CN105372372B - A kind of detection method of febuxostat tablet - Google Patents
A kind of detection method of febuxostat tablet Download PDFInfo
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- CN105372372B CN105372372B CN201510880714.0A CN201510880714A CN105372372B CN 105372372 B CN105372372 B CN 105372372B CN 201510880714 A CN201510880714 A CN 201510880714A CN 105372372 B CN105372372 B CN 105372372B
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- Prior art keywords
- febuxostat
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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 118
- 229960005101 febuxostat Drugs 0.000 title claims abstract description 118
- 238000001514 detection method Methods 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 claims abstract description 77
- 238000000034 method Methods 0.000 claims abstract description 45
- 238000004090 dissolution Methods 0.000 claims abstract description 31
- 239000000463 material Substances 0.000 claims abstract description 27
- 238000003556 assay Methods 0.000 claims abstract description 21
- 238000007689 inspection Methods 0.000 claims abstract description 14
- 230000000813 microbial effect Effects 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 267
- 239000000243 solution Substances 0.000 claims description 67
- 239000013558 reference substance Substances 0.000 claims description 55
- 239000012085 test solution Substances 0.000 claims description 52
- 239000011248 coating agent Substances 0.000 claims description 44
- 238000000576 coating method Methods 0.000 claims description 44
- 239000003826 tablet Substances 0.000 claims description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 33
- 238000010790 dilution Methods 0.000 claims description 33
- 239000012895 dilution Substances 0.000 claims description 33
- 238000012360 testing method Methods 0.000 claims description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- 239000000843 powder Substances 0.000 claims description 30
- 239000000523 sample Substances 0.000 claims description 30
- 239000000706 filtrate Substances 0.000 claims description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 23
- 239000012535 impurity Substances 0.000 claims description 20
- 238000005063 solubilization Methods 0.000 claims description 20
- 230000007928 solubilization Effects 0.000 claims description 20
- 238000002604 ultrasonography Methods 0.000 claims description 20
- 239000002609 medium Substances 0.000 claims description 19
- 239000000047 product Substances 0.000 claims description 14
- 239000000945 filler Substances 0.000 claims description 13
- 238000002798 spectrophotometry method Methods 0.000 claims description 12
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 11
- 239000012071 phase Substances 0.000 claims description 11
- 239000000377 silicon dioxide Substances 0.000 claims description 11
- 239000012738 dissolution medium Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 230000014759 maintenance of location Effects 0.000 claims description 10
- 238000010521 absorption reaction Methods 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- 239000008363 phosphate buffer Substances 0.000 claims description 9
- 238000011978 dissolution method Methods 0.000 claims description 8
- 230000033228 biological regulation Effects 0.000 claims description 6
- 238000000870 ultraviolet spectroscopy Methods 0.000 claims description 6
- 101100515520 Arabidopsis thaliana XI-J gene Proteins 0.000 claims description 5
- 238000010812 external standard method Methods 0.000 claims description 5
- 239000004744 fabric Substances 0.000 claims description 5
- 239000007941 film coated tablet Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 239000007791 liquid phase Substances 0.000 claims description 4
- 230000002087 whitening effect Effects 0.000 claims description 3
- 239000000413 hydrolysate Substances 0.000 claims description 2
- 239000012488 sample solution Substances 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 abstract description 21
- 239000003814 drug Substances 0.000 abstract description 21
- 239000008101 lactose Substances 0.000 abstract description 21
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 abstract description 15
- 229920000168 Microcrystalline cellulose Polymers 0.000 abstract description 12
- 235000019813 microcrystalline cellulose Nutrition 0.000 abstract description 12
- 235000019359 magnesium stearate Nutrition 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 8
- 230000006641 stabilisation Effects 0.000 abstract description 3
- 238000011105 stabilization Methods 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000013078 crystal Substances 0.000 description 9
- 201000005569 Gout Diseases 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000008213 purified water Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000000853 adhesive Substances 0.000 description 6
- 230000001070 adhesive effect Effects 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 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
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- 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 description 4
- 206010013786 Dry skin Diseases 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 4
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 4
- 239000000428 dust Substances 0.000 description 4
- 239000000835 fiber Substances 0.000 description 4
- 238000005429 filling process Methods 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 238000004806 packaging method and process Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 4
- 238000012797 qualification 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
- 229940116269 uric acid Drugs 0.000 description 4
- 235000020985 whole grains Nutrition 0.000 description 4
- 201000001431 Hyperuricemia Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 238000007605 air drying Methods 0.000 description 3
- 239000012490 blank solution Substances 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000007888 film coating Substances 0.000 description 3
- 238000009501 film coating Methods 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 239000011122 softwood Substances 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 230000004584 weight gain Effects 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 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
- 230000003796 beauty Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- DKXULEFCEORBJK-UHFFFAOYSA-N magnesium;octadecanoic acid Chemical compound [Mg].CCCCCCCCCCCCCCCCCC(O)=O DKXULEFCEORBJK-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000008279 sol 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
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-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
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base 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
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical class C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical class [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 238000012850 discrimination method Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 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
- 239000008187 granular material Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000008832 photodamage Effects 0.000 description 1
- 238000005375 photometry Methods 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 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
- 230000003252 repetitive effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940126673 western medicines Drugs 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
-
- G—PHYSICS
- 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
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/33—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using ultraviolet light
-
- 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
- G01N30/90—Plate chromatography, e.g. thin layer or paper chromatography
-
- 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
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pathology (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The present invention provides a kind of detection method of febuxostat tablet, the tablet calculates by weight, is made of 40~120 parts of Febuxostats, 95~165 parts of microcrystalline celluloses, 20~60 parts of lactose, 10~27 parts of Ac-Di-Sols and 1~3 part of magnesium stearate；The detection method includes character, discriminating, inspection and assay project；Wherein differentiate it is that the Febuxostat in preparation is differentiated；Inspection is to carry out related material, dissolution rate, microbial limit and weight differential to this preparation respectively to check；Assay is that Febuxostat is measured.The present invention establishes system, complete, effective quality determining method, achieveed the purpose that it is effective control drug quality, ensure that product quality stabilization and clinical application safely, effectively.
Description
It is on December 14th, 2012 applying date that the application, which is, Application No. 2012105440901, a kind of entitled " non-cloth
The divisional application of the application for a patent for invention of sotan tablet and preparation method thereof and detection method ".
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
One group of different substantiality disease that gout increases for blood uric acid caused by purine metabolic disturbance and (or) sour acatharsia.Second
After secondary world war, as the raising of various countries' economic level, the change of dietary structure, population aging, service life extend, high lithemia
Mass formed by blood stasis is as the high morbidity of the elderly.
Gout is exactly the common disease of the developed countries such as America and Europe from ancient times.In the past 20 years, Asia hyperuricemia and gout
Illness rate have the trend significantly increased.
Allopurinol is that clinically only one is used for the medicine for suppressing uric acid generation, and as the gold curative of gout
Thing is widely used in clinic, but is tieed up since allopurinol only has inhibitory action to the XOR of reduced form, it is necessary to repeat heavy dose of administration
Hold higher levels of drugs.Many patients are to Allopurinol allergy, invalid or be not resistant to.And Febuxostat (febuxostat) is then
It is a species specificity xanthine oxidase inhibitor.Compared with Allopurinol, Febuxostat prevent gout break out the effect of and medicine
The incidence of adverse reaction is similar, but suppresses uric acid generation intensity higher.Existing European Union ratifies its application for quotation with FDA, is used for
The treatment of the chronic excessive disease gout of uric acid.Clinical study results show：The Clinical efficacy and security of Febuxostat have
Satisfactory result.
But since Febuxostat is purine analogue, inevitably causes to be related to purine and pyridine is metabolized other enzymes
The influence of activity, therefore be administered in allopurinol treatment, it is necessary to repeat heavy dose to maintain higher levels of drugs, it have impact on non-
The treatment curative effect of cloth sotan.
In addition, at present to Febuxostat medicine also without a set of stringent reliable quality inspection standard.If without stringent
Quality standard, obtained product cannot ensure its quality, as a result will influence the clinical efficacy of the medicine；It is so non-to improve
The therapeutic effect of cloth sotan medicine, it is ensured that medication safely, effectively and product quality stabilization, formulate a stringent reliable matter
Amount standard becomes the basic demand ensured drug quality.With the development of Modern Instrument Analytical Technique, high performance liquid chromatography etc.
