JPWO2019124544A1 - トリフルリジン及び/又はチピラシル由来の類縁物質の検出方法 - Google Patents
トリフルリジン及び/又はチピラシル由来の類縁物質の検出方法 Download PDFInfo
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- JPWO2019124544A1 JPWO2019124544A1 JP2019560592A JP2019560592A JPWO2019124544A1 JP WO2019124544 A1 JPWO2019124544 A1 JP WO2019124544A1 JP 2019560592 A JP2019560592 A JP 2019560592A JP 2019560592 A JP2019560592 A JP 2019560592A JP WO2019124544 A1 JPWO2019124544 A1 JP WO2019124544A1
- Authority
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- Japan
- Prior art keywords
- salt
- tipiracil
- trifluridine
- mobile phase
- related substance
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000126 substance Substances 0.000 title claims abstract description 210
- 229960002952 tipiracil Drugs 0.000 title claims abstract description 115
- QQHMKNYGKVVGCZ-UHFFFAOYSA-N tipiracil Chemical compound N1C(=O)NC(=O)C(Cl)=C1CN1C(=N)CCC1 QQHMKNYGKVVGCZ-UHFFFAOYSA-N 0.000 title claims abstract description 115
- 238000000034 method Methods 0.000 title claims abstract description 69
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 title claims description 103
- 229960003962 trifluridine Drugs 0.000 title claims description 102
- 239000012071 phase Substances 0.000 claims abstract description 112
- 150000003839 salts Chemical class 0.000 claims abstract description 111
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 56
- 239000008346 aqueous phase Substances 0.000 claims abstract description 34
- 239000012074 organic phase Substances 0.000 claims abstract description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 93
- 230000014759 maintenance of location Effects 0.000 claims description 69
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 52
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 26
- -1 2-oxopyrrolidine-1-yl Chemical group 0.000 claims description 20
- 229940000425 combination drug Drugs 0.000 claims description 20
- VSSDRILYYMTHSP-XLPZGREQSA-N methyl 1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2,4-dioxopyrimidine-5-carboxylate Chemical compound O=C1NC(=O)C(C(=O)OC)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 VSSDRILYYMTHSP-XLPZGREQSA-N 0.000 claims description 14
- 238000003908 quality control method Methods 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 8
- 238000001514 detection method Methods 0.000 claims description 6
- 239000012535 impurity Substances 0.000 claims description 6
- LMNPKIOZMGYQIU-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyrimidine-2,4-dione Chemical compound FC(F)(F)C1=CNC(=O)NC1=O LMNPKIOZMGYQIU-UHFFFAOYSA-N 0.000 claims description 5
- ZXYAAVBXHKCJJB-UHFFFAOYSA-N uracil-5-carboxylic acid Chemical compound OC(=O)C1=CNC(=O)NC1=O ZXYAAVBXHKCJJB-UHFFFAOYSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- NJBMZYSKLWQXLJ-UHFFFAOYSA-N 3,4-dihydro-2h-pyrrol-5-amine Chemical compound NC1=NCCC1 NJBMZYSKLWQXLJ-UHFFFAOYSA-N 0.000 claims description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 93
