of reference substance solution, the record chromatogram in contrast; In the need testing solution chromatogram, if any the impurity A peak, calculate with external standard method, should be greater than 1%; Desolventize outside peak and the adjuvant peak, the peak area sum of other impurity should be not more than 1 times of own control peak area;
(3) microbial limit: get this preparation, with reference to " method of Chinese pharmacopoeia two appendix XI J in 2010 is calculated;
(4) weight differential: get this preparation, accurately weighed, it is heavy to calculate average sheet, distinguishes accurately weighed every weight again, should meet " the regulation of two appendix I of Chinese pharmacopoeia version in 2010 A.
Described detection method comprises:
(1) character: this preparation is Film coated tablets, remove coating after, whitening color or off-white color;
(2) assay:
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Mobile phase is that methanol-transfer pH with triethylamine is 5.0 0.3% acetic acid=70:30, adopts UV to detect, and the detection wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed the Febuxostat peak and is calculated, and should be not less than 2000;
Algoscopy: get 20 in this preparation, accurately weighed, porphyrize, precision takes by weighing the fine powder that is equivalent to Febuxostat 10mg, put in the 50mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolving and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in the 25mL measuring bottle, add methanol and be diluted to scale, shake up, as need testing solution; In addition precision takes by weighing Febuxostat reference substance 10mg and puts in the 50mL measuring bottle, and it is an amount of to add methanol, ultrasonicly makes dissolving, adds methanol to scale, and precision is measured 5mL and put in the 25mL measuring bottle respectively, adds methanol and is diluted to scale, shakes up, in contrast product solution; Precision is measured above-mentioned reference substance solution and each 10 μ L of need testing solution, and the injection liquid chromatography records chromatogram respectively;
(3) differentiate:
(1) liquid phase is differentiated: under the assay item, the retention time of the test sample main peak all retention time with the reference substance peak is consistent;
(2) ultraviolet is differentiated: get this preparation fine powder that is equivalent to Febuxostat 6mg, put in the 100mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolving and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in the 50mL measuring bottle, add methanol and be diluted to scale, shake up, with reference to " ultraviolet visible spectrophotometry of two appendix IV of Chinese pharmacopoeia version in 2010 A is measured, and at the wavelength place of 215nm and 315nm absorption maximum is arranged;
(4) check:
(1) dissolution: concrete operations are as follows: get this preparation, with reference to " dissolution method of two appendix X of Chinese pharmacopoeia version in 2010 C the second method, take the 1000mL phosphate buffer of pH=6.8 as dissolution medium, rotating speed is that per minute 50 turns, in accordance with the law operation, and in 30 minutes sampling 10mL, filter, get subsequent filtrate 2mL, put in the 25mL measuring bottle, add the stripping medium to scale, shake up, as need testing solution; In addition precision takes by weighing Febuxostat reference substance 16mg, puts in the 50mL measuring bottle, adds dissolve with methanol and is diluted to scale, shakes up, and precision pipettes 2mL and puts in the 100mL measuring bottle again, adds the stripping medium to scale, shakes up, in contrast product solution; With reference to " spectrophotography of two records of Chinese pharmacopoeia version in 2010 IV A is measured trap at 317nm wavelength place; Calculate every stripping quantity;
(2) related substance:
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Mobile phase is that methanol-transfer pH with triethylamine is 5.0 0.3% acetic acid=70:30, adopts UV to detect, and the detection wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed the Febuxostat peak and is calculated, and should be not less than 2000;
Algoscopy: get this preparation sheet powder that is equivalent to contain Febuxostat 10mg, put in the 50mL measuring bottle, it is an amount of to add methanol, ultrasonicly makes dissolving, lets cool, and adds methanol and is diluted to scale, shakes up, and filters, and gets subsequent filtrate as need testing solution; Precision pipettes above-mentioned need testing solution 1mL again, is diluted to 1% own control product solution with methanol; Precision takes by weighing impurity A reference substance 10mg in addition, and the amount that is diluted to the impure A of every 1mL with methanol is 2 μ g, and product solution is got above-mentioned need testing solution, each 10 μ L injecting chromatograph of reference substance solution, the record chromatogram in contrast; In the need testing solution chromatogram, if any the impurity A peak, calculate with external standard method, should be greater than 1%; Desolventize outside peak and the adjuvant peak, the peak area sum of other impurity should be not more than 1 times of own control peak area;
(3) microbial limit: get this preparation, with reference to " method of Chinese pharmacopoeia two appendix XI J in 2010 is calculated;
(4) weight differential: get this preparation, accurately weighed, it is heavy to calculate average sheet, distinguishes accurately weighed every weight again, should meet " the regulation of two appendix I of Chinese pharmacopoeia version in 2010 A.
In order to ensure prescription and preparation technology's science, reasonable, feasible of Febuxostat tablet of the present invention, the applicant has carried out series of experimental research and investigation.
One, prescription research:
1, crude drug character
Febuxostat is white or off-white color crystalline powder; Insoluble in water.Therefore, when drafting the prescription of tablet, the dissolution of medicine is an aspect of considering emphatically.
2, the character of adjuvant and selection
As can be known, the adjuvant that uses among the ADENURIC is lactose, microcrystalline Cellulose, magnesium stearate etc. from the relevant information of the ADENURIC of European Union approval.
The lactose compact property is good, and uses lactose unilateral more smooth as filler, and outward appearance is better.
Microcrystalline Cellulose has good flowability and compressibility as filler, the rapid disintegrate of imbibition, and granule is very thin after the disintegrate
Cross-linking sodium carboxymethyl cellulose has extremely strong disintegrate ability.Especially applicable for the medicine that hydrophobicity is strong.
Magnesium stearate is lubricant, is easy to the granule mixing, makes unilateral smooth.
3, prescription screening
Because Febuxostat is water-soluble hardly, therefore, when carrying out prescription screening mainly take disintegration of tablet, dissolution etc. for main investigation index, the results are shown in Table 1.
Table 1 prescription screening result
| The supplementary material title | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 |
| Febuxostat | 4.0g | 4.0g | 4.0g | 4.0g |
| Microcrystalline Cellulose | 8.1g | 6.8g | 5.5g | 5.5g |
| Lactose | -- | 1.0g | 2.0g | 2.0g |
| Cross-linking sodium carboxymethyl cellulose | (0.3g outward) | (0.6g outward) | (0.9g outward) | (0.5g outward) 0.4g (interior) |
| Magnesium stearate | 0.1g | 0.1g | 0.1g | 0.1g |
| Appearance character | Unilateral slightly rough | Unilateral slightly rough | Unilateral bright and clean | Unilateral bright and clean attractive in appearance |
| Disintegration (min) | 20 | 14 | 8 | 7 |
| Dissolution is surveyed (%) | ---- | ---- | 81.3 | 88.6 |
The result: design sheet weight average does not add lactose at 0.25g in four prescriptions in prescription 1, and unilateral some is coarse, and the disintegrate of tablet and stripping are not ideal; Strengthened the consumption of lactose and disintegrating agent in prescription 2, disintegration time and stripping make moderate progress, but undesirable; Strengthened the consumption of disintegrating agent in 3 at prescription, strengthened behind the lactose consumption unilateral bright and clean attractive in appearance, but in disintegrating procedue the granule of accidental not disintegrate.Have in 4 half disintegrating agent to add in changing into so will write out a prescription, disintegration and stripping meet the requirements, and be comparatively desirable.