Analysis method is more and more widely used in the quality control of medicine.
The content of the invention
It is an object of the present invention to provide a kind of febuxostat tablet and preparation method thereof and detection method.Pin of the present invention
To the deficiencies in the prior art, the prescription and preparation process of febuxostat tablet are optimized, make it to hyperuricemia and
The effect of diseases such as gout, is more notable, and establish system, complete, effective component differentiates and content assaying method,
The quality of the medicine can be effectively controlled, so that it is guaranteed that its clinical efficacy.
Technical scheme：A kind of febuxostat tablet, calculates by weight, be by 40~120 parts of Febuxostats,
95~165 parts of microcrystalline celluloses, 20~60 parts of lactose, 10~27 parts of Ac-Di-Sols and 1~3 part of magnesium stearate system
Into.
Preferable febuxostat tablet is by 80g Febuxostats, 110g microcrystalline celluloses, 40g lactose, 18g crosslinking carboxylic first
Made of base sodium cellulosate and 2g magnesium stearates.
The preparation method of foregoing febuxostat tablet comprises the following steps：
(1) preparation of label：
1. taking Febuxostat, lactose, 80 mesh sieve nets are crossed respectively, it is spare；
2. Febuxostat is uniformly mixed with microcrystalline cellulose, lactose, partial cross-linked sodium carboxymethylcellulose, add appropriate
Purified water softwood, the granulation of 18 mesh sieve nets, 70 DEG C of dryings, 18 mesh sieve whole grains, add surplus cross-linked carboxymethyl fiber sodium and hard
Fatty acid magnesium, is uniformly mixed；
3. intermediate detects, tabletting after qualification, obtains plain piece；
(2) film coating：
1. taking ethanol, purified water to be placed in blender, premix coating powder is added in the case where being stirred continuously, continues to stir
1 it is small when, coating solution is filtered with 100 mesh sieve nets, spare；
2. plain piece is placed in coating pan, opens coating pan and start air draft and dust exhaust apparatus, while with 40 DEG C~45 DEG C
Hot-air pre-heating, is heated evenly plain piece, and sops up the fine powder being adsorbed in plain piece；Coating pan is started, regulates coating solution spraying
Granularity and spray velocity, on the label that prepared Coating Solution is equably sparged to rotation；After coating, continue with cold
Air-dry dry 10 minutes, coating weight gain 3%-5%.
In the preparation method of foregoing febuxostat tablet, mixing with tabletting filling process, ambient humidity control exists
Less than 50%.
The detection method of foregoing febuxostat tablet includes character, discriminating, inspection and assay project；Wherein differentiating is
Febuxostat in preparation is differentiated；Inspection be this preparation is carried out respectively related material, dissolution rate, microbial limit and
Weight differential is checked；Assay is that Febuxostat is measured.
Concrete content assay method is：
Chromatographic condition and system suitability：It is filler with octadecylsilane chemically bonded silica；Mobile phase is first
Alcohol-with triethylamine tune pH be 5.0 0.3% acetic acid=70：30, detected using UV, Detection wavelength 317nm, flow velocity is
1.0mL/min；Number of theoretical plate is calculated by Febuxostat peak, should be not less than 2000；
Determination method：20, this preparation is taken, accurately weighed, finely ground, precision weighs the fine powder equivalent to Febuxostat 10mg, puts
In 50mL measuring bottles, add methanol ultrasound to dissolve Febuxostat and be diluted to scale, shake up, filter, take subsequent filtrate 5mL, put 25mL
In measuring bottle, methanol dilution is added to be shaken up, as test solution to scale；Another precision weighs Febuxostat reference substance 10mg and puts
In 50mL measuring bottles, add methanol appropriate, ultrasound makes dissolving, adds methanol to scale, and the accurate 5mL that measures is put in 25mL measuring bottles respectively, is added
Methanol dilution shakes up, as reference substance solution to scale；Precision measures above-mentioned reference substance solution and each 10 μ L of test solution,
Liquid chromatograph is injected separately into, records chromatogram.
Specifically discrimination method is：
(1) liquid phase differentiates：Under assay item, the retention time of the retention time of test sample main peak with reference substance peak
Unanimously；
(2) ultraviolet discriminating：This preparation fine powder equivalent to Febuxostat 6mg is taken, is put in 100mL measuring bottles, adds methanol ultrasonic
Dissolve Febuxostat and be diluted to scale, shake up, filter, take subsequent filtrate 5mL, put in 50mL measuring bottles, add methanol dilution to quarter
Degree, shakes up, reference《Chinese Pharmacopoeia》The UV-VIS spectrophotometry of two IV A of annex of version in 2010 is measured,
There is absorption maximum at the wavelength of 215nm and 315nm.
Particular exam method is：
(1) dissolution rate：Concrete operations are as follows：Take this preparation, reference《Chinese Pharmacopoeia》Two Ⅹ C of annex of version in 2010
The dissolution method of two methods, using the 1000mL phosphate buffers of pH=6.8 as dissolution medium, rotating speed is 50 turns per minute,
Operate in accordance with the law, and 10mL was sampled in 30 minutes, filtration, takes subsequent filtrate 2mL, put in 25mL measuring bottles, and solubilization goes out medium to quarter
Degree, shakes up, as test solution；Another precision weighs Febuxostat reference substance 16mg, puts in 50mL measuring bottles, adds methanol dissolving simultaneously
Scale is diluted to, is shaken up, then precision pipettes 2mL and puts in 100mL measuring bottles, solubilization goes out medium to scale, shakes up, as control
Product solution；Reference《Chinese Pharmacopoeia》The spectrophotometry of the two record IV A of version in 2010, measures trap at 317nm wavelength；
Calculate the stripping quantity of every；
(2) related material：
Chromatographic condition and system suitability：It is filler with octadecylsilane chemically bonded silica；Mobile phase is first
Alcohol-with triethylamine tune pH be 5.0 0.3% acetic acid=70：30, detected using UV, Detection wavelength 317nm, flow velocity is
1.0mL/min；Number of theoretical plate is calculated by Febuxostat peak, should be not less than 2000；
Determination method：This preparation piece powder equivalent to the 10mg containing Febuxostat is taken, puts in 50mL measuring bottles, adds methanol appropriate, is surpassed
Sound makes dissolving, lets cool, and adds methanol dilution to shake up to scale, filter, take subsequent filtrate as test solution；Precision pipettes again
Test solution 1mL is stated, with methanol dilution into 1% own control product solution；Another precision weighs impurity A reference substance 10mg, uses first
The amount that alcohol is diluted to the impure A of every 1mL is 2 μ g, as reference substance solution, takes each 10 μ of above-mentioned test solution, reference substance solution
L injecting chromatographs, record chromatogram；In test solution chromatogram, if any impurity A peak, calculated, should be not greater than with external standard method
1%；In addition to solvent peak and auxiliary material peak, the sum of peak area of other impurities should be not more than 1 times of own control peak area；
(3) microbial limit：Take this preparation, reference《Chinese Pharmacopoeia》The method of two Ⅺ J of annex in 2010 calculates；
(4) weight differential：This preparation is taken, it is accurately weighed, average piece weight, then weight every accurately weighed respectively are calculated,
It should meet《Chinese Pharmacopoeia》The regulation of two I A of annex of version in 2010.