- 238000005259 measurement Methods 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- REFMEZARFCPESH-UHFFFAOYSA-M sodium;heptane-1-sulfonate Chemical compound [Na+].CCCCCCCS([O-])(=O)=O REFMEZARFCPESH-UHFFFAOYSA-M 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 13
- 239000000243 solution Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 150000002500 ions Chemical class 0.000 description 8
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 8
- 235000019796 monopotassium phosphate Nutrition 0.000 description 8
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 8
- 235000019799 monosodium phosphate Nutrition 0.000 description 8
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 8
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 8
- 239000006172 buffering agent Substances 0.000 description 7
- 238000004811 liquid chromatography Methods 0.000 description 7
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 6
- 239000000654 additive Substances 0.000 description 6
- 238000013329 compounding Methods 0.000 description 6
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- KGHYQYACJRXCAT-UHFFFAOYSA-N tipiracil hydrochloride Chemical compound Cl.N1C(=O)NC(=O)C(Cl)=C1CN1C(=N)CCC1 KGHYQYACJRXCAT-UHFFFAOYSA-N 0.000 description 4
- 229960001740 tipiracil hydrochloride Drugs 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 229940127557 pharmaceutical product Drugs 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- BXVCXZREYQLVTA-UHFFFAOYSA-N 5-chloro-6-(chloromethyl)-1h-pyrimidine-2,4-dione Chemical compound ClCC=1NC(=O)NC(=O)C=1Cl BXVCXZREYQLVTA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- VPCPZTXQFZXMLO-UHFFFAOYSA-N 5-(trifluoromethyl)-1H-pyrimidine-2,4-dione Chemical compound FC(C=1C(NC(NC1)=O)=O)(F)F.FC(C=1C(NC(NC1)=O)=O)(F)F VPCPZTXQFZXMLO-UHFFFAOYSA-N 0.000 description 1
- HPUJXJOTSHCLMN-UHFFFAOYSA-N 5-chloro-6-(2-iminopyrrolidin-1-yl)-1-methylpyrimidine-2,4-dione Chemical compound ClC=1C(NC(N(C1N1C(CCC1)=N)C)=O)=O HPUJXJOTSHCLMN-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- VHSSESVAKURAGI-UHFFFAOYSA-N OP(O)(=O)OP(O)(O)=O.OP(O)(=O)OP(O)(O)=O Chemical compound OP(O)(=O)OP(O)(O)=O.OP(O)(=O)OP(O)(O)=O VHSSESVAKURAGI-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 125000003289 ascorbyl group Chemical class [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 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
- 239000002526 disodium citrate Substances 0.000 description 1
- 235000019262 disodium citrate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- AKRQHOWXVSDJEF-UHFFFAOYSA-N heptane-1-sulfonic acid Chemical compound CCCCCCCS(O)(=O)=O AKRQHOWXVSDJEF-UHFFFAOYSA-N 0.000 description 1
- GVBFBKODLPVQOA-UHFFFAOYSA-N heptane-1-sulfonic acid;sodium Chemical compound [Na].CCCCCCCS(O)(=O)=O GVBFBKODLPVQOA-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