Conclusion: 4 the prescription of tentatively will writing out a prescription is write out a prescription as study on the stability.
Two, Study of operational conditions
1, the selection of binding agent
Because the Febuxostat material is more puckery, its flowability is not good enough, therefore adopts wet granule compression tablet technique, and binding agent is screened.
According to prescription 4 preparation mixed powders, adopting respectively 50% alcoholic solution, purified water, 2%PVP-k30 aqueous solution is that binding agent is granulated, observing effect, the row filter of going forward side by side.The results are shown in Table 2.
Table 2 binding agent the selection result
Annotate: the above 18 mesh sieve granulating process that all adopt.
Conclusion: adopt 50% ethanol as binding agent, material viscosity is larger, can't granulate; Adopt water and 2%PVP-k30 aqueous solution as binding agent, uniform particles, complete, good fluidity, tablet weight variation is little, and both consider from simple process and economic angle without obviously difference, directly adopt purified water as binding agent.
2, the mensuration of critical relative humidity
For the preparation of solid preparation, the moisture absorption of preparation process Chinese medicine powder is the link that must pay close attention to.Must measure the critical relative humidity of drug powder, and operating environment is controlled.
Method: prepare respectively CH
3COOK, MgCl
2, KNO
3, NaBr, NaCl, KCl, KNO
2Saturated solution, the saturated solution of preparation is inserted respectively in the silica gel drier, placed 72 hours in 25 ℃, obtain respectively relative humidity and be 20.0%, 33.0%, 42.8%, 59.7%, 75.3%, 84.3%, 92.5% constant humidity solution.
With the medicinal mixture that prepared in phosphorus pentoxide desiccator dry 48 hours, put into the mixture about 2g in the weighing botle bottom of constant weight, behind the precision weighing, place the exsiccator that fills 7 kinds of different saturated solutions to keep 72 hours, precise weighing, calculate the moisture absorption percentage rate, the results are shown in Table 3.
The moisture absorption percentage rate of medicated powder under the different relative humiditys of table 3
| Solution | RH％（25℃） | Moisture absorption percentage rate (%) |
| CH 3COOK | 20.0 | 1.98 |
| MgCl 2 | 33.0 | 2.22 |
| KNO 3 | 42.8 | 2.44 |
| NaBr | 59.7 | 3.82 |
| NaCl | 75.3 | 5.93 |
| KCl | 84.3 | 8.26 |
| KNO 2 | 92.5 | 11.14 |
Take the hydroscopicity data as vertical coordinate, the relative humidity data are the abscissa mapping, the results are shown in Figure 1.As seen from Figure 1, obviously strengthen in 50% above moisture absorption, therefore, the critical relative humidity that can determine finished product is 50%.In mixing and tabletting filling process, ambient humidity is controlled at below 50%.
Three, formulation and technology demonstration test
Method: with the prescription that screening process is determined, 200 in preparation sample (lot number: 080909), and film coating, take plain sheet hardness, coated tablet outward appearance, tablet weight variation, dissolution, related substance and content as investigating index, estimate.
1, outward appearance
This preparation is Film coated tablets, removes the aobvious off-white color of film-coat.
2, tablet weight variation inspection
Get at random 20 of coated tablet, the precision weighing sheet is heavy successively, record numerical value, and sheet average weight 0.2581g, maximum overgauge 3.3%, maximum minus deviation 4.4% meets the pharmacopeia relevant regulations.
3, hardness measurement
The hardness of element sheet has important impact to coating, and General Requirements sheet hardness is more than 5Kg.Get lower 10 of tablet weight variation item, measure hardness, the results are shown in Table 4.
Table 4 hardness measurement result
| Sample number | Hardness (Kg) |
| 1 | 6.25 |
| 2 | 7.23 |
| 3 | 7.56 |
| 4 | 8.22 |
| 5 | 7.56 |
| 6 | 7.88 |
| 7 | 7.33 |
| 8 | 7.96 |
| 9 | 7.14 |
| 10 | 7.37 |
Average sheet is 7.45Kg heavily, and hardness is moderate, is fit to coating.
4, assay
Get the sample under the tablet weight variation item, measure according to method under the assay item, the assay result is 100.5%.
5, Dissolution Rate Testing
Get this preparation, measure according to method under the quality standard Dissolution Rate Testing item, the result is 95.5%.
Conclusion: can find out that from above-mentioned Dissolution Rate Testing result the dissolution of preproduction is more than 80%, drug-eluting is good, and is up to specification.
6, determination of related substances
Measure by quality standard determination of related substances method, the impurity A result is 0.387%; Other related substance result is 0.059%.
The study on determination method of impurity A (being the Febuxostat hydrolyzate) sees the patent application document that name that the applicant and present specification submit on the same day is called " a kind of preparation method of Febuxostat raw material and detection method " for details.
7, influence factor's investigation
(1) exposure experiments to light:
Get this preparation, putting illumination is that 4500LX ± 500LX shone 10 days, by sampling in 0,5,10 day, measures indices, the results are shown in Table 5.
Table 5 Febuxostat sheet exposure experiments to light result
Result of the test shows, this preparation illumination 5,10 days, indices and 0 day relatively, indices has no significant change.
(2) hot test
Get this preparation, put under 60 ℃ of temperature and placed 10 days, by sampling in 0,5,10 day, measure indices, the results are shown in Table 6.
Table 6 Febuxostat sheet hot test result
Result of the test shows, places 5,10 days for 60 ℃, and indices and 0 day comparison indices have no significant change.
(3) high humility test
Get this preparation, put in the constant-temperature enclosed vessel, placed 10 days under respectively at relative humidity 92.5% and 75% ± 1% condition at 25 ℃, by sampling in 0,5,10 day, during relative humidity 92.5% condition, respectively moisture absorption 13.2% and 14.4% in 5,10 days; During relative humidity 75% ± 1% condition, respectively moisture absorption 1.8% and 2.1% in 5,10 days; So the sample when getting relative humidity 75% ± 1% condition is measured indices, the results are shown in Table 7.
Table 7 Febuxostat sheet high humility result of the test
Result of the test shows that relative humidity 75% ± 1% was placed 5,10 days, indices and comparison in 0 day, and indices has no significant change.
In addition, in order to ensure detection method science of the present invention, reasonable, feasible, the applicant has carried out series of experimental research and investigation.
One, character: measure four batch samples and be Film coated tablets, except aobvious off-white color behind the coating, the results are shown in Table 8.
Table 8 measurement result
Two, differentiate
1, in the chromatogram that records under the assay item, what the retention time of need testing solution main peak should be with the reference substance solution main peak is consistent.Identification result sees Table 9.
2, intend adopting the x powder diffraction to measure Febuxostat crystal formation characteristic peak, after use raw material and adjuvant were measured respectively, the discovery adjuvant was measured influential to crystal formation, therefore adopt.
3, ultraviolet is differentiated: get this preparation fine powder an amount of (being equivalent to approximately Febuxostat 6mg), put in the 100mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolving and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in the 50mL measuring bottle, add methanol and be diluted to scale, shake up, with reference to " ultraviolet visible spectrophotometry of two appendix IV of Chinese pharmacopoeia version in 2010 A is measured, and at the wavelength place of 215nm and 315nm absorption maximum is arranged.The results are shown in Table 9.