The detection method includes：
(1) character：This preparation is Film coated tablets, after removing coating, whitening color or off-white color；
(2) assay：
Chromatographic condition and system suitability：It is filler with octadecylsilane chemically bonded silica；Mobile phase is first
Alcohol-with triethylamine tune pH be 5.0 0.3% acetic acid=70：30, detected using UV, Detection wavelength 317nm, flow velocity is
1.0mL/min；Number of theoretical plate is calculated by Febuxostat peak, should be not less than 2000；
Determination method：20, this preparation is taken, accurately weighed, finely ground, precision weighs the fine powder equivalent to Febuxostat 10mg, puts
In 50mL measuring bottles, add methanol ultrasound to dissolve Febuxostat and be diluted to scale, shake up, filter, take subsequent filtrate 5mL, put 25mL
In measuring bottle, methanol dilution is added to be shaken up, as test solution to scale；Another precision weighs Febuxostat reference substance 10mg and puts
In 50mL measuring bottles, add methanol appropriate, ultrasound makes dissolving, adds methanol to scale, and the accurate 5mL that measures is put in 25mL measuring bottles respectively, is added
Methanol dilution shakes up, as reference substance solution to scale；Precision measures above-mentioned reference substance solution and each 10 μ L of test solution,
Liquid chromatograph is injected separately into, records chromatogram；
(3) differentiate：
(1) liquid phase differentiates：Under assay item, the retention time of the retention time of test sample main peak with reference substance peak
Unanimously；
(2) ultraviolet discriminating：This preparation fine powder equivalent to Febuxostat 6mg is taken, is put in 100mL measuring bottles, adds methanol ultrasonic
Dissolve Febuxostat and be diluted to scale, shake up, filter, take subsequent filtrate 5mL, put in 50mL measuring bottles, add methanol dilution to quarter
Degree, shakes up, reference《Chinese Pharmacopoeia》The UV-VIS spectrophotometry of two IV A of annex of version in 2010 is measured,
There is absorption maximum at the wavelength of 215nm and 315nm；
(4) check：
(1) dissolution rate：Concrete operations are as follows：Take this preparation, reference《Chinese Pharmacopoeia》Two Ⅹ C of annex of version in 2010
The dissolution method of two methods, using the 1000mL phosphate buffers of pH=6.8 as dissolution medium, rotating speed is 50 turns per minute,
Operate in accordance with the law, and 10mL was sampled in 30 minutes, filtration, takes subsequent filtrate 2mL, put in 25mL measuring bottles, and solubilization goes out medium to quarter
Degree, shakes up, as test solution；Another precision weighs Febuxostat reference substance 16mg, puts in 50mL measuring bottles, adds methanol dissolving simultaneously
Scale is diluted to, is shaken up, then precision pipettes 2mL and puts in 100mL measuring bottles, solubilization goes out medium to scale, shakes up, as control
Product solution；Reference《Chinese Pharmacopoeia》The spectrophotometry of two IV A of record of version in 2010, measures trap at 317nm wavelength；
Calculate the stripping quantity of every；
(2) related material：
Chromatographic condition and system suitability：It is filler with octadecylsilane chemically bonded silica；Mobile phase is first
Alcohol-with triethylamine tune pH be 5.0 0.3% acetic acid=70：30, detected using UV, Detection wavelength 317nm, flow velocity is
1.0mL/min；Number of theoretical plate is calculated by Febuxostat peak, should be not less than 2000；
Determination method：This preparation piece powder equivalent to the 10mg containing Febuxostat is taken, puts in 50mL measuring bottles, adds methanol appropriate, is surpassed
Sound makes dissolving, lets cool, and adds methanol dilution to shake up to scale, filter, take subsequent filtrate as test solution；Precision pipettes again
Test solution 1mL is stated, with methanol dilution into 1% own control product solution；Another precision weighs impurity A reference substance 10mg, uses first
The amount that alcohol is diluted to the impure A of every 1mL is 2 μ g, as reference substance solution, takes each 10 μ of above-mentioned test solution, reference substance solution
L injecting chromatographs, record chromatogram；In test solution chromatogram, if any impurity A peak, calculated, should be not greater than with external standard method
1%；In addition to solvent peak and auxiliary material peak, the sum of peak area of other impurities should be not more than 1 times of own control peak area；
(3) microbial limit：Take this preparation, reference《Chinese Pharmacopoeia》The method of two Ⅺ J of annex in 2010 calculates；
(4) weight differential：This preparation is taken, it is accurately weighed, average piece weight, then weight every accurately weighed respectively are calculated,
It should meet《Chinese Pharmacopoeia》The regulation of two I A of annex of version in 2010.
Prescription and preparation process science, reasonable, feasible, applicant in order to ensure febuxostat tablet of the present invention
Series of experimental research and investigation are carried out.
First, formulation study：
1st, bulk pharmaceutical chemicals property
Febuxostat is white or off-white color crystalline powder；It is insoluble in water.Therefore, when drafting the prescription of tablet,
The dissolution rate of medicine is an aspect considered emphatically.
2nd, the property of auxiliary material and selection
It was found from from the relevant information of the ADENURIC of European Union's approval, the auxiliary material used in ADENURIC is lactose, crystallite
Cellulose, magnesium stearate etc..
Lactose compact property is good, and uses lactose unilateral more smooth as filler, and appearance is preferable.
Microcrystalline cellulose has good mobility and compressibility as filler, and water swelling is disintegrated rapidly, after disintegration
Particle is very thin
Ac-Di-Sol has extremely strong disintegration ability.It is especially suitable for the strong medicine of hydrophobicity.
Magnesium stearate is lubricant, is easy to particle mixing, makes unilateral smooth.
3rd, prescription screening
Since Febuxostat is practically insoluble in water, when carrying out prescription screening mainly with disintegration time limited of tablet, molten
Out-degree etc. is main inspection target, the results are shown in Table 1.
1 prescription screening result of table
| 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 |
| Ac-Di-Sol | 0.3g (outer) | 0.6g (outer) | 0.9g (outer) | 0.5g (outer) 0.4g (interior) |
| Magnesium stearate | 0.1g | 0.1g | 0.1g | 0.1g |
| Appearance character | It is unilateral slightly rough | It is unilateral slightly rough | It is unilateral bright and clean | Unilateral bright and clean beauty |
| Disintegration time limited (min) | 20 | 14 | 8 | 7 |
| Dissolution rate surveys (%) | ---- | ---- | 81.3 | 88.6 |
As a result：Piece weight is designed in four prescriptions in 0.25g, does not add lactose in prescription 1, it is unilateral that some are coarse, and
The disintegration and dissolution of tablet are not ideal；The dosage of lactose and disintegrant is increased in prescription 2, disintegration time and dissolution are
Improve, but it is undesirable；The dosage of disintegrant is increased in prescription 3, increases unilateral bright and clean beauty after lactose dosage, but
The accidental particle not being disintegrated in disintegrating procedue.So by the disintegrant for having half in prescription 4 be changed in plus, disintegration time limited and molten
Go out to meet the requirements, it is ideal.
Conclusion：Tentatively by the prescription of prescription 4 as study on the stability prescription.
2nd, Study of operational conditions
1st, the selection of adhesive
Since Febuxostat material is more puckery, its mobility is not good enough, therefore uses wet granule compression tablet technique, and to adhesive
Screened.
Mixed powder is prepared according to prescription 4, it is viscous that 50% ethanol solution, purified water, 2%PVP-k30 aqueous solutions, which is respectively adopted,
Mixture is pelletized, observing effect, and is screened.It the results are shown in Table 2.
2 adhesive the selection result of table
Note：18 mesh sieve granulating process are used above.
Conclusion：Using 50% ethanol as adhesive, material viscosity is larger, can not pelletize；Using water and 2%PVP-k30
Aqueous solution is as adhesive, and particle is uniform, and completely, good fluidity, tablet weight variation is small, both are without significant difference, from simple process
And economic angle considers, directly using purified water as adhesive.
2nd, the measure of critical relative moisture
For the preparation of solid pharmaceutical preparation, the moisture absorption of drug powder is a ring that must be paid close attention in preparation process
Section.The critical relative moisture of drug powder must be measured, and operating environment is controlled by.
Method：CH is prepared respectively3COOK、MgCl2、KNO3、NaBr、NaCl、KCl、KNO2Saturated solution, by the full of preparation
Be respectively implanted with solution in silica gel drier, in 25 DEG C place 72 it is small when, respectively obtain relative humidity for 20.0%, 33.0%,
42.8%th, 59.7%, 75.3%, 84.3%, 92.5% constant humidity solution.
When by the medicinal mixture prepared, drying 48 is small in phosphorus pentoxide desiccator, in the measuring cup of constant weight
Bottom is put into the mixture of 2g or so, after precision weighing, is placed in the drier for filling 7 kinds of different saturated solutions and keeps 72 small
When, precise weighing, calculates Moisture percentage, the results are shown in Table 3.