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- 238000007561 laser diffraction method Methods 0.000 description 1
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- 238000001819 mass spectrum Methods 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- HWPKGOGLCKPRLZ-UHFFFAOYSA-M monosodium citrate Chemical compound [Na+].OC(=O)CC(O)(C([O-])=O)CC(O)=O HWPKGOGLCKPRLZ-UHFFFAOYSA-M 0.000 description 1
- 239000002524 monosodium citrate Substances 0.000 description 1
- 235000018342 monosodium citrate Nutrition 0.000 description 1
- DIAIBWNEUYXDNL-UHFFFAOYSA-N n,n-dihexylhexan-1-amine Chemical compound CCCCCCN(CCCCCC)CCCCCC DIAIBWNEUYXDNL-UHFFFAOYSA-N 0.000 description 1
- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
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- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- SCPYDCQAZCOKTP-UHFFFAOYSA-N silanol Chemical compound [SiH3]O SCPYDCQAZCOKTP-UHFFFAOYSA-N 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 229940083575 sodium dodecyl sulfate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- XQCHMGAOAWZUPI-UHFFFAOYSA-M sodium;butane-1-sulfonate Chemical compound [Na+].CCCCS([O-])(=O)=O XQCHMGAOAWZUPI-UHFFFAOYSA-M 0.000 description 1
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 1
- QWSZRRAAFHGKCH-UHFFFAOYSA-M sodium;hexane-1-sulfonate Chemical compound [Na+].CCCCCCS([O-])(=O)=O QWSZRRAAFHGKCH-UHFFFAOYSA-M 0.000 description 1
- HRQDCDQDOPSGBR-UHFFFAOYSA-M sodium;octane-1-sulfonate Chemical compound [Na+].CCCCCCCCS([O-])(=O)=O HRQDCDQDOPSGBR-UHFFFAOYSA-M 0.000 description 1
- ROBLTDOHDSGGDT-UHFFFAOYSA-M sodium;pentane-1-sulfonate Chemical compound [Na+].CCCCCS([O-])(=O)=O ROBLTDOHDSGGDT-UHFFFAOYSA-M 0.000 description 1
- NPAWNPCNZAPTKA-UHFFFAOYSA-M sodium;propane-1-sulfonate Chemical compound [Na+].CCCS([O-])(=O)=O NPAWNPCNZAPTKA-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229940073455 tetraethylammonium hydroxide Drugs 0.000 description 1
- LRGJRHZIDJQFCL-UHFFFAOYSA-M tetraethylazanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC LRGJRHZIDJQFCL-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- KYWVDGFGRYJLPE-UHFFFAOYSA-N trimethylazanium;acetate Chemical compound CN(C)C.CC(O)=O KYWVDGFGRYJLPE-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 235000019263 trisodium citrate Nutrition 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
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Abstract
Description
類縁物質1:トリフルオロチミン、
類縁物質2:2−イミノピロリジン、
類縁物質3:5−クロロ−6−{(2−オキソピロリジン−1−イル)メチル}ピリミジン−2,4−(1H、3H)−ジオン、
類縁物質4:2’−デオキシ−5−メトキシカルボニルウリジン、
類縁物質5:5−カルボキシウラシル。
より好ましくは、有機相がアセトニトリルからなり、かつ類縁物質3及びチピラシルの保持時間におけるアセトニトリルが移動相全体の5〜20容量%である高速液体クロマトグラフィーによる方法である。
より好ましくは、移動相がアセトニトリル及びリン酸又はリン酸二水素カリウムを含む水相からなり、かつ類縁物質3及びチピラシルの保持時間におけるアセトニトリルが移動相全体の7〜15%である高速液体クロマトグラフィーによる方法である。
・検出器:紫外吸光光度計(波長は210nm)
・カラム:内径4.6mm,長さ15cmのステンレス管に5μmの液体クロマトグラフィー用オクタデシルシリル化シリカゲルカラム
・カラム温度:40℃
・流量:0.6〜1.0mL/分
