CA1077502A - Microcrystalline 3-(alpha-acetonylbenzyl)-4-hydroxycoumarin (warfarin) compositions thereof methods of making and using - Google Patents
Microcrystalline 3-(alpha-acetonylbenzyl)-4-hydroxycoumarin (warfarin) compositions thereof methods of making and usingInfo
- Publication number
- CA1077502A CA1077502A CA232,784A CA232784A CA1077502A CA 1077502 A CA1077502 A CA 1077502A CA 232784 A CA232784 A CA 232784A CA 1077502 A CA1077502 A CA 1077502A
- Authority
- CA
- Canada
- Prior art keywords
- warfarin
- acid
- microcrystalline
- buffer
- sodium
- 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.)
- Expired
Links
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 title claims abstract description 87
- 229960005080 warfarin Drugs 0.000 title claims abstract description 78
- 238000000034 method Methods 0.000 title claims abstract description 46
- 239000000203 mixture Substances 0.000 title claims abstract description 32
- 239000013078 crystal Substances 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims description 77
- BBOSKMPTDUUMKL-UHFFFAOYSA-N 4-hydroxy-3-(3-hydroxy-1-phenylbut-3-enyl)chromen-2-one Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=C)O)C1=CC=CC=C1 BBOSKMPTDUUMKL-UHFFFAOYSA-N 0.000 claims description 41
- 239000000872 buffer Substances 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 27
- 150000001412 amines Chemical class 0.000 claims description 24
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 239000007853 buffer solution Substances 0.000 claims description 14
- 239000012535 impurity Substances 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 230000003472 neutralizing effect Effects 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 239000012736 aqueous medium Substances 0.000 claims description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 4
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
- 238000013019 agitation Methods 0.000 claims description 3
- -1 alkali metal dihydrogen phosphate Chemical class 0.000 claims description 3
- 238000005119 centrifugation Methods 0.000 claims description 3
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 claims description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 3
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 3
- AOSFMYBATFLTAQ-UHFFFAOYSA-N 1-amino-3-(benzimidazol-1-yl)propan-2-ol Chemical compound C1=CC=C2N(CC(O)CN)C=NC2=C1 AOSFMYBATFLTAQ-UHFFFAOYSA-N 0.000 claims description 2
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 claims description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005695 Ammonium acetate Substances 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000021317 phosphate Nutrition 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- 235000011083 sodium citrates Nutrition 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims 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 claims 1
- 235000011054 acetic acid Nutrition 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- 235000015165 citric acid Nutrition 0.000 claims 1
- 235000019253 formic acid Nutrition 0.000 claims 1
- 238000010979 pH adjustment Methods 0.000 claims 1
- 235000019260 propionic acid Nutrition 0.000 claims 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims 1
- 239000011975 tartaric acid Substances 0.000 claims 1
- 235000002906 tartaric acid Nutrition 0.000 claims 1
- 239000003128 rodenticide Substances 0.000 abstract description 29
- 239000003146 anticoagulant agent Substances 0.000 abstract description 25
- 229940127219 anticoagulant drug Drugs 0.000 abstract description 24
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 6
- 230000020477 pH reduction Effects 0.000 abstract description 4
- 239000012670 alkaline solution Substances 0.000 abstract description 2
- KYITYFHKDODNCQ-UHFFFAOYSA-M sodium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [Na+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 KYITYFHKDODNCQ-UHFFFAOYSA-M 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 239000000523 sample Substances 0.000 description 13
- 150000002085 enols Chemical class 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- VXIXUWQIVKSKSA-UHFFFAOYSA-N 4-hydroxycoumarin Chemical compound C1=CC=CC2=C1OC(=O)C=C2O VXIXUWQIVKSKSA-UHFFFAOYSA-N 0.000 description 10
- 238000007792 addition Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 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 9
- 241000283984 Rodentia Species 0.000 description 9
- 159000000000 sodium salts Chemical class 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000008213 purified water Substances 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 235000013305 food Nutrition 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 238000006386 neutralization reaction Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 206010053567 Coagulopathies Diseases 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 230000035602 clotting Effects 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 230000001119 rodenticidal effect Effects 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 229960002647 warfarin sodium Drugs 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 240000008042 Zea mays Species 0.000 description 3
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 3
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000002429 anti-coagulating effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000008366 buffered solution Substances 0.000 description 3