The Moisture percentage of medicinal powder under the different relative humidity of table 3
| Solution | RH% (25 DEG C) | Moisture percentage (%) |
| CH3COOK | 20.0 | 1.98 |
| MgCl2 | 33.0 | 2.22 |
| KNO3 | 42.8 | 2.44 |
| NaBr | 59.7 | 3.82 |
| NaCl | 75.3 | 5.93 |
| KCl | 84.3 | 8.26 |
| KNO2 | 92.5 | 11.14 |
Using hydroscopicity data as ordinate, relative humidity data is mapped for abscissa, the result is shown in Figure 1.It can be seen by Fig. 1
Go out, moisture absorption is remarkably reinforced more than 50%, accordingly, it can be determined that the critical relative moisture of finished product is 50%.Filled out in mixing and tabletting
During filling, ambient humidity is controlled below 50%.
3rd, formulation and technology checking test
Method：The prescription determined with screening process, prepares 200 (lot numbers of sample：080909), and film coating, with element
Piece hardness, coating tablet appearance, tablet weight variation, dissolution rate, in relation to material and content be inspection target, is evaluated.
1st, appearance
This preparation is Film coated tablets, removes film-coating and shows off-white color.
2nd, tablet weight variation inspection
Coating tablet 20 is taken at random, successively precision weighing piece weight, record numerical value, piece average weight 0.2581g, maximum positively biased
Poor 3.3%, maximum minus deviation 4.4%, meets pharmacopeia relevant regulations.
3rd, Determination of Hardness
The hardness of plain piece has important influence to coating, generally requires piece hardness in more than 5Kg.Take 10 under tablet weight variation item
Piece, measures hardness, the results are shown in Table 4.
4 Determination of Hardness result of table
| 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 piece weight is 7.45Kg, and hardness is moderate, is adapted to coating.
4th, assay
The sample under tablet weight variation item is taken, is measured according to method under assay item, assay result is
100.5%.
5th, Dissolution Rate Testing
This preparation is taken, is measured according to method under quality standard Dissolution Rate Testing item, is as a result 95.5%.
Conclusion：The dissolution rate of preproduction is can be seen that more than 80% from above-mentioned dissolution test result, and drug-eluting is good
It is good, meet regulation.
6th, related substance-measuring
It is measured by the related substance-measuring method of quality standard, impurity A result is 0.387%；Other related material knots
Fruit is 0.059%.
The study on determination method of impurity A (i.e. Febuxostat hydrolysate), refers to the applicant and present specification on the same day
The patent application document of entitled " preparation method and detection method of a kind of febuxostat raw material " submitted.
7th, the investigation of influence factor
(1) exposure experiments to light：
This preparation is taken, illumination is put and is irradiated 10 days for 4500LX ± 500LX, sampled by 0,5,10 day, measures indices, knot
Fruit is shown in Table 5.
5 febuxostat tablet exposure experiments to light result of table
Result of the test shows that this preparation illumination 5,10 days, compared with 0 day, indices have no significant change indices.
(2) hot test
This preparation is taken, is placed 10 days at a temperature of putting 60 DEG C, was sampled by 0,5,10 day, indices is measured, the results are shown in Table 6.
6 febuxostat tablet hot test result of table
Result of the test shows that 60 DEG C are placed 5,10 days, and indices indices compared with 0 day have no significant change.
(3) high humility is tested
This preparation is taken, is put in constant-temperature enclosed vessel, at 25 DEG C under the conditions of relative humidity 92.5% and 75% ± 1%
Place 10 days, sampled by 0,5,10 day, during 92.5% condition of relative humidity, difference moisture absorption 13.2% and 14.4% in 5,10 days；Phase
During to 75% ± 1% condition of humidity, difference moisture absorption 1.8% and 2.1% in 5,10 days；So take 75% ± 1% condition of relative humidity
When sample, measure indices, the results are shown in Table 7.
7 febuxostat tablet high humility result of the test of table
Result of the test shows that relative humidity 75% ± 1% is placed 5,10 days, and for indices compared with 0 day, indices are equal
Without significant change.
In addition, in order to ensure detection method science, reasonable, feasible, applicant carried out series of experimental research
And investigation.
First, character：It is Film coated tablets to measure four batches of samples, except off-white color is shown after coating, the results are shown in Table 8.
8 measurement result of table
2nd, differentiate
1st, in the chromatogram recorded under assay item, the retention time of test solution main peak should be with reference substance solution
Main peak it is consistent.Identification result is shown in Table 9.
2nd, intend, using x powder diffractions measure Febuxostat crystal form characteristic peak, after measuring respectively using raw material and auxiliary material, finding
Auxiliary material has an impact crystal form measure, therefore does not use.
3rd, ultraviolet discriminating：Take this preparation fine powder appropriate (being approximately equivalent to Febuxostat 6mg), put in 100mL measuring bottles, add methanol
Ultrasound dissolves Febuxostat and is diluted to scale, shakes up, and filtration, takes subsequent filtrate 5mL, put in 50mL measuring bottles, add methanol dilution
To scale, shake up, reference《Chinese Pharmacopoeia》The UV-VIS spectrophotometry measure of two IV A of annex of version in 2010,
There is absorption maximum at the wavelength of 215nm and 315nm.It the results are shown in Table 9.
Table 9 differentiates measurement result
3rd, check
1st, weight differential：Febuxostat tablet 20 is taken, it is accurately weighed, average piece weight is calculated, then it is every accurately weighed respectively
Weight.For the weight of every compared with being averaged piece again, limit test of weight variation is ± 7.5%, measures four batches, the results are shown in Table 10.
10 inspection result of table
2nd, limit test of microbe：Take febuxostat tablet, reference《Chinese Pharmacopoeia》The method of two Ⅺ J of annex in 2010,
Measure four batches, the results are shown in Table 11.
11 limit test of microbe result of table
3rd, the methodological study of dissolution rate and measure
3.1 instrument：ZRS-8G type medicament dissolution instruments；6010 ultraviolet-visible spectrophotometer of Agilent.
3.2 measured concentrations determine：Febuxostat bulk pharmaceutical chemicals about 8mg is taken, is put in 100mL measuring bottles, adds methanol ultrasonic dissolution
And scale is diluted to, shake up, then measure 1mL, 2mL, 3mL, 5mL respectively and respectively put in 25mL measuring bottles, scale is diluted with water to, is shaken
It is even, reference《Chinese Pharmacopoeia》UV, visible light-spectrophotometry of two IV A of annex of version in 2010, measures at 317nm wavelength
Trap, the trap for as a result measuring the solution that 2mL puts 25mL measuring bottles are more suitable.
3.3 febuxostat tablets of the present invention (use novel crystal forms, its crystal form preparation method refers to the applicant and this Shen
Please a kind of patent application document of entitled " preparation method and detection method of febuxostat raw material " submitted on the same day of file)
Dissolution situation in various media and the piece with Febuxostat (patent crystal form, its patent publication No. are CN1275126A) preparation
Comparative studies.
Take sample, reference《Chinese Pharmacopoeia》The dissolution method of two annex of version in 2010, Ⅹ the second methods of C, respectively with
The water of 1000mL, 0.1mol/L hydrochloric acid solutions, (9.15g citric acids, 40.43g dipotassium hydrogen phosphates, add water to the buffer salt of pH=5.5
To 1000mL) and phosphate buffer (pH=6.8) be dissolution medium, rotating speed is set to 100 turns per minute, operates in accordance with the law, through 5,
10th, 20,30,45,60 minutes when, separately sampled 10mL (while fluid infusion 10mL), filtration, precision pipettes subsequent filtrate 2mL, puts 25mL
In measuring bottle, solubilization goes out medium to scale, shakes up, as test solution.Precision is weighed in Febuxostat reference substance 16mg,
Put in 50mL measuring bottles, add methanol to dissolve and be diluted to scale, shake up, then precision pipettes 2mL, puts in 100mL measuring bottles, solubilization goes out to be situated between
Matter is diluted to scale, shakes up, as reference substance solution.Take above two solution, reference《Chinese Pharmacopoeia》Version two is attached within 2010
The spectrophotometry of IV A is recorded, trap is measured at 317nm wavelength, calculates the stripping quantity of every.It the results are shown in Table 12 and figure
2。
Measurement result in 12 two kinds of each media of crystal form of table
From the data and stripping curve of two kinds of crystal form difference dissolution mediums, novel crystal forms prepared by the present invention are brilliant with patent
The In Vitro Dissolution behavior of sample prepared by type is basically identical.