・移動相:各実施例に記載
・グラジエント:各実施例に記載
高速液体クロマトグラフィーで測定する試料は以下の通り調製した。
カラム:Inertsil ODS−4、GLサイエンス社製
移動相:リン酸二水素ナトリウム二水和物1.4g及び1−ヘプタンスルホン酸ナトリウム0.9gを水900mLに溶かし,リン酸を加えてpH2.7に調整した。この液にメタノール100mLを加えて移動相とした。
カラム:Inertsil ODS−4、GLサイエンス社製
移動相:リン酸二水素ナトリウム二水和物1.5g及び1−ヘプタンスルホン酸ナトリウム0.9gを水900mLに溶かし,リン酸を加えてpH2.7に調整した。この液にメタノール100mLを加えて移動相とした。
カラム:Inertsil ODS−4、GLサイエンス社製
移動相:リン酸二水素ナトリウム二水和物1.4g及び1−ヘプタンスルホン酸ナトリウム1.0gを水900mLに溶かし,リン酸を加えてpH2.8に調整した。この液にメタノール100mLを加えて移動相とした。
カラム:Inertsil ODS−4、GLサイエンス社製
移動相:リン酸二水素ナトリウム二水和物1.4g及び1−ヘプタンスルホン酸ナトリウム0.9gを水900mLに溶かし,リン酸を加えてpH2.7に調整した。この液にメタノール95mLを加えて移動相とした。
カラム:Wakosil−II 5C18 RS、和光純薬製
移動相:リン酸二水素ナトリウム二水和物1.4g及び1−ヘプタンスルホン酸ナトリウム0.9gを水900mLに溶かし,リン酸を加えてpH2.7に調整した。この液にメタノール100mLを加えて移動相とした。
カラム:Wakosil−II 5C18 RS、和光純薬製
移動相:リン酸二水素ナトリウム二水和物3.1g及び1−ヘプタンスルホン酸ナトリウム2.0gを水2000mLに溶かし,リン酸を加えてpH2.7に調整した。この液950mLにメタノール50mLを加えて移動相とした。
カラム:Wakosil−II 5C18 RS、和光純薬製
移動相:リン酸二水素カリウム1.25g及び1−ヘプタンスルホン酸ナトリウム1.01gを水920mLに溶かし,アセトニトリル80mLを加えて移動相とした。
カラム:Inertsil ODS−3、GLサイエンス社製
移動相:1−ヘプタンスルホン酸ナトリウム1.88gを水1860mLに溶かし,アセトニトリル140mLを加え,リン酸を加えてpH2.7に調整した。
カラム:Wakosil−II 5C18 RS、和光純薬製
移動相:1−ヘプタンスルホン酸ナトリウム1.01gをとり、水を加えて1000mLとした。この液850mLにメタノール150mLを加え、リン酸を加えてpH2.7に調整した。
チピラシル塩酸塩の濃度が約0.8mg/mLとなるよう水/アセトニトリル混合溶液(23:2)に溶解させ、適宜希釈した溶液をチピラシルのみ含む試料とした。
移動相:リン酸二水素カリウム1.25g及び1−ヘプタンスルホン酸ナトリウム1.01gを水920mLに溶かし,アセトニトリル80mLを加えて移動相とした。
Claims (13)
- トリフルリジン又はその塩、及びチピラシル又はその塩を含む試料を有機相及び水相からなる移動相を用いる高速液体クロマトグラフィーに供する工程を含む、トリフルリジン由来の類縁物質及びチピラシル由来の類縁物質の一方又は両方を検出するための方法。
- 前記類縁物質が下記類縁物質1〜5からなる群より選ばれる少なくとも1つである、請求項1に記載の方法:
類縁物質1:トリフルオロチミン、
類縁物質2:2−イミノピロリジン、
類縁物質3:5−クロロ−6−{(2−オキソピロリジン−1−イル)メチル}ピリミジン−2,4−(1H、3H)−ジオン、
類縁物質4:2’−デオキシ−5−メトキシカルボニルウリジン、
類縁物質5:5−カルボキシウラシル。 - 前記類縁物質が類縁物質3を含み、高速液体クロマトグラフィーにおける類縁物質3とトリフルリジンとの保持時間が1.0分以上異なっている、請求項2に記載の方法。
- 類縁物質1〜5、トリフルリジン及びチピラシルの保持時間における移動相全体に対する有機相の割合がいずれも7〜15容量%である、請求項2又は3に記載の方法。
- 前記有機相がメタノールを含む、請求項1〜4のいずれか1項に記載の方法。
- 水相が、リン酸もしくはその塩またはこれらの混合物を含む、請求項1〜5のいずれか1項に記載の方法。
- 類縁物質1、3、4及びトリフルリジンの保持時間における移動相全体に対する有機相の割合のうち、最も大きい値と最も小さい値との差が、移動相全体の5容量%以下である、請求項2〜6のいずれか1項に記載の方法。
- 移動相のpHが2.0〜5.0である、請求項1〜7のいずか1項に記載の方法。
- トリフルリジン又はその塩、及びチピラシル又はその塩を含む配合剤の品質管理に用いられる2’−デオキシ−5−メトキシカルボニルウリジン(類縁物質4)。
- トリフルリジン又はその塩、及びチピラシル又はその塩を含む配合剤の不純物検出の際に標準品として用いるための2’−デオキシ−5−メトキシカルボニルウリジン(類縁物質4)。
- 2’−デオキシ−5−メトキシカルボニルウリジン(類縁物質4)の、トリフルリジン又はその塩、及びチピラシル又はその塩を含む配合剤の品質管理の際の標準品としての使用。
- 2’−デオキシ−5−メトキシカルボニルウリジン(類縁物質4)からなる、トリフルリジン又はその塩、及びチピラシル又はその塩を含む配合剤の不純物検出の際の標準品。
- トリフルリジン又はその塩、及びチピラシル又はその塩を含む配合剤から単離することを特徴とする2’−デオキシ−5−メトキシカルボニルウリジン(類縁物質4)の製造方法。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2017246043 | 2017-12-22 | ||
JP2017246043 | 2017-12-22 | ||
US15/952,367 | 2018-04-13 | ||
US15/952,367 US10866219B2 (en) | 2017-12-22 | 2018-04-13 | Method for detecting trifluridine- and/or tipiracil-related substance |
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CN201810427364.6A CN109959733B (zh) | 2017-12-22 | 2018-05-07 | 源自曲氟尿苷及/或替吡嘧啶的类似物质的检测方法 |
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