Table 9 is differentiated measurement result
Three, check
1, weight differential: get 20 of Febuxostat sheets, accurately weighed, it is heavy to calculate average sheet, distinguishes accurately weighed every weight again.Every weight and average sheet anharmonic ratio, limit test of weight variation is ± 7.5%, measures four batches, the results are shown in Table 10.
Table 10 check result
2, limit test of microbe: get the Febuxostat sheet, with reference to " method of Chinese pharmacopoeia two appendix XI J in 2010 is measured four batches, the results are shown in Table 11.
Table 11 limit test of microbe result
3, the methodological study of dissolution and mensuration
3.1 instrument: ZRS-8G type medicament dissolution instrument; Agilent 6010 ultraviolet-visible spectrophotometers.
3.2 measure determining of concentration: get the about 8mg of Febuxostat crude drug, put in the 100mL measuring bottle, add the methanol ultrasonic dissolution and be diluted to scale, shake up, measure respectively 1mL, 2mL, 3mL, 5mL again and respectively put in the 25mL measuring bottle, thin up is to scale, shake up, with reference to " UV, visible light-spectrophotography of two appendix IV of Chinese pharmacopoeia version in 2010 A is measured trap at 317nm wavelength place, the result is measured 2mL, and to put the trap of solution of 25mL measuring bottle comparatively suitable.
3.3 Febuxostat sheet of the present invention (adopts novel crystal forms, its crystal formation preparation method sees the patent application document that name that the applicant and present specification submit on the same day is called " a kind of preparation method of Febuxostat raw material and detection method " for details) stripping situation in various media and with the comparative study of the sheet of Febuxostat (patent crystal formation, its patent publication No. are CN1275126A) preparation.
Sample thief, with reference to " the dissolution method of two appendix X of Chinese pharmacopoeia version in 2010 C the second method, respectively with the water of 1000mL, 0.1mol/L hydrochloric acid solution, the buffer salt of pH=5.5 (9.15g citric acid, 40.43g dipotassium hydrogen phosphate, add water to 1000mL) and phosphate buffer (pH=6.8) be dissolution medium, rotating speed is made as per minute 100 and turns, in accordance with the law operation, through 5,10,20,30,45, in the time of 60 minutes, simultaneously fluid infusion of the 10mL(that takes a sample respectively 10mL), filter, precision pipettes subsequent filtrate 2mL, put in the 25mL measuring bottle, add the stripping medium to scale, shake up, as need testing solution.Precision takes by weighing at Febuxostat reference substance 16mg, puts in the 50mL measuring bottle, adds dissolve with methanol and is diluted to scale, shakes up, and precision pipettes 2mL again, puts in the 100mL measuring bottle, adds the stripping medium to scale, shakes up, in contrast product solution.Get above-mentioned two kinds of solution, with reference to " spectrophotography of two appendix IV of Chinese pharmacopoeia version in 2010 A is measured trap at 317nm wavelength place, calculates every stripping quantity.The results are shown in Table 12 and Fig. 2.
Measurement result in two kinds of each media of crystal formation of table 12
By the data of the different dissolution mediums of two kinds of crystal formations and stripping curve as can be known, the novel crystal forms of the present invention's preparation is basically identical with the In Vitro Dissolution behavior of the sample that the patent crystal formation prepares.
3.4 adjuvant interference test
Getting the blank right amount of auxiliary materials (being equivalent to approximately contain Febuxostat 16mg) of this preparation puts in the 50mL measuring bottle, add dissolve with methanol and be diluted to scale, shake up, precision pipettes 2mL again, puts in the 100mL measuring bottle, thin up is to scale, shake up, get mentioned solution, with reference to " the spectrophotography of two appendix IV of Chinese pharmacopoeia version in 2010 A, measure trap at 317nm wavelength place, as a result adjuvant interference measurement not.
3.5 the selection of rotating speed
Get the Febuxostat sheet, with reference to " dissolution method of two appendix X of Chinese pharmacopoeia version in 2010 C the second method is take 1000mL phosphate buffer (pH=6.8) as dissolution medium, rotating speed turns for being made as respectively per minute 50,75,100, in accordance with the law operation, in the time of 5,10,20,30,45,60 minutes, 10mL takes a sample respectively, (and simultaneously fluid infusion 10mL) filters, precision pipettes subsequent filtrate 2mL, puts in the 25mL measuring bottle, adds the stripping medium to scale, shake up, as need testing solution.Precision takes by weighing at Febuxostat reference substance 16mg, puts in the 50mL measuring bottle, adds dissolve with methanol and is diluted to scale, shakes up, and precision pipettes 2mL again, puts in the 100mL measuring bottle, adds the stripping medium to scale, shakes up, in contrast product solution.Get above-mentioned two kinds of solution, with reference to " spectrophotography of two appendix IV of Chinese pharmacopoeia version in 2010 A is measured trap at 317nm wavelength place.Calculate every stripping quantity.The results are shown in Table 13.
The mensuration of table 13 selection of speed
When this preparation is 50 rev/mins, 75 rev/mins and 100 rev/mins at rotating speed, the dissolution of 45 minutes these preparations is all about 90%, consider that the mensuration of dissolution is to the situation of quality of the pharmaceutical preparations resolution capability, selected than the slow-speed of revolution, the rotating speed of this preparation dissolution determination is decided to be per minute 50 and turns, and be 30 minutes sample time.
3.6 dissolution method
Dissolution Rate Testing condition and the method for this preparation are with reference to " two appendix X of Chinese pharmacopoeia version in 2010 C tests.The dissolution medium of this preparation is selected 1000mL phosphate buffer (pH=6.8); " two appendix X of Chinese pharmacopoeia version in 2010 C the second method, rotating speed is 50 rev/mins, sampling in 30 minutes, the dissolution of employing UV method working sample in employing.
3.7 linear relationship
Precision takes by weighing Febuxostat crude drug 12.8mg, put in the 100mL measuring bottle, add dissolve with methanol and be diluted to scale, shake up, precision measures 1,3,5,7,10mL puts respectively in the 100mL measuring bottle, adds the stripping medium to scale, shakes up, with reference to " spectrophotography of two records of Chinese pharmacopoeia version in 2010 IV A is measured trap at 317nm wavelength place.The results are shown in Table 14 and Fig. 3.
The mensuration of table 14 working curve
| Concentration (μ g/mL) | 1.287 | 3.861 | 6.435 | 9.009 | 12.870 |
| Trap (A) | 0.094 | 0.281 | 0.457 | 0.653 | 0.912 |
As shown in Figure 3, linear equation is Y=0.0708X+0.0054, R
2=0.9996 shows in 1.287-12.870 μ g/mL concentration range and is good linear.
3.8 stability test
Precision takes by weighing this preparation sheet powder an amount of (containing approximately Febuxostat 16mg), puts in the 50mL measuring bottle, adds dissolve with methanol and is diluted to scale, shakes up, and filters, and gets subsequent filtrate 2mL and puts in the 100mL measuring bottle, adds the stripping medium to scale, shakes up, as need testing solution.Respectively at getting mentioned solution in 0,1,2,3,4 hour, with reference to " spectrophotographys of two records of Chinese pharmacopoeia version in 2010 IV A are measured trap at 317nm wavelength place.The results are shown in Table 15.