3.4 auxiliary material interference tests
Take the blank auxiliary appropriate (being approximately equivalent to contain Febuxostat 16mg) of this preparation to put in 50mL measuring bottles, add methanol to dissolve
And scale is diluted to, shake up, then precision pipettes 2mL, puts in 100mL measuring bottles, is diluted with water to scale, shakes up, and takes above-mentioned solution,
Reference《Chinese Pharmacopoeia》The spectrophotometry of two IV A of annex of version in 2010, measures trap at 317nm wavelength, as a result auxiliary
Expect not interference measurement.
The selection of 3.5 rotating speeds
Take febuxostat tablet, reference《Chinese Pharmacopoeia》The dissolution method of two annex of version in 2010, Ⅹ the second methods of C,
With 1000mL phosphate buffers (pH=6.8) for dissolution medium, rotating speed is is set to 50,75,100 turns per minute, in accordance with the law
Operation, during through 5,10,20,30,45,60 minutes, separately sampled 10mL, (and fluid infusion 10mL at the same time) filtration, precision pipettes continuous filter
Liquid 2mL, puts in 25mL measuring bottles, and solubilization goes out medium to scale, shakes up, as test solution.Precision is weighed in Fei Busuo
Smooth reference substance 16mg, puts in 50mL measuring bottles, adds methanol to dissolve and is diluted to scale, shakes up, then precision pipettes 2mL, puts 100mL amounts
In bottle, solubilization goes out medium to scale, shakes up, as reference substance solution.Take above two solution, reference《Chinese Pharmacopoeia》
The spectrophotometry of two IV A of annex of version in 2010, measures trap at 317nm wavelength.Calculate the stripping quantity of every.
It the results are shown in Table 13.
The measure of 13 selection of speed of table
When rotating speed is 50 revs/min, 75 revs/min and 100 revs/min, the dissolution rate of 45 minutes this preparations exists this preparation
90% or so, it is contemplated that the measure of dissolution rate has selected compared with the slow-speed of revolution, the dissolution of this preparation the situation of quality of the pharmaceutical preparations resolution capability
The rotating speed of degree measure is set to 50 turns per minute, and sample time is 30 minutes.
3.6 dissolution method
The Dissolution Rate Testing condition and method of this preparation, reference《Chinese Pharmacopoeia》Two Ⅹ C of annex of version in 2010 are tried
Test.The dissolution medium of this preparation selects 1000mL phosphate buffers (pH=6.8)；Using《Chinese Pharmacopoeia》Version two in 2010
Ⅹ the second methods of C of annex, rotating speed are 50 revs/min, are sampled within 30 minutes, using the dissolution rate of UV method determination samples.
3.7 linear relationship
Precision weighs febuxostat raw material medicine 12.8mg, puts in 100mL measuring bottles, adds methanol to dissolve and is diluted to scale, shakes
Even, precision measurement 1,3,5,7,10mL are put in 100mL measuring bottles respectively, and solubilization goes out medium to scale, shakes up, reference《China
Pharmacopeia》The spectrophotometry of two IV A of record of version in 2010, measures trap at 317nm wavelength.It the results are shown in Table 14 and Fig. 3.
The measure of 14 working curve of table
| 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 |
From the figure 3, it may be seen that linear equation is Y=0.0708X+0.0054, R2=0.9996 shows in 1.287-12.870 μ g/
It is in good linear in mL concentration ranges.
3.8 stability test
It is appropriate (containing about Febuxostat 16mg) that precision weighs this preparation piece powder, puts in 50mL measuring bottles, adds methanol to dissolve and dilute
Release to scale, shake up, filter, take subsequent filtrate 2mL to put in 100mL measuring bottles, solubilization goes out medium to scale, shakes up, as confession
Test sample solution.Above-mentioned solution, reference are taken when 0,1,2,3,4 is small《Chinese Pharmacopoeia》The light splitting of two IV A of record of version in 2010
Photometry, measures trap at 317nm wavelength.It the results are shown in Table 15.
The measure of 15 stability test of table
| Time (h) | 0 | 1 | 2 | 3 | 4 | It is average | Rsd% |
| Trap (A) | 0.437 | 0.429 | 0.433 | 0.435 | 0.430 | 0.433 | 0.77 |
3.9 recovery test
Precision weighs each three parts of febuxostat raw material medicine 9.6mg, 16mg, 19.2mg, puts respectively in 50mL measuring bottles, and by place
Square ratio adds various auxiliary materials, adds methanol to dissolve and is diluted to scale, shakes up, and filters, takes subsequent filtrate 2mL to put in 100mL measuring bottles,
Solubilization goes out medium to scale, shakes up, as test solution.Another precision weighs Febuxostat reference substance 16mg, puts 50mL
In measuring bottle, add methanol to dissolve and be diluted to scale, shake up, then precision pipettes 2mL and puts in 100mL measuring bottles, solubilization goes out medium
To scale, shake up, as reference substance solution.Above-mentioned solution, reference are taken respectively《Chinese Pharmacopoeia》Two IV A of annex of version in 2010
Spectrophotometry, at 317nm wavelength measure trap.It the results are shown in Table 9.
16 determination of recovery rates result of table
The measure of 3.10 stripping curves
Take this preparation (four batches), reference《Chinese Pharmacopoeia》The dissolution determination of two annex of version in 2010, Ⅹ the second methods of C
Method, with 1000mL phosphate buffers (pH=6.8) for dissolution medium, rotating speed is 50 turns per minute, is operated in accordance with the law, and in 5,
10th, 20,30,45,60 minutes separately sampled 10mL (and fluid infusion 10mL at the same time), filtration, take subsequent filtrate 2mL, put in 25mL measuring bottles,
Solubilization goes out medium to scale, shakes up, as test solution；Another precision weighs Febuxostat reference substance 16mg, puts 50mL
In measuring bottle, add methanol to dissolve and be diluted to scale, shake up, then precision pipettes 2mL and puts in 100mL measuring bottles, solubilization goes out medium
To scale, shake up, as reference substance solution.Above-mentioned solution, reference are taken respectively《Chinese Pharmacopoeia》Two IV A's of record of version in 2010
Spectrophotometry, measures trap at 317nm wavelength.It the results are shown in Table 17.
The measure of 17 stripping curve of table
The measure of 3.11 dissolution rates
Take this preparation (four batches), reference《Chinese Pharmacopoeia》The dissolution method of two the second methods of annex XC of version in 2010,
With 1000mL phosphate buffers (pH=6.8) for dissolution medium, rotating speed is 50 turns per minute, is operated in accordance with the law, and in 30 minutes
Separately sampled 10mL (and fluid infusion 10mL at the same time), filtration, takes subsequent filtrate 2mL, puts in 25mL measuring bottles, and solubilization goes out medium to quarter
Degree, shakes up, as test solution；Another precision weighs Febuxostat reference substance 16mg, puts in 50mL measuring bottles, adds methanol dissolving simultaneously
Scale is diluted to, is shaken up, then precision pipettes 2mL and puts in 100mL measuring bottles, solubilization goes out medium to scale, shakes up, as control
Product solution.Reference《Chinese Pharmacopoeia》The spectrophotometry of two IV A of record of version in 2010, measures trap at 317nm wavelength.
It the results are shown in Table 18.
18 dissolution determination result of table
| Lot number | 080909 | 081007 | 081008 | 081009 |
| Dissolution rate (%) | 95.5 | 96.9 | 98.1 | 98.7 |
4th, Related substances separation
4.1 chromatographic condition
Instrument model：Japanese Shimadzu LC-10ATvp, SPD-10Avp detector；
Chromatographic column：Using octadecylsilane chemically bonded silica as filler；
Mobile phase：The acetic acid of methanol -0.3% (triethylamine tune pH is 5.0) (70：30)；
Flow velocity is 1.0mL/min, and column temperature is room temperature, and wavelength 317nm, sample size is 10 μ L.
The preparation of 4.2 test solutions
Take this preparation piece powder appropriate (being approximately equivalent to contain Febuxostat 10mg), put in 50mL measuring bottles, add methanol appropriate, ultrasound
Make dissolving, let cool, add methanol dilution to shake up to scale, filter, take subsequent filtrate as test solution.