- 230000003139 buffering effect Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 235000005822 corn Nutrition 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000013081 microcrystal Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- MJKVTPMWOKAVMS-UHFFFAOYSA-N 3-hydroxy-1-benzopyran-2-one Chemical compound C1=CC=C2OC(=O)C(O)=CC2=C1 MJKVTPMWOKAVMS-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 229930194542 Keto Natural products 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 229940058020 2-amino-2-methyl-1-propanol Drugs 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241000288673 Chiroptera Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000005667 attractant Substances 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000701 coagulant Substances 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 239000003959 coumarin anticoagulant Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008369 fruit flavor Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- HTYIXCKSEQQCJO-UHFFFAOYSA-N phenaglycodol Chemical compound CC(C)(O)C(C)(O)C1=CC=C(Cl)C=C1 HTYIXCKSEQQCJO-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
- C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
- C07D311/46—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Hematology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/496,932 US4113744A (en) | 1974-08-13 | 1974-08-13 | Microcrystalline 3-(alpha-acetonylbenzyl)-4-hydroxycoumarin (warfarin) and methods of making |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1077502A true CA1077502A (en) | 1980-05-13 |
Family
ID=23974780
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA232,784A Expired CA1077502A (en) | 1974-08-13 | 1975-07-31 | Microcrystalline 3-(alpha-acetonylbenzyl)-4-hydroxycoumarin (warfarin) compositions thereof methods of making and using |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4113744A (OSRAM) |
| JP (1) | JPS5835967B2 (OSRAM) |
| BE (1) | BE832395A (OSRAM) |
| BR (1) | BR7504996A (OSRAM) |
| CA (1) | CA1077502A (OSRAM) |
| DE (1) | DE2535228A1 (OSRAM) |
| ES (1) | ES440221A1 (OSRAM) |
| FR (1) | FR2281754A1 (OSRAM) |
| GB (1) | GB1513399A (OSRAM) |
| IN (1) | IN141166B (OSRAM) |
| LU (1) | LU73199A1 (OSRAM) |
| NL (1) | NL7509661A (OSRAM) |
| ZA (1) | ZA754795B (OSRAM) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5696274A (en) * | 1995-12-28 | 1997-12-09 | Hoechst Celanese Corporation | Syntheses based on 2-hydroxyacetophenone |
| AU4068299A (en) * | 1998-03-30 | 1999-10-18 | Sloan-Kettering Institute For Cancer Research | Bismuth-213 generator and uses thereof |
| US6512005B2 (en) | 2001-02-28 | 2003-01-28 | Taro Pharmaceutical Industries, Ltd. | Process for synthesis of pure warfarin acid, warfarin alkali metal salts and corresponding clathrates |
| US6673944B2 (en) | 2001-02-28 | 2004-01-06 | Taro Pharmaceutical Industries, Ltd. | Preparation of warfarin sodium from warfarin acid |
| US6610862B2 (en) | 2001-02-28 | 2003-08-26 | Taro Pharmaceutical Industries Ltd. | Preparation of warfarin sodium from warfarin sodium-2-propanol clathrate by solvent expulsion |
| CA2439488A1 (en) * | 2001-02-28 | 2002-09-12 | Taro Pharmaceutical Industries Ltd. | Process for purification of warfarin acid, warfarin alkali metal salts and corresponding clathrates |
| EP1589930A2 (en) * | 2003-01-08 | 2005-11-02 | Flacco-Nesselroad Family Trust | Combination therapy for anticoagulation |
| GB0329303D0 (en) * | 2003-12-18 | 2004-01-21 | Whelan Ian P | Rodenticide bait system |
| GB2635614A (en) * | 2023-07-22 | 2025-05-21 | Liqmeds Worldwide Ltd | A ready-to-use oral liquid formulation of warfarin sodium |
| WO2025022245A1 (en) * | 2023-07-22 | 2025-01-30 | Liqmeds Worldwide Limited | A ready-to-use oral liquid formulation of warfarin sodium |
| CN117169390B (zh) * | 2023-10-18 | 2024-05-03 | 宁波市疾病预防控制中心(宁波市健康教育与促进中心) | 一种测定血液中安妥的方法、试剂盒及应用 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2666064A (en) * | 1951-07-10 | 1954-01-12 | S B Penick & Company Inc | Manufacture of 3-(alpha-phenyl-beta-acetylethyl)-4-hydroxycoumarin |
| US2777859A (en) * | 1953-02-05 | 1957-01-15 | Wisconsin Alumni Res Found | Warfarin-alkali metal derivatives and processes of preparing the same |
| US2752360A (en) * | 1953-03-23 | 1956-06-26 | S B Penick & Company Inc | Improvement in the manufacture of 3-substituted 4-hydroxycoumarins |
| US2932652A (en) * | 1957-02-11 | 1960-04-12 | Nicholas M Molnar | 3-(1'-(alpha-naphthyl) 3'-oxo-butyl) 4-hydroxy coumarin and salts thereof |
-
1974
- 1974-08-13 US US05/496,932 patent/US4113744A/en not_active Expired - Lifetime
-
1975
- 1975-07-25 ZA ZA754795A patent/ZA754795B/xx unknown
- 1975-07-31 CA CA232,784A patent/CA1077502A/en not_active Expired
- 1975-07-31 IN IN1515/CAL/1975A patent/IN141166B/en unknown
- 1975-08-05 BR BR7504996A patent/BR7504996A/pt unknown
- 1975-08-07 DE DE19752535228 patent/DE2535228A1/de not_active Withdrawn
- 1975-08-07 JP JP50095464A patent/JPS5835967B2/ja not_active Expired
- 1975-08-12 FR FR7525087A patent/FR2281754A1/fr active Granted
- 1975-08-13 LU LU73199A patent/LU73199A1/xx unknown
- 1975-08-13 ES ES440221A patent/ES440221A1/es not_active Expired
- 1975-08-13 BE BE159171A patent/BE832395A/xx unknown
- 1975-08-13 NL NL7509661A patent/NL7509661A/xx not_active Application Discontinuation
- 1975-08-13 GB GB33672/75A patent/GB1513399A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| LU73199A1 (OSRAM) | 1976-08-13 |
| BR7504996A (pt) | 1976-08-31 |
| NL7509661A (nl) | 1976-02-17 |
| IN141166B (OSRAM) | 1977-01-29 |
| JPS5835967B2 (ja) | 1983-08-05 |
| JPS5141361A (OSRAM) | 1976-04-07 |
| AU8356175A (en) | 1977-02-03 |
| GB1513399A (en) | 1978-06-07 |
| DE2535228A1 (de) | 1976-02-26 |
| ZA754795B (en) | 1977-03-30 |
| FR2281754B1 (OSRAM) | 1978-11-10 |
| BE832395A (fr) | 1976-02-13 |
| US4113744A (en) | 1978-09-12 |
| FR2281754A1 (fr) | 1976-03-12 |
| ES440221A1 (es) | 1977-03-01 |
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| Date | Code | Title | Description |
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| MKEX | Expiry |