The mensuration of table 15 stability test
| Time (h) | 0 | 1 | 2 | 3 | 4 | On average | Rsd％ |
| Trap (A) | 0.437 | 0.429 | 0.433 | 0.435 | 0.430 | 0.433 | 0.77 |
3.9 recovery test
Precision takes by weighing each three parts of Febuxostat crude drug 9.6mg, 16mg, 19.2mg, put respectively in the 50mL measuring bottle, and add various adjuvants in the prescription ratio, add dissolve with methanol and be diluted to scale, shake up, filter, getting subsequent filtrate 2mL puts in the 100mL measuring bottle, add the stripping medium to scale, shake up, as need testing solution.In addition precision takes by weighing Febuxostat reference substance 16mg, puts in the 50mL measuring bottle, adds dissolve with methanol and is diluted to scale, shakes up, and precision pipettes 2mL and puts in the 100mL measuring bottle again, adds the stripping medium to scale, shakes up, in contrast product solution.Get respectively mentioned solution, with reference to " spectrophotography of two appendix IV of Chinese pharmacopoeia version in 2010 A is measured trap at 317nm wavelength place.The results are shown in Table 9.
Table 16 determination of recovery rates result
3.10 the mensuration of stripping curve
Get this preparation (four batches), with reference to " dissolution method of two appendix X of Chinese pharmacopoeia version in 2010 C the second method, take 1000mL phosphate buffer (pH=6.8) as dissolution medium, rotating speed is that per minute 50 turns, in accordance with the law operation, and took a sample respectively in 5,10,20,30,45,60 minutes 10mL(and simultaneously fluid infusion 10mL), filter, get subsequent filtrate 2mL, put in the 25mL measuring bottle, add the stripping medium to scale, shake up, as need testing solution; In addition precision takes by weighing Febuxostat reference substance 16mg, puts in the 50mL measuring bottle, adds dissolve with methanol and is diluted to scale, shakes up, and precision pipettes 2mL and puts in the 100mL measuring bottle again, adds the stripping medium to scale, shakes up, in contrast product solution.Get respectively mentioned solution, with reference to " spectrophotography of two records of Chinese pharmacopoeia version in 2010 IV A is measured trap at 317nm wavelength place.The results are shown in Table 17.
The mensuration of table 17 stripping curve
3.11 the mensuration of dissolution
Get this preparation (four batches), with reference to " dissolution method of two appendix XC the second methods of Chinese pharmacopoeia version in 2010, take 1000mL phosphate buffer (pH=6.8) as dissolution medium, rotating speed is that per minute 50 turns, in accordance with the law operation, and took a sample respectively in 30 minutes 10mL(and simultaneously fluid infusion 10mL), filter, get subsequent filtrate 2mL, put in the 25mL measuring bottle, add the stripping medium to scale, shake up, as need testing solution; In addition precision takes by weighing Febuxostat reference substance 16mg, puts in the 50mL measuring bottle, adds dissolve with methanol and is diluted to scale, shakes up, and precision pipettes 2mL and puts in the 100mL measuring bottle again, adds the stripping medium to scale, shakes up, in contrast product solution.With reference to " spectrophotography of two records of Chinese pharmacopoeia version in 2010 IV A is measured trap at 317nm wavelength place.The results are shown in Table 18.
Table 18 dissolution determination result
| Lot number | 080909 | 081007 | 081008 | 081009 |
| Dissolution (%) | 95.5 | 96.9 | 98.1 | 98.7 |
4, related substance inspection
4.1 chromatographic condition
Instrument model: Japanese Shimadzu LC-10ATvp, SPD-10Avp detector;
Chromatographic column: take octadecylsilane chemically bonded silica as filler;
Mobile phase: methanol-0.3% acetic acid (it is 5.0 that triethylamine is transferred pH) (70:30);
Flow velocity is 1.0mL/min, and column temperature is room temperature, and wavelength is 317nm, and sample size is 10 μ L.
4.2 the preparation of need testing solution
Get this preparation sheet powder an amount of (being equivalent to approximately contain Febuxostat 10mg), put in the 50mL measuring bottle, it is an amount of to add methanol, ultrasonicly makes dissolving, lets cool, and adds methanol and is diluted to scale, shakes up, and filters, and gets subsequent filtrate as need testing solution.
4.3 the blank interference test of adjuvant
The preparation of adjuvant blank solution: according to prescription, get this pharmaceutical adjunct blank an amount of (being equivalent to approximately contain Febuxostat 10mg), put in the 50mL measuring bottle, it is an amount of to add methanol, ultrasonicly make dissolving, let cool, add methanol and be diluted to scale, shake up, filter, get subsequent filtrate as the adjuvant blank solution.
Measure blank solution 10 μ L sample introductions, spectrogram shows blank noiseless as a result.
4.4 failure test
Acid degradation product: get need testing solution 2mL, add 1mol/L hydrochloric acid 1mL, shake up, place half an hour, transfer to neutrality with the 1mol/L sodium hydroxide, and get final product.
Alkaline degradation product: get need testing solution 2mL, add 1mol/L sodium hydroxide 1mL, shake up, place half an hour, transfer to neutrality with 1mol/L hydrochloric acid, and get final product.
Oxidative breakdown product: get need testing solution 2mL, add hydrogen peroxide 2mL, shake up, place half an hour, immediately sample introduction.
High temperature destroys: get need testing solution 5mL, put that heating let cool after 3 hours in the 80 degree baking ovens, add to 5mL with methanol.
Photo damage: get need testing solution 5mL, under 4500 ± 500LX high light, placed 3 hours, add to 5mL with methanol after taking out.
Get respectively each 10 μ L injecting chromatograph of above-mentioned degraded solutions, the record spectrogram, the result shows that this formulation soln is comparatively stable to acid, hydrogen peroxide, light and high temperature, and is more unstable to alkali.
4.5 minimum detects
Get this preparation need testing solution 1mL and put in the 100mL measuring bottle, add methanol and be diluted to scale, shake up, as 1% solution, get respectively again 1% solution and be diluted to 0.01%, 0.02% and 0.03% solution with methanol.
Get respectively each 10 μ L sample introduction of 0.01%, 0.02% and 0.03% above-mentioned solution, the record spectrogram, the result shows that the minimum detectable activity of this preparation is 0.20ng, minimum limit of detection is 0.03%.
4.6 algoscopy:
Get this preparation sheet powder an amount of (being equivalent to approximately contain Febuxostat 10mg), put in the 50mL measuring bottle, it is an amount of to add methanol, ultrasonicly makes dissolving, lets cool, and adds methanol and is diluted to scale, shakes up, and filters, and gets subsequent filtrate as need testing solution.Precision pipettes above-mentioned need testing solution 1mL again, is diluted to 1% own control product solution with methanol; Precision takes by weighing impurity A (retention time was about about 4 minutes) reference substance 10mg in addition, and the amount that is diluted to the impure A of every 1mL with methanol is 2 μ g, and product solution is got each 10 μ L injecting chromatograph of mentioned solution in contrast, the record chromatogram.In the need testing solution chromatogram, if any the impurity A peak, calculate with external standard method, should be greater than 1%(1%); Desolventize outside peak and the adjuvant peak, the peak area sum of other impurity should be not more than 1 times (1%) of own control peak area.Measure four batches and the results are shown in Table 19.
The inspection of table 19 related substance
| Lot number | 080909 | 081007 | 081008 | 081009 |
| Impurity A | 0.387 | 0.037 | 0.391 | 0.183 |
| Other impurity | 0.059 | 0.048 | 0.048 | 0.068 |
Four, assay
Adopt the HPLC method to carry out the methodological study of assay, and measured the content of sample.The content limit of stipulating this preparation is 95.0-105.0%.