4.3 auxiliary material blank interference tests
The preparation of auxiliary material blank solution：According to prescription, this pharmaceutical adjunct blank is taken (to be approximately equivalent to contain Febuxostat in right amount
10mg), put in 50mL measuring bottles, add methanol appropriate, ultrasound makes dissolving, lets cool, and adds methanol dilution to shake up to scale, filter, take continuous
Filtrate is as auxiliary material blank solution.
10 μ L sample introductions of blank solution are measured, as a result spectrogram shows that blank is noiseless.
4.4 failure test
Acid degradation product：Test solution 2mL is taken, adds 1mol/L hydrochloric acid 1mL, shakes up, half an hour is placed, with 1mol/L hydrogen
Sodium oxide molybdena is adjusted to neutrality, to obtain the final product.
Alkaline degradation product：Test solution 2mL is taken, adds 1mol/L sodium hydroxide 1mL, shakes up, places half an hour, is used
1mol/L hydrochloric acid is adjusted to neutrality, to obtain the final product.
Oxidative breakdown product：Test solution 2mL is taken, adds hydrogen peroxide 2mL, shakes up, places half an hour, immediately sample introduction.
High temperature：Test solution 5mL is taken, is let cool after putting when heating 3 is small in 80 degree of baking ovens, 5mL is added to methanol.
Photo damage：Test solution 5mL is taken, when placement 3 is small under the strong light of 4500 ± 500LX, is added to after taking-up with methanol
5mL。
Each 10 μ L injecting chromatographs of above-mentioned degraded solutions are taken respectively, record spectrogram, the results showed that this formulation soln is to sour, double
Oxygen water, light and high temperature are relatively stable, more unstable to alkali.
4.5 minimum detections
Take this preparation test solution 1mL to put in 100mL measuring bottles, add methanol dilution to shake up to scale, as 1% solution,
1% solution methanol dilution is taken respectively again into 0.01%, 0.02% and 0.03% solution.
Each 10 μ L sample introductions of the solution of above-mentioned 0.01%, 0.02% and 0.03% are taken respectively, record spectrogram, the results showed that this system
The minimum detectable activity of agent is 0.20ng, and minimum limit of detection is 0.03%.
4.6 determination method：
Take this preparation piece powder appropriate (being approximately equivalent to contain Febuxostat 10mg), put in 50mL measuring bottles, add methanol appropriate, ultrasound
Make dissolving, let cool, add methanol dilution to shake up to scale, filter, take subsequent filtrate as test solution.Precision pipettes above-mentioned again
Test solution 1mL, with methanol dilution into 1% own control product solution；Another precision weighs impurity A, and (retention time is about 4 minutes
Left and right) reference substance 10mg, the amount with methanol dilution into the impure A of every 1mL is 2 μ g, as reference substance solution, takes above-mentioned solution each
10 μ L injecting chromatographs, record chromatogram.In test solution chromatogram, if any impurity A peak, calculated with external standard method, should must not
More than 1% (1%)；In addition to solvent peak and auxiliary material peak, the sum of peak area of other impurities should be not more than the 1 of own control peak area
Again (1%).Measure four batches the results are shown in Table 19.
19 Related substances separation of table
| Lot number | 080909 | 081007 | 081008 | 081009 |
| Impurity A | 0.387 | 0.037 | 0.391 | 0.183 |
| Other impurities | 0.059 | 0.048 | 0.048 | 0.068 |
4th, assay
The methodological study of assay is carried out using HPLC methods, and determines the content of sample.Provide containing for this preparation
Amount limit is 95.0-105.0%.
1st, instrument model：Japanese Shimadzu LC-10ATvp；SPD-10Avp detectors.
2nd, chromatographic condition
It is filler with octadecylsilane chemically bonded silica；The acetic acid of methanol -0.3% (triethylamine tune pH is 5.0) (70：
30), detected using UV, Detection wavelength 317nm.Flow velocity is 1.0mL/L.
3rd, repetitive test
Take same batch of sample appropriate (containing about Febuxostat 10mg), it is six parts respectively, accurately weighed, put in 50mL measuring bottles, add
Appropriate methanol, ultrasound make dissolving, add methanol to shake up, filter to scale.The accurate subsequent filtrate 5mL that measures is put in 25mL measuring bottles respectively,
Methanol dilution is added to be shaken up, as test solution to scale；Another precision weighs Febuxostat reference substance 10mg and puts 50mL measuring bottles
In, add methanol appropriate, ultrasound makes dissolving, adds methanol to scale, and the accurate 5mL that measures is put in 25mL measuring bottles respectively, adds methanol dilution
To scale, shake up, as reference substance solution.Precision measures above-mentioned reference substance solution and each 10 μ L of test solution are injected separately into liquid
Chromatography, records chromatogram, calculates the content of determination sample, the results are shown in Table 20.
The repeated measurement result of table 20
4th, test solution stability
The lower first part of test solution of repeated item is taken, takes 10 μ L to inject liquid chromatograph when 0,2,4,6,8 is small,
Record chromatogram, to obtain the final product.It the results are shown in Table 21.
21 Stability Determination result of table
| Time (hour)) | 0 | 2 | 4 | 6 | 8 | It is average | RSD% |
| Peak area (A) × 103 | 1158 | 1165 | 1156 | 1161 | 1159 | 1159.8 | 0.29 |
5th, recovery test
Precision weighs Febuxostat reference substance 8,10, three parts of 12mg difference, puts in 50mL measuring bottles, is added in prescription ratio auxiliary
Material, adds the appropriate ultrasound of methanol to dissolve Febuxostat, then adds methanol dilution to shake up, filter, precision pipettes subsequent filtrate to scale
5mL, puts in 25 measuring bottles, adds methanol dilution to be shaken up, as test solution to scale.Another precision weighs Febuxostat reference substance
10mg is put in 50mL measuring bottles, adds methanol appropriate, and ultrasound makes dissolving, adds methanol to scale, and the accurate 5mL that measures puts 25mL measuring bottles respectively
In, add methanol dilution to be shaken up, as reference substance solution to scale.Precision measures above-mentioned reference substance solution and test solution is each
10 μ L are injected separately into liquid chromatograph, record chromatogram, calculate the rate of recovery.It the results are shown in Table 22.
22 determination of recovery rates result of table
6th, assay
Chromatographic condition and system suitability：It is filler with octadecylsilane chemically bonded silica；The second of methanol -0.3%
Acid (triethylamine tune pH is 5.0) (70：30), detected using UV, Detection wavelength 317nm, flow velocity 1.0mL/min；Theoretical plate
Number is calculated by Febuxostat peak, should be not less than 2000.
20, this preparation is taken, accurately weighed, finely ground, precision weighs appropriate (being approximately equivalent to Febuxostat 10mg), puts 50mL
In measuring bottle, add methanol ultrasound to dissolve Febuxostat and be diluted to scale, shake up, filter, take subsequent filtrate 5mL, put 25mL measuring bottles
In, add methanol dilution to be shaken up, as test solution to scale.Another precision weighs Febuxostat reference substance 10mg and puts 50mL amounts
In bottle, add methanol appropriate, ultrasound makes dissolving, adds methanol to scale, and the accurate 5mL that measures is put in 25mL measuring bottles respectively, adds methanol dilute
Release to scale, shake up, as reference substance solution.Precision measures above-mentioned reference substance solution and each 10 μ L of test solution are injected separately into
Liquid chromatograph, records chromatogram, and result of calculation is shown in Table 23.
23 assay result of table
| Lot number | 080909 | 081007 | 081008 | 081009 |
| Labelled amount content (%) | 100.5 | 100.0 | 100.2 | 100.1 |
5th, stability testing method and result
According to《Chinese Pharmacopoeia》Version two-shift system agent medicine stability in 2010 requires to investigate the stability of febuxostat tablet.
1st, accelerated test：(sample lot number：081007、081008、081009)
Take this preparation, respectively simulation listing packaging, be placed in 40 DEG C ± 2 DEG C, humidity placed for 75% ± 5% time, in 0,1,
2nd, sample within 3,6 months, detection.It the results are shown in Table 24.
24 accelerated test result of table
5.2 long term test：(sample lot number：081007、081008、081009)
Take this preparation, respectively simulation listing packaging, be placed in 25 DEG C ± 2 DEG C, relative humidity preserved for 60% ± 10%, in 0,
3rd, sample within 6,12,18 months, detection.It the results are shown in Table 25.
