MXPA06007356A - New compositions containing quinoline compounds - Google Patents
New compositions containing quinoline compoundsInfo
- Publication number
- MXPA06007356A MXPA06007356A MXPA/A/2006/007356A MXPA06007356A MXPA06007356A MX PA06007356 A MXPA06007356 A MX PA06007356A MX PA06007356 A MXPA06007356 A MX PA06007356A MX PA06007356 A MXPA06007356 A MX PA06007356A
- Authority
- MX
- Mexico
- Prior art keywords
- carbon atoms
- branched
- salt
- linear
- alkyl
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 74
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 88
- 239000011780 sodium chloride Substances 0.000 claims abstract description 82
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 38
- 239000007787 solid Substances 0.000 claims abstract description 38
- 150000001768 cations Chemical class 0.000 claims abstract description 23
- 229910052751 metal Inorganic materials 0.000 claims abstract description 22
- 239000002184 metal Substances 0.000 claims abstract description 22
- 239000000546 pharmaceutic aid Substances 0.000 claims abstract description 21
- 238000003860 storage Methods 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 13
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 84
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- BLTDCIWCFCUQCB-UHFFFAOYSA-N quinoline-3-carboxamide Chemical class C1=CC=CC2=CC(C(=O)N)=CN=C21 BLTDCIWCFCUQCB-UHFFFAOYSA-N 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- 239000000460 chlorine Substances 0.000 claims description 29
- 229910052801 chlorine Inorganic materials 0.000 claims description 28
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 28
- 125000004122 cyclic group Chemical group 0.000 claims description 28
- 239000011737 fluorine Substances 0.000 claims description 28
- 229910052731 fluorine Inorganic materials 0.000 claims description 28
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 28
- 239000008187 granular material Substances 0.000 claims description 24
- 125000003342 alkenyl group Chemical group 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 21
- 238000005469 granulation Methods 0.000 claims description 16
- 230000003179 granulation Effects 0.000 claims description 16
- 239000011734 sodium Substances 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 14
- 125000004414 alkyl thio group Chemical group 0.000 claims description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 14
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 claims description 13
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 13
- 239000000594 mannitol Substances 0.000 claims description 13
- 235000010355 mannitol Nutrition 0.000 claims description 13
- 238000006297 dehydration reaction Methods 0.000 claims description 12
- 229910052708 sodium Inorganic materials 0.000 claims description 12
- 159000000000 sodium salts Chemical class 0.000 claims description 12
- VSGNNIFQASZAOI-UHFFFAOYSA-L Calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 11
- 239000001639 calcium acetate Substances 0.000 claims description 11
- 235000011092 calcium acetate Nutrition 0.000 claims description 11
- 229960005147 calcium acetate Drugs 0.000 claims description 11
- 239000000314 lubricant Substances 0.000 claims description 11
- -1 methylenedioxy Chemical group 0.000 claims description 11
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 11
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(E)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 claims description 11
- 238000005507 spraying Methods 0.000 claims description 10
- 159000000007 calcium salts Chemical class 0.000 claims description 9
- 239000011575 calcium Substances 0.000 claims description 8
- 230000001264 neutralization Effects 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- 125000005466 alkylenyl group Chemical group 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- 125000005997 bromomethyl group Chemical group 0.000 claims description 7
- 125000004773 chlorofluoromethyl group Chemical group [H]C(F)(Cl)* 0.000 claims description 7
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 7
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 6
- 229910052791 calcium Inorganic materials 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L Calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- 229940032147 Starch Drugs 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000000969 carrier Substances 0.000 claims description 4
- 159000000002 lithium salts Chemical class 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 150000003751 zinc Chemical class 0.000 claims description 3
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N Carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Chemical class 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical class [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 2
- 235000011132 calcium sulphate Nutrition 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 2
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 2
- 239000008109 sodium starch glycolate Substances 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- 239000007791 liquid phase Substances 0.000 claims 3
- 229960001681 Croscarmellose Sodium Drugs 0.000 claims 1
- 229920002785 Croscarmellose sodium Polymers 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 235000019700 dicalcium phosphate Nutrition 0.000 claims 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- 229910052744 lithium Inorganic materials 0.000 claims 1
- 150000003385 sodium Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 14
- 230000000087 stabilizing Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 66
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 30