1, instrument model: Japanese Shimadzu LC-10ATvp; The SPD-10Avp detector.
2, chromatographic condition
Be filler with octadecylsilane chemically bonded silica; Methanol-0.3% acetic acid (it is 5.0 that triethylamine is transferred pH) (70:30) adopts UV to detect, and the detection wavelength is 317nm.Flow velocity is 1.0mL/L.
3, replica test
Get same batch sample an amount of (containing approximately Febuxostat 10mg), six parts respectively, accurately weighed, put in the 50mL measuring bottle, it is an amount of to add methanol, ultrasonicly makes dissolving, adds methanol to scale, shakes up, and filters.Precision is measured subsequent filtrate 5mL and is put in the 25mL measuring bottle respectively, adds methanol and is diluted to scale, shakes up, as need testing solution; In addition precision takes by weighing Febuxostat reference substance 10mg and puts in the 50mL measuring bottle, and it is an amount of to add methanol, ultrasonicly makes dissolving, adds methanol to scale, and precision is measured 5mL and put in the 25mL measuring bottle respectively, adds methanol and is diluted to scale, shakes up, in contrast product solution.Precision is measured above-mentioned reference substance solution and each 10 μ L difference injection liquid chromatography of need testing solution, the record chromatogram, and the content of calculating working sample the results are shown in Table 20.
The repeated measurement result of table 20
4, need testing solution stability
Get repeatability lower first part of need testing solution, get 10 μ L injection liquid chromatographies respectively at 0,2,4,6,8 hour, the record chromatogram, and get final product.The results are shown in Table 21.
Table 21 Stability Determination result
| Time (hour)) | 0 | 2 | 4 | 6 | 8 | On average | RSD% |
| Peak area (A) * 10 3 | 1158 | 1165 | 1156 | 1161 | 1159 | 1159.8 | 0.29 |
5, recovery test
Precision takes by weighing three parts respectively of Febuxostat reference substance 8,10,12mg, put in the 50mL measuring bottle, add adjuvant in the prescription ratio, add an amount of ultrasonic Febuxostat dissolving that makes of methanol, add again methanol and be diluted to scale, shake up, filter, precision pipettes subsequent filtrate 5mL, put in 25 measuring bottles, add methanol and be diluted to scale, shake up, as need testing solution.In addition precision takes by weighing Febuxostat reference substance 10mg and puts in the 50mL measuring bottle, and it is an amount of to add methanol, ultrasonicly makes dissolving, adds methanol to scale, and precision is measured 5mL and put in the 25mL measuring bottle respectively, adds methanol and is diluted to scale, shakes up, in contrast product solution.Precision is measured above-mentioned reference substance solution and each 10 μ L difference injection liquid chromatography of need testing solution, record chromatogram, calculate recovery rate.The results are shown in Table 22.
Table 22 determination of recovery rates result
6, assay
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Methanol-0.3% acetic acid (it is 5.0 that triethylamine is transferred pH) (70:30) adopts UV to detect, and the detection wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed the Febuxostat peak and is calculated, and should be not less than 2000.
Get 20 in this preparation, accurately weighed, porphyrize, precision takes by weighing in right amount (being equivalent to approximately Febuxostat 10mg), put in the 50mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolving and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in the 25mL measuring bottle, add methanol and be diluted to scale, shake up, as need testing solution.In addition precision takes by weighing Febuxostat reference substance 10mg and puts in the 50mL measuring bottle, and it is an amount of to add methanol, ultrasonicly makes dissolving, adds methanol to scale, and precision is measured 5mL and put in the 25mL measuring bottle respectively, adds methanol and is diluted to scale, shakes up, in contrast product solution.Precision is measured above-mentioned reference substance solution and each 10 μ L difference injection liquid chromatography of need testing solution, the record chromatogram, and result of calculation sees Table 23.
Table 23 assay result
| Lot number | 080909 | 081007 | 081008 | 081009 |
| Labelled amount content (%) | 100.5 | 100.0 | 100.2 | 100.1 |
Five, stability testing method and result
According to " stability of Febuxostat sheet is investigated in the stability requirement of Chinese pharmacopoeia version two-shift system in 2010 agent medicine.
1, accelerated test: (sample lot number: 081007,081008,081009)
Get this preparation, simulation listing packing respectively, placing 40 ℃ ± 2 ℃, humidity is to place for 75% ± 5% time, in sampling in 0,1,2,3,6 month, detects.The results are shown in Table 24.
Table 24 accelerated test result
5.2 long term test: (sample lot number: 081007,081008,081009)
Get this preparation, simulation listing packing respectively, placing 25 ℃ ± 2 ℃, relative humidity is 60% ± 10% to preserve, and in sampling in 0,3,6,12,18 month, detects.The results are shown in Table 25.
Table 25 long-term test results
Six, conclusion and evaluation
According to chemicals stability study technological guidance principle this preparation has been carried out stability test.(1) pilot sample is carried out influence factor's experiments such as illumination, high temperature, high humidity, the result shows: every investigation index all meets the clinical sample quality draft standard of using without significant change; (2) three batch samples are accelerated test 6 months (40 ℃, RH 75% condition under) under simulation listing packing, and after 6 months, every investigation index all meets the clinical sample quality draft standard of using without significant change to this preparation through above-mentioned condition accelerated test; (3) three batch samples simulation listing packing, under 25 ℃ ± 2 ℃, the condition of relative humidity 60% ± 10%, investigate 6 months through keeping sample for a long time after, every investigation index is without significant change, all meet the clinical sample quality draft standard of using, keep sample for a long time to investigate to test and still carrying out.
Compared with prior art, the present invention improves prescription and the preparation technology of Febuxostat tablet, is stable preparation process, feasible, and the Febuxostat tablet quality of preparation is well stable, makes its curative effect to diseases such as hyperuricemia and gouts more remarkable; And, the present invention is directed to Febuxostat tablet after the improvement and set up system, complete, effective quality determining method, the specificity of described method is strong, precision is high, favorable reproducibility, the response rate high, measurement result is accurate, reach the purpose of effective control drug quality, thereby guaranteed stable and clinical application safe, effective of product quality.Package materials selection is proper, and it is good to place for a long time sample stability.
Description of drawings
Fig. 1 is the moisture absorption percentage curves figure of medicated powder under the different relative humiditys;
Fig. 2 is the different dissolution medium comparative graph of two kinds of crystal formations;
Fig. 3 right and wrong Bu Suotan sheet dissolution linear relationship working curve diagram.
The specific embodiment
The present invention is further illustrated below in conjunction with embodiment.