25 long-term test results of table
6th, conclusion and evaluation
Stability test has been carried out to this preparation according to chemicals stability study technological guidance principle.(1) to trial-production
Sample carries out the experiment of the influence factors such as illumination, high temperature, high humidity, the results showed that：Every inspection target meets and faces without significant change
Bed uses sample quality draft standard；(2) three batches of samples accelerated test 6 months (40 DEG C, RH 75% under simulation listing packaging
Under part), for this preparation after above-mentioned condition accelerated test 6 months, every inspection target meets clinic sample without significant change
Quality standard draft；(3) three batches of sample simulation listing packagings, under conditions of 25 DEG C ± 2 DEG C, relative humidity 60% ± 10%,
After keeping sample investigate 6 months for a long time, every inspection target meets clinic sample quality draft standard, length without significant change
Phase, which keeps sample to investigate to test, still to carry out.
Compared with prior art, the present invention improves the prescription and preparation process of febuxostat tablet, is to prepare
Process stabilizing, feasible, the Febuxostat tablet quality of preparation is well stablized, and makes the effect of it is to diseases such as hyperuricemia and gouts
It is more notable；Examined moreover, the present invention establishes system, complete, effective quality for improved febuxostat tablet
Survey method, the specificity of the method is strong, precision is high, favorable reproducibility, the rate of recovery are high, measurement result is accurate, has reached effective
Control drug quality purpose, ensure that product quality stabilization and clinical application safely, effectively.Packaging material selects
Select proper, long-term to place sample stability good.
Brief description of the drawings
Fig. 1 is the Moisture percentage curve map of medicinal powder under different relative humidity；
Fig. 2 is two kinds of crystal form difference dissolution medium comparative graphs；
Fig. 3 is febuxostat tablet dissolution rate linear relationship working curve diagram.
Embodiment
With reference to embodiment, the present invention is further illustrated.
Embodiment 1：The febuxostat tablet is handed over by 80g Febuxostats, 110g microcrystalline celluloses, 40g lactose, 18g
Join made of sodium carboxymethylcellulose and 2g magnesium stearates.Febuxostat, lactose are taken, crosses 80 mesh sieve nets respectively, it is spare；By 80g
Febuxostat is uniformly mixed with 110g microcrystalline celluloses, 40g lactose, 8g Ac-Di-Sols, adds appropriate purified water
Softwood processed, the granulation of 18 mesh sieve nets, 70 DEG C of dryings, 18 mesh sieve whole grains, add surplus cross-linked carboxymethyl fiber sodium and 2g stearic acid
Magnesium, is uniformly mixed；Intermediate detects, and tabletting after qualification, obtains plain piece；370g ethanol, 100g purified waters is taken to be placed in blender,
In the case of being stirred continuously add 30g premix coating powder, continue stirring 1 it is small when, coating solution is filtered with 100 mesh sieve nets, spare；Will
Plain piece is placed in coating pan, is opened coating pan and is simultaneously started air draft and dust exhaust apparatus, while with 40 DEG C~45 DEG C hot-air pre-heatings, makes element
Piece is heated evenly, and sops up the fine powder being adsorbed in plain piece；Coating pan is started, regulates coating solution granularity of spray and spraying speed
Spend, on the label that prepared Coating Solution is equably sparged to rotation；After coating, continue to be divided with cold air drying 10
Clock, coating weight gain 3%-5%；Mixing with tabletting filling process, ambient humidity is controlled below 50%.
Embodiment 2：The febuxostat tablet is handed over by 120g Febuxostats, 165g microcrystalline celluloses, 60g lactose, 27g
Join made of sodium carboxymethylcellulose and 3g magnesium stearates.Febuxostat, lactose are taken, crosses 80 mesh sieve nets respectively, it is spare；By 120g
Febuxostat is uniformly mixed with 165g microcrystalline celluloses, 60g lactose, 12g Ac-Di-Sols, adds appropriate purified water
Softwood processed, the granulation of 18 mesh sieve nets, 70 DEG C of dryings, 18 mesh sieve whole grains, add surplus cross-linked carboxymethyl fiber sodium and 3g stearic acid
Magnesium, is uniformly mixed；Intermediate detects, and tabletting after qualification, obtains plain piece；550g ethanol, 150g purified waters is taken to be placed in blender,
In the case of being stirred continuously add 45g premix coating powder, continue stirring 1 it is small when, coating solution is filtered with 100 mesh sieve nets, spare；Will
Plain piece is placed in coating pan, is opened coating pan and is simultaneously started air draft and dust exhaust apparatus, while with 40 DEG C~45 DEG C hot-air pre-heatings, makes element
Piece is heated evenly, and sops up the fine powder being adsorbed in plain piece；Coating pan is started, regulates coating solution granularity of spray and spraying speed
Spend, on the label that prepared Coating Solution is equably sparged to rotation；After coating, continue to be divided with cold air drying 10
Clock, coating weight gain 3%-5%；Mixing with tabletting filling process, ambient humidity is controlled below 50%.
Embodiment 3：The febuxostat tablet is by 40g Febuxostats, 95g microcrystalline celluloses, 20g lactose, 10g crosslinkings
Made of sodium carboxymethylcellulose and 1g magnesium stearates.Febuxostat, lactose are taken, crosses 80 mesh sieve nets respectively, it is spare；40g is non-
Cloth sotan is uniformly mixed with 95g microcrystalline celluloses, 20g lactose, 4g Ac-Di-Sols, and it is soft to add appropriate purified water system
Material, the granulation of 18 mesh sieve nets, 70 DEG C of dryings, 18 mesh sieve whole grains, add surplus cross-linked carboxymethyl fiber sodium and 1g magnesium stearates, mix
Close uniform；Intermediate detects, and tabletting after qualification, obtains plain piece；Take 185g ethanol, 50g purified waters to be placed in blender, constantly stirring
In the case of mixing add 15g premix coating powder, continue stirring 1 it is small when, coating solution is filtered with 100 mesh sieve nets, spare；Plain piece is put
In in coating pan, open coating pan and simultaneously start air draft and dust exhaust apparatus, while with 40 DEG C~45 DEG C hot-air pre-heatings, plain piece is heated
Uniformly, and the fine powder being adsorbed in plain piece is sopped up；Coating pan is started, regulates coating solution granularity of spray and spray velocity, will be matched somebody with somebody
The Coating Solution made is equably sparged on the label of rotation；After coating, continue to use cold air drying 10 minutes, coating increases
Weight 3%-5%；Mixing with tabletting filling process, ambient humidity is controlled below 50%.