Embodiment 1: described Febuxostat tablet is made by 80g Febuxostat, 110g microcrystalline Cellulose, 40g lactose, 18g cross-linking sodium carboxymethyl cellulose and 2g magnesium stearate.Get Febuxostat, lactose, cross respectively 80 eye mesh screens, for subsequent use; With 80g Febuxostat and 110g microcrystalline Cellulose, 40g lactose, 8g cross-linking sodium carboxymethyl cellulose mix homogeneously, add an amount of purified water soft material processed, 18 eye mesh screens are granulated, 70 ℃ of dryings, 18 mesh sieve granulate add surplus cross-linked carboxymethyl fiber sodium and 2g magnesium stearate, mix homogeneously; Intermediate detects, and qualified rear tabletting gets plain sheet; Get 370g ethanol, the 100g purified water places agitator, adds 30g premix coating powder in situation about constantly stirring, and continues to stir 1 hour, coating solution filters with 100 eye mesh screens, and is for subsequent use; Plain sheet is placed in the coating pan, open coating pan and start air draft and dust exhaust apparatus, use simultaneously 40 ℃～45 ℃ hot-air pre-heatings, plain sheet is heated evenly, and sops up the fine powder that is adsorbed on the plain sheet; Start coating pan, regulate coating solution granularity of spray and spray velocity, the coating solution for preparing is sparged on the label of rotation equably; After coating is complete, continue to use cold air drying 10 minutes, coating weightening finish 3%-5% gets final product; In mixing and tabletting filling process, ambient humidity is controlled at below 50%.
Embodiment 2: described Febuxostat tablet is made by 120g Febuxostat, 165g microcrystalline Cellulose, 60g lactose, 27g cross-linking sodium carboxymethyl cellulose and 3g magnesium stearate.Get Febuxostat, lactose, cross respectively 80 eye mesh screens, for subsequent use; With 120g Febuxostat and 165g microcrystalline Cellulose, 60g lactose, 12g cross-linking sodium carboxymethyl cellulose mix homogeneously, add an amount of purified water soft material processed, 18 eye mesh screens are granulated, 70 ℃ of dryings, 18 mesh sieve granulate add surplus cross-linked carboxymethyl fiber sodium and 3g magnesium stearate, mix homogeneously; Intermediate detects, and qualified rear tabletting gets plain sheet; Get 550g ethanol, the 150g purified water places agitator, adds 45g premix coating powder in situation about constantly stirring, and continues to stir 1 hour, coating solution filters with 100 eye mesh screens, and is for subsequent use; Plain sheet is placed in the coating pan, open coating pan and start air draft and dust exhaust apparatus, use simultaneously 40 ℃～45 ℃ hot-air pre-heatings, plain sheet is heated evenly, and sops up the fine powder that is adsorbed on the plain sheet; Start coating pan, regulate coating solution granularity of spray and spray velocity, the coating solution for preparing is sparged on the label of rotation equably; After coating is complete, continue to use cold air drying 10 minutes, coating weightening finish 3%-5% gets final product; In mixing and tabletting filling process, ambient humidity is controlled at below 50%.
Embodiment 3: described Febuxostat tablet is made by 40g Febuxostat, 95g microcrystalline Cellulose, 20g lactose, 10g cross-linking sodium carboxymethyl cellulose and 1g magnesium stearate.Get Febuxostat, lactose, cross respectively 80 eye mesh screens, for subsequent use; With 40g Febuxostat and 95g microcrystalline Cellulose, 20g lactose, 4g cross-linking sodium carboxymethyl cellulose mix homogeneously, add an amount of purified water soft material processed, 18 eye mesh screens are granulated, 70 ℃ of dryings, 18 mesh sieve granulate add surplus cross-linked carboxymethyl fiber sodium and 1g magnesium stearate, mix homogeneously; Intermediate detects, and qualified rear tabletting gets plain sheet; Get 185g ethanol, the 50g purified water places agitator, adds 15g premix coating powder in situation about constantly stirring, and continues to stir 1 hour, coating solution filters with 100 eye mesh screens, and is for subsequent use; Plain sheet is placed in the coating pan, open coating pan and start air draft and dust exhaust apparatus, use simultaneously 40 ℃～45 ℃ hot-air pre-heatings, plain sheet is heated evenly, and sops up the fine powder that is adsorbed on the plain sheet; Start coating pan, regulate coating solution granularity of spray and spray velocity, the coating solution for preparing is sparged on the label of rotation equably; After coating is complete, continue to use cold air drying 10 minutes, coating weightening finish 3%-5% gets final product; In mixing and tabletting filling process, ambient humidity is controlled at below 50%.
Embodiment 4: the complete detection method of Febuxostat tablet of the present invention is:
(1) character: this preparation is Film coated tablets, remove coating after, whitening color or off-white color;
(2) assay:
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Mobile phase is that methanol-transfer pH with triethylamine is 5.0 0.3% acetic acid=70:30, adopts UV to detect, and the detection wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed the Febuxostat peak and is calculated, and should be not less than 2000;
Algoscopy: get 20 in this preparation, accurately weighed, porphyrize, precision takes by weighing the fine powder that is equivalent to Febuxostat 10mg, put in the 50mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolving and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in the 25mL measuring bottle, add methanol and be diluted to scale, shake up, as need testing solution; In addition precision takes by weighing Febuxostat reference substance 10mg and puts in the 50mL measuring bottle, and it is an amount of to add methanol, ultrasonicly makes dissolving, adds methanol to scale, and precision is measured 5mL and put in the 25mL measuring bottle respectively, adds methanol and is diluted to scale, shakes up, in contrast product solution; Precision is measured above-mentioned reference substance solution and each 10 μ L of need testing solution, and the injection liquid chromatography records chromatogram respectively;
(3) differentiate:
(1) liquid phase is differentiated: under the assay item, the retention time of the test sample main peak all retention time with the reference substance peak is consistent;
(2) ultraviolet is differentiated: get this preparation fine powder that is equivalent to Febuxostat 6mg, put in the 100mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolving and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in the 50mL measuring bottle, add methanol and be diluted to scale, shake up, with reference to " ultraviolet visible spectrophotometry of two appendix IV of Chinese pharmacopoeia version in 2010 A is measured, and at the wavelength place of 215nm and 315nm absorption maximum is arranged;
(4) check:
(1) dissolution: concrete operations are as follows: get this preparation, with reference to " dissolution method of two appendix X of Chinese pharmacopoeia version in 2010 C the second method, take the 1000mL phosphate buffer of pH=6.8 as dissolution medium, rotating speed is that per minute 50 turns, in accordance with the law operation, and in 30 minutes sampling 10mL, filter, get subsequent filtrate 2mL, put in the 25mL measuring bottle, add the stripping medium to scale, shake up, as need testing solution; In addition precision takes by weighing Febuxostat reference substance 16mg, puts in the 50mL measuring bottle, adds dissolve with methanol and is diluted to scale, shakes up, and precision pipettes 2mL and puts in the 100mL measuring bottle again, adds the stripping medium to scale, shakes up, in contrast product solution; With reference to " spectrophotography of two records of Chinese pharmacopoeia version in 2010 IV A is measured trap at 317nm wavelength place; Calculate every stripping quantity;
(2) related substance:
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Mobile phase is that methanol-transfer pH with triethylamine is 5.0 0.3% acetic acid=70:30, adopts UV to detect, and the detection wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed the Febuxostat peak and is calculated, and should be not less than 2000;
Algoscopy: get this preparation sheet powder that is equivalent to contain Febuxostat 10mg, put in the 50mL measuring bottle, it is an amount of to add methanol, ultrasonicly makes dissolving, lets cool, and adds methanol and is diluted to scale, shakes up, and filters, and gets subsequent filtrate as need testing solution; Precision pipettes above-mentioned need testing solution 1mL again, is diluted to 1% own control product solution with methanol; Precision takes by weighing impurity A reference substance 10mg in addition, and the amount that is diluted to the impure A of every 1mL with methanol is 2 μ g, and product solution is got above-mentioned need testing solution, each 10 μ L injecting chromatograph of reference substance solution, the record chromatogram in contrast; In the need testing solution chromatogram, if any the impurity A peak, calculate with external standard method, should be greater than 1%; Desolventize outside peak and the adjuvant peak, the peak area sum of other impurity should be not more than 1 times of own control peak area;
(3) microbial limit: get this preparation, with reference to " method of Chinese pharmacopoeia two appendix XI J in 2010 is calculated;
(4) weight differential: get this preparation, accurately weighed, it is heavy to calculate average sheet, distinguishes accurately weighed every weight again, should meet " the regulation of two appendix I of Chinese pharmacopoeia version in 2010 A.
Claims (9)
1. a Febuxostat tablet is characterized in that: calculate by weight, made by 40～120 parts of Febuxostats, 95～165 parts of microcrystalline Cellulose, 20～60 parts of lactose, 10～27 parts of cross-linking sodium carboxymethyl celluloses and 1～3 part of magnesium stearate.
2. Febuxostat tablet according to claim 1 is characterized in that: made by 80g Febuxostat, 110g microcrystalline Cellulose, 40g lactose, 18g cross-linking sodium carboxymethyl cellulose and 2g magnesium stearate.
3. the preparation method of Febuxostat tablet as claimed in claim 1 or 2 is characterized in that, described preparation method may further comprise the steps:
(1) preparation of label:
1. get Febuxostat, lactose, cross respectively 80 eye mesh screens, for subsequent use;
2. with Febuxostat and microcrystalline Cellulose, lactose, partial cross-linked sodium carboxymethyl cellulose mix homogeneously, add an amount of purified water soft material processed, 18 eye mesh screens are granulated, 70 ℃ of dryings, 18 mesh sieve granulate add surplus cross-linked carboxymethyl fiber sodium and magnesium stearate, mix homogeneously;
3. intermediate detects, and qualified rear tabletting gets plain sheet;
(2) film coating:
1. get ethanol, purified water places agitator, adds the premix coating powder in situation about constantly stirring, and continues to stir 1 hour, coating solution filters with 100 eye mesh screens, and is for subsequent use;
2. plain sheet is placed in the coating pan, open coating pan and start air draft and dust exhaust apparatus, use simultaneously 40 ℃～45 ℃ hot-air pre-heatings, plain sheet is heated evenly, and sops up the fine powder that is adsorbed on the plain sheet; Start coating pan, regulate coating solution granularity of spray and spray velocity, the coating solution for preparing is sparged on the label of rotation equably; After coating is complete, continue to use cold air drying 10 minutes, coating weightening finish 3%-5% gets final product.
4. the preparation method of Febuxostat tablet according to claim 3 is characterized in that: mix and the tabletting filling process in, ambient humidity is controlled at below 50%.
5. the detection method of Febuxostat tablet as claimed in claim 1 or 2, it is characterized in that: described detection method comprises character, discriminating, inspection and assay project; Wherein differentiate it is that the Febuxostat in the preparation is differentiated; Inspection is respectively this preparation to be carried out related substance, dissolution, microbial limit and weight differential to check; Assay is that Febuxostat is measured.
6. the detection method of Febuxostat tablet according to claim 5 is characterized in that: concrete content assaying method is:
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Mobile phase is that methanol-transfer pH with triethylamine is 5.0 0.3% acetic acid=70:30, adopts UV to detect, and the detection wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed the Febuxostat peak and is calculated, and should be not less than 2000;
Algoscopy: get 20 in this preparation, accurately weighed, porphyrize, precision takes by weighing the fine powder that is equivalent to Febuxostat 10mg, put in the 50mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolving and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in the 25mL measuring bottle, add methanol and be diluted to scale, shake up, as need testing solution; In addition precision takes by weighing Febuxostat reference substance 10mg and puts in the 50mL measuring bottle, and it is an amount of to add methanol, ultrasonicly makes dissolving, adds methanol to scale, and precision is measured 5mL and put in the 25mL measuring bottle respectively, adds methanol and is diluted to scale, shakes up, in contrast product solution; Precision is measured above-mentioned reference substance solution and each 10 μ L of need testing solution, and the injection liquid chromatography records chromatogram respectively.
7. according to claim 5 or the detection method of 6 described Febuxostat tablets, it is characterized in that concrete discrimination method is:
(1) liquid phase is differentiated: under the assay item, the retention time of the test sample main peak all retention time with the reference substance peak is consistent;
(2) ultraviolet is differentiated: get this preparation fine powder that is equivalent to Febuxostat 6mg, put in the 100mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolving and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in the 50mL measuring bottle, add methanol and be diluted to scale, shake up, with reference to " ultraviolet visible spectrophotometry of two appendix IV of Chinese pharmacopoeia version in 2010 A is measured, and at the wavelength place of 215nm and 315nm absorption maximum is arranged.
8. the detection method of Febuxostat tablet according to claim 7 is characterized in that, the particular exam method is:
(1) dissolution: concrete operations are as follows: get this preparation, with reference to " dissolution method of two appendix X of Chinese pharmacopoeia version in 2010 C the second method, take the 1000mL phosphate buffer of pH=6.8 as dissolution medium, rotating speed is that per minute 50 turns, in accordance with the law operation, and in 30 minutes sampling 10mL, filter, get subsequent filtrate 2mL, put in the 25mL measuring bottle, add the stripping medium to scale, shake up, as need testing solution; In addition precision takes by weighing Febuxostat reference substance 16mg, puts in the 50mL measuring bottle, adds dissolve with methanol and is diluted to scale, shakes up, and precision pipettes 2mL and puts in the 100mL measuring bottle again, adds the stripping medium to scale, shakes up, in contrast product solution; With reference to " spectrophotography of two records of Chinese pharmacopoeia version in 2010 IV A is measured trap at 317nm wavelength place; Calculate every stripping quantity;
(2) related substance:
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Mobile phase is that methanol-transfer pH with triethylamine is 5.0 0.3% acetic acid=70:30, adopts UV to detect, and the detection wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed the Febuxostat peak and is calculated, and should be not less than 2000;
Algoscopy: get this preparation sheet powder that is equivalent to contain Febuxostat 10mg, put in the 50mL measuring bottle, it is an amount of to add methanol, ultrasonicly makes dissolving, lets cool, and adds methanol and is diluted to scale, shakes up, and filters, and gets subsequent filtrate as need testing solution; Precision pipettes above-mentioned need testing solution 1mL again, is diluted to 1% own control product solution with methanol; Precision takes by weighing impurity A reference substance 10mg in addition, and the amount that is diluted to the impure A of every 1mL with methanol is 2 μ g, and product solution is got above-mentioned need testing solution, each 10 μ L injecting chromatograph of reference substance solution, the record chromatogram in contrast; In the need testing solution chromatogram, if any the impurity A peak, calculate with external standard method, should be greater than 1%; Desolventize outside peak and the adjuvant peak, the peak area sum of other impurity should be not more than 1 times of own control peak area;
(3) microbial limit: get this preparation, with reference to " method of Chinese pharmacopoeia two appendix XI J in 2010 is calculated;
(4) weight differential: get this preparation, accurately weighed, it is heavy to calculate average sheet, distinguishes accurately weighed every weight again, should meet " the regulation of two appendix I of Chinese pharmacopoeia version in 2010 A.