Embodiment 4：The complete detection method of febuxostat tablet of the present invention is：
(1) character：This preparation is Film coated tablets, after removing coating, whitening color or off-white color；
(2) assay：
Chromatographic condition and system suitability：It is filler with octadecylsilane chemically bonded silica；Mobile phase is first
Alcohol-with triethylamine tune pH be 5.0 0.3% acetic acid=70：30, detected using UV, Detection wavelength 317nm, flow velocity is
1.0mL/min；Number of theoretical plate is calculated by Febuxostat peak, should be not less than 2000；
Determination method：20, this preparation is taken, accurately weighed, finely ground, precision weighs the fine powder equivalent to Febuxostat 10mg, puts
In 50mL measuring bottles, add methanol ultrasound to dissolve Febuxostat and be diluted to scale, shake up, filter, take subsequent filtrate 5mL, put 25mL
In measuring bottle, methanol dilution is added to be shaken up, as test solution to scale；Another precision weighs Febuxostat reference substance 10mg and puts
In 50mL measuring bottles, add methanol appropriate, ultrasound makes dissolving, adds methanol to scale, and the accurate 5mL that measures is put in 25mL measuring bottles respectively, is added
Methanol dilution shakes up, as reference substance solution to scale；Precision measures above-mentioned reference substance solution and each 10 μ L of test solution,
Liquid chromatograph is injected separately into, records chromatogram；
(3) differentiate：
(1) liquid phase differentiates：Under assay item, the retention time of the retention time of test sample main peak with reference substance peak
Unanimously；
(2) ultraviolet discriminating：This preparation fine powder equivalent to Febuxostat 6mg is taken, is put in 100mL measuring bottles, adds methanol ultrasonic
Dissolve Febuxostat and be diluted to scale, shake up, filter, take subsequent filtrate 5mL, put in 50mL measuring bottles, add methanol dilution to quarter
Degree, shakes up, reference《Chinese Pharmacopoeia》The UV-VIS spectrophotometry of two IV A of annex of version in 2010 is measured,
There is absorption maximum at the wavelength of 215nm and 315nm；
(4) check：
(1) dissolution rate：Concrete operations are as follows：Take this preparation, reference《Chinese Pharmacopoeia》Two Ⅹ C of annex of version in 2010
The dissolution method of two methods, using the 1000mL phosphate buffers of pH=6.8 as dissolution medium, rotating speed is 50 turns per minute,
Operate in accordance with the law, and 10mL was sampled in 30 minutes, filtration, takes subsequent filtrate 2mL, put in 25mL measuring bottles, and solubilization goes out medium to quarter
Degree, shakes up, as test solution；Another precision weighs Febuxostat reference substance 16mg, puts in 50mL measuring bottles, adds methanol dissolving simultaneously
Scale is diluted to, is shaken up, then precision pipettes 2mL and puts in 100mL measuring bottles, solubilization goes out medium to scale, shakes up, as control
Product solution；Reference《Chinese Pharmacopoeia》The spectrophotometry of the two record IV A of version in 2010, measures trap at 317nm wavelength；
Calculate the stripping quantity of every；
(2) related material：
Chromatographic condition and system suitability：It is filler with octadecylsilane chemically bonded silica；Mobile phase is first
Alcohol-with triethylamine tune pH be 5.0 0.3% acetic acid=70：30, detected using UV, Detection wavelength 317nm, flow velocity is
1.0mL/min；Number of theoretical plate is calculated by Febuxostat peak, should be not less than 2000；
Determination method：This preparation piece powder equivalent to the 10mg containing Febuxostat is taken, puts in 50mL measuring bottles, adds methanol appropriate, is surpassed
Sound makes dissolving, lets cool, and adds methanol dilution to shake up to scale, filter, take subsequent filtrate as test solution；Precision pipettes again
Test solution 1mL is stated, with methanol dilution into 1% own control product solution；Another precision weighs impurity A reference substance 10mg, uses first
The amount that alcohol is diluted to the impure A of every 1mL is 2 μ g, as reference substance solution, takes each 10 μ of above-mentioned test solution, reference substance solution
L injecting chromatographs, record chromatogram；In test solution chromatogram, if any impurity A peak, calculated, should be not greater than with external standard method
1%；In addition to solvent peak and auxiliary material peak, the sum of peak area of other impurities should be not more than 1 times of own control peak area；
(3) microbial limit：Take this preparation, reference《Chinese Pharmacopoeia》The method of two Ⅺ J of annex in 2010 calculates；
(4) weight differential：This preparation is taken, it is accurately weighed, average piece weight, then weight every accurately weighed respectively are calculated,
It should meet《Chinese Pharmacopoeia》The regulation of two I A of annex of version in 2010.
Claims (1)
1. the detection method of febuxostat tablet, it is characterised in that：The detection method includes character, discriminating, inspection and content
Measure project；Wherein differentiate it is that the Febuxostat in preparation is differentiated；Inspection be this preparation is carried out respectively related material,
Dissolution rate, microbial limit and weight differential are checked；Assay is that Febuxostat is measured；The detection side
Method includes：
(1) character：This preparation is Film coated tablets, after removing coating, whitening color or off-white color；
(2) assay：
Chromatographic condition and system suitability：It is filler with octadecylsilane chemically bonded silica；Mobile phase is methanol-use
Triethylamine tune pH is 5.0 0.3% acetic acid=70：30, detected using UV, Detection wavelength 317nm, flow velocity 1.0mL/min；
Number of theoretical plate is calculated by Febuxostat peak, should be not less than 2000；
Determination method：20, this preparation is taken, accurately weighed, finely ground, precision weighs the fine powder equivalent to Febuxostat 10mg, puts 50mL
In measuring bottle, add methanol ultrasound to dissolve Febuxostat and be diluted to scale, shake up, filter, take subsequent filtrate 5mL, put 25mL measuring bottles
In, add methanol dilution to be shaken up, as test solution to scale；Another precision weighs Febuxostat reference substance 10mg and puts 50mL amounts
In bottle, add methanol appropriate, ultrasound makes dissolving, adds methanol to scale, and the accurate 5mL that measures is put in 25mL measuring bottles respectively, adds methanol dilute
Release to scale, shake up, as reference substance solution；Precision measures above-mentioned reference substance solution and each 10 μ L of test solution, notes respectively
Enter liquid chromatograph, record chromatogram；
(3) differentiate：
(1) liquid phase differentiates：Under assay item, the retention time one of the retention time of test sample main peak with reference substance peak
Cause；
(2) ultraviolet discriminating：This preparation fine powder equivalent to Febuxostat 6mg is taken, is put in 100mL measuring bottles, adds methanol ultrasound to make non-
Cloth sotan dissolves and is diluted to scale, shakes up, and filtration, takes subsequent filtrate 5mL, put in 50mL measuring bottles, add methanol dilution to be shaken to scale
It is even, reference《Chinese Pharmacopoeia》The UV-VIS spectrophotometry of two IV A of annex of version in 2010 is measured, 215nm with
There is absorption maximum at the wavelength of 315nm；
(4) check：
(1) dissolution rate：Concrete operations are as follows：Take this preparation, reference《Chinese Pharmacopoeia》Two annex of version in 2010, Ⅹ the second methods of C
Dissolution method, using the 1000mL phosphate buffers of pH=6.8 as dissolution medium, rotating speed is 50 turns per minute, is grasped in accordance with the law
Make, and 10mL was sampled in 30 minutes, filtration, takes subsequent filtrate 2mL, put in 25mL measuring bottles, solubilization goes out medium to scale, shakes
It is even, as test solution；Another precision weighs Febuxostat reference substance 16mg, puts in 50mL measuring bottles, adds methanol to dissolve and dilute
To scale, shake up, then precision pipettes 2mL and puts in 100mL measuring bottles, solubilization goes out medium to scale, shakes up, molten as reference substance
Liquid；Reference《Chinese Pharmacopoeia》The spectrophotometry of the two record IV A of version in 2010, measures trap at 317nm wavelength；Calculate
Go out the stripping quantity of every；
(2) related material：
Chromatographic condition and system suitability：It is filler with octadecylsilane chemically bonded silica；Mobile phase is methanol-use
Triethylamine tune pH is 5.0 0.3% acetic acid=70：30, detected using UV, Detection wavelength 317nm, flow velocity 1.0mL/min；
Number of theoretical plate is calculated by Febuxostat peak, should be not less than 2000；
Determination method：This preparation piece powder equivalent to the 10mg containing Febuxostat is taken, puts in 50mL measuring bottles, adds methanol appropriate, ultrasound makes
Dissolving, lets cool, and adds methanol dilution to shake up to scale, filter, take subsequent filtrate as test solution；Precision pipettes above-mentioned confession again
Test sample solution 1mL, with methanol dilution into 1% own control product solution；Another precision weighs impurity A reference substance 10mg, dilute with methanol
The amount for being interpreted into the impure A of every 1mL is 2 μ g, as reference substance solution, takes each 10 μ L notes of above-mentioned test solution, reference substance solution
Enter chromatograph, record chromatogram；In test solution chromatogram, if any impurity A peak, calculated, should be not greater than with external standard method
1%；In addition to solvent peak and auxiliary material peak, the sum of peak area of other impurities should be not more than 1 times of own control peak area；Wherein,
Impurity A is Febuxostat hydrolysate in ZL201210545350.7；
(3) microbial limit：Take this preparation, reference《Chinese Pharmacopoeia》The method of two Ⅺ J of annex in 2010 calculates；
(4) weight differential：This preparation is taken, it is accurately weighed, average piece weight, then weight every accurately weighed respectively are calculated, should be accorded with
Close《Chinese Pharmacopoeia》The regulation of two I A of annex of version in 2010.
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| 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 |
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| Publication number | Publication date |
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| CN102988326A (en) | 2013-03-27 |
| CN102988326B (en) | 2016-01-20 |
| CN105372372A (en) | 2016-03-02 |
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