9. according to claim 5 or the detection method of 6 described Febuxostat tablets, it is characterized in that described detection method comprises:
(1) character: this preparation is Film coated tablets, remove coating after, whitening color or off-white color;
(2) assay:
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Mobile phase is that methanol-transfer pH with triethylamine is 5.0 0.3% acetic acid=70:30, adopts UV to detect, and the detection wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed the Febuxostat peak and is calculated, and should be not less than 2000;
Algoscopy: get 20 in this preparation, accurately weighed, porphyrize, precision takes by weighing the fine powder that is equivalent to Febuxostat 10mg, put in the 50mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolving and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in the 25mL measuring bottle, add methanol and be diluted to scale, shake up, as need testing solution; In addition precision takes by weighing Febuxostat reference substance 10mg and puts in the 50mL measuring bottle, and it is an amount of to add methanol, ultrasonicly makes dissolving, adds methanol to scale, and precision is measured 5mL and put in the 25mL measuring bottle respectively, adds methanol and is diluted to scale, shakes up, in contrast product solution; Precision is measured above-mentioned reference substance solution and each 10 μ L of need testing solution, and the injection liquid chromatography records chromatogram respectively;
(3) differentiate:
(1) liquid phase is differentiated: under the assay item, the retention time of the test sample main peak all retention time with the reference substance peak is consistent;
(2) ultraviolet is differentiated: get this preparation fine powder that is equivalent to Febuxostat 6mg, put in the 100mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolving and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in the 50mL measuring bottle, add methanol and be diluted to scale, shake up, with reference to " ultraviolet visible spectrophotometry of two appendix IV of Chinese pharmacopoeia version in 2010 A is measured, and at the wavelength place of 215nm and 315nm absorption maximum is arranged;
(4) check:
(1) dissolution: concrete operations are as follows: get this preparation, with reference to " dissolution method of two appendix X of Chinese pharmacopoeia version in 2010 C the second method, take the 1000mL phosphate buffer of pH=6.8 as dissolution medium, rotating speed is that per minute 50 turns, in accordance with the law operation, and in 30 minutes sampling 10mL, filter, get subsequent filtrate 2mL, put in the 25mL measuring bottle, add the stripping medium to scale, shake up, as need testing solution; In addition precision takes by weighing Febuxostat reference substance 16mg, puts in the 50mL measuring bottle, adds dissolve with methanol and is diluted to scale, shakes up, and precision pipettes 2mL and puts in the 100mL measuring bottle again, adds the stripping medium to scale, shakes up, in contrast product solution; With reference to " spectrophotography of two records of Chinese pharmacopoeia version in 2010 IV A is measured trap at 317nm wavelength place; Calculate every stripping quantity;
(2) related substance:
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Mobile phase is that methanol-transfer pH with triethylamine is 5.0 0.3% acetic acid=70:30, adopts UV to detect, and the detection wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed the Febuxostat peak and is calculated, and should be not less than 2000;
Algoscopy: get this preparation sheet powder that is equivalent to contain Febuxostat 10mg, put in the 50mL measuring bottle, it is an amount of to add methanol, ultrasonicly makes dissolving, lets cool, and adds methanol and is diluted to scale, shakes up, and filters, and gets subsequent filtrate as need testing solution; Precision pipettes above-mentioned need testing solution 1mL again, is diluted to 1% own control product solution with methanol; Precision takes by weighing impurity A reference substance 10mg in addition, and the amount that is diluted to the impure A of every 1mL with methanol is 2 μ g, and product solution is got above-mentioned need testing solution, each 10 μ L injecting chromatograph of reference substance solution, the record chromatogram in contrast; In the need testing solution chromatogram, if any the impurity A peak, calculate with external standard method, should be greater than 1%; Desolventize outside peak and the adjuvant peak, the peak area sum of other impurity should be not more than 1 times of own control peak area;
(3) microbial limit: get this preparation, with reference to " method of Chinese pharmacopoeia two appendix XI J in 2010 is calculated;
(4) weight differential: get this preparation, accurately weighed, it is heavy to calculate average sheet, distinguishes accurately weighed every weight again, should meet " the regulation of two appendix I of Chinese pharmacopoeia version in 2010 A.
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|---|---|---|---|---|
| CN103389346A (en) * | 2013-07-18 | 2013-11-13 | 湖北华世通潜龙药业有限公司 | A method for determining febuxostat and impurities in an oral preparation by HPLC |
| CN107179286A (en) * | 2017-06-29 | 2017-09-19 | 远大医药（中国）有限公司 | A kind of method for determining indapamide content |
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| CN111504928B (en) * | 2020-06-05 | 2023-06-16 | 深圳麦德凯诺医药科技有限公司 | Method for detecting dissolution rate of calcium acetate tablets |
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| CN102552197A (en) * | 2011-12-28 | 2012-07-11 | 辰欣药业股份有限公司 | Tablet containing febuxostat and preparation method of the tablet |
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| CN101881756B (en) * | 2009-05-04 | 2012-12-05 | 南京海辰药业有限公司 | Method for analyzing and separating Febuxostat and intermediates thereof by high performance liquid chromatography |
| CN101929988B (en) * | 2009-06-26 | 2014-05-07 | 北京德众万全药物技术开发有限公司 | Method for detecting febuxostat-associated matters by using high performance liquid chromatography |
| CN101671314B (en) * | 2009-09-17 | 2011-11-23 | 中国药科大学 | Uloric crystal and preparation method thereof |
| WO2011141933A2 (en) * | 2010-05-12 | 2011-11-17 | Msn Laboratories Limited | Process for preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid and its pharmaceutically acceptable salts |
| CN102565225A (en) * | 2011-12-29 | 2012-07-11 | 辰欣药业股份有限公司 | Method for determining related substances by utilizing high performance liquid chromatography in febuxostat synthesis process |
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| CN102018705A (en) * | 2010-12-17 | 2011-04-20 | 江苏同禾药业有限公司 | Pharmaceutical composition containing febuxostat crystals and preparation method thereof |
| CN102488665A (en) * | 2011-12-15 | 2012-06-13 | 宁夏康亚药业有限公司 | Febuxostat tablet and preparation method thereof |
| CN102552197A (en) * | 2011-12-28 | 2012-07-11 | 辰欣药业股份有限公司 | Tablet containing febuxostat and preparation method of the tablet |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103389346A (en) * | 2013-07-18 | 2013-11-13 | 湖北华世通潜龙药业有限公司 | A method for determining febuxostat and impurities in an oral preparation by HPLC |
| CN103389346B (en) * | 2013-07-18 | 2014-08-06 | 湖北华世通潜龙药业有限公司 | A method for determining febuxostat and impurities in an oral preparation by HPLC |
| CN107179286A (en) * | 2017-06-29 | 2017-09-19 | 远大医药（中国）有限公司 | A kind of method for determining indapamide content |
Also Published As
| Publication number | Publication date |
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| CN105372372A (en) | 2016-03-02 |
| CN105372372B (en) | 2018-05-01 |
| CN102988326B (en) | 2016-01-20 |
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Address after: 550014 Luodian County, Qiannan Buyei and Miao Autonomous Prefecture, Jiefang Road Province Ping Town, No., No. 96 Patentee after: Xinbang Pharmacy Co., Ltd., Guizhou Address before: 227 No. 550014 Guizhou Guiyang Xinbang Baiyun Road Economic Development Zone Patentee before: Xinbang Pharmacy Co., Ltd., Guizhou |
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