- 230000015556 catabolic process Effects 0.000 description 22
- 230000004059 degradation Effects 0.000 description 22
- 238000006731 degradation reaction Methods 0.000 description 22
- 239000000243 solution Substances 0.000 description 19
- 239000002775 capsule Substances 0.000 description 15
- 239000001187 sodium carbonate Substances 0.000 description 15
- 229910000029 sodium carbonate Inorganic materials 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 10
- 150000003388 sodium compounds Chemical class 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000007906 compression Methods 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 238000005755 formation reaction Methods 0.000 description 5
- 239000012439 solid excipient Substances 0.000 description 5
- SGOOQMRIPALTEL-UHFFFAOYSA-N Roquinimex Chemical compound OC=1C2=CC=CC=C2N(C)C(=O)C=1C(=O)N(C)C1=CC=CC=C1 SGOOQMRIPALTEL-UHFFFAOYSA-N 0.000 description 4
- 238000010494 dissociation reaction Methods 0.000 description 4
- 230000005593 dissociations Effects 0.000 description 4
- CCGKOQOJPYTBIH-UHFFFAOYSA-N Ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 3
- GKWPCEFFIHSJOE-UHFFFAOYSA-N Laquinimod Chemical compound OC=1C2=C(Cl)C=CC=C2N(C)C(=O)C=1C(=O)N(CC)C1=CC=CC=C1 GKWPCEFFIHSJOE-UHFFFAOYSA-N 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- DIKSYHCCYVYKRO-UHFFFAOYSA-N N,5-diethyl-4-hydroxy-1-methyl-2-oxo-N-phenylquinoline-3-carboxamide Chemical compound OC=1C2=C(CC)C=CC=C2N(C)C(=O)C=1C(=O)N(CC)C1=CC=CC=C1 DIKSYHCCYVYKRO-UHFFFAOYSA-N 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 238000002144 chemical decomposition reaction Methods 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- VTLYFUHAOXGGBS-UHFFFAOYSA-N fe3+ Chemical class [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 159000000001 potassium salts Chemical class 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- PASHVRUKOFIRIK-UHFFFAOYSA-L calcium sulfate dihydrate Chemical compound O.O.[Ca+2].[O-]S([O-])(=O)=O PASHVRUKOFIRIK-UHFFFAOYSA-L 0.000 description 2
- 239000011247 coating layer Substances 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000008016 pharmaceutical coating Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 229960003522 roquinimex Drugs 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000009827 uniform distribution Methods 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- WSVLPVUVIUVCRA-RJMJUYIDSA-N (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol;hydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-RJMJUYIDSA-N 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- MCRNHLQVPJEMSQ-JITBQSAISA-N C(C=CC(=O)O)(=O)O.C(CCCCCCCCCCCCCCCCC)[Na] Chemical compound C(C=CC(=O)O)(=O)O.C(CCCCCCCCCCCCCCCCC)[Na] MCRNHLQVPJEMSQ-JITBQSAISA-N 0.000 description 1
- 229960001021 Lactose Monohydrate Drugs 0.000 description 1
- 241000083652 Osca Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000002051 biphasic Effects 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000002587 enol group Chemical group 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- YHGPYBQVSJBGHH-UHFFFAOYSA-H iron(3+);trisulfate;pentahydrate Chemical compound O.O.O.O.O.[Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O YHGPYBQVSJBGHH-UHFFFAOYSA-H 0.000 description 1
- 150000002561 ketenes Chemical class 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 150000002696 manganese Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 235000019691 monocalcium phosphate Nutrition 0.000 description 1
- 230000003472 neutralizing Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000004430 oxygen atoms Chemical group O* 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000004436 sodium atoms Chemical group 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- POECFFCNUXZPJT-UHFFFAOYSA-M sodium;carbonic acid;hydrogen carbonate Chemical compound [Na+].OC(O)=O.OC([O-])=O POECFFCNUXZPJT-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- BEAZKUGSCHFXIQ-UHFFFAOYSA-L zinc;diacetate;dihydrate Chemical compound O.O.[Zn+2].CC([O-])=O.CC([O-])=O BEAZKUGSCHFXIQ-UHFFFAOYSA-L 0.000 description 1
Abstract
A stable solid pharmaceutical composition consisting essentially of an effective amount of a salt of formula (II) together with an alkaline-reacting component maintaining the pH preferably above 8, or a salt with a divalent metal cation;and at least one pharmaceutical excipient;said salt of formula (II) being essentially stable during storage at room temperature for a period of at least 3 years. A process for stabilizing the salt of formula (II). A crystalline salt of formula (II) and a process for preparing said salt.
Description
NEW COMPOSITIONS CONTAINING QUINOLINE COMPOUNDS
FIELD OF THE INVENTION The present invention relates to stable compositions containing a salt of a 3-quinolinecarboxamide derivative, to methods for making such a salt, and to methods for the manufacture of a solid pharmaceutical formulation with improved stability during long storage. term, at room temperature.
BACKGROUND OF THE INVENTION The 3-quinolinecarboxamide derivatives are described in US Patent Nos. 4,547,511, 6,077,851, 6,133,285 and 6,121,287. The term "3-quinolinecarboxamide derivative" as used in this specification designates the undissociated acid form, hereinafter referred to as the neutral form, of the compound of formula (I), ie, the form as given in formula (I).
Unexpectedly it was found that some 3-quinolinecarboxamide derivatives in the neutral form, described in the prior patents of the United States are susceptible to ref .: 173753 chemical degradation in the solid state, and, in particular, when they occur in pharmaceutical formulations. . Some salts of the 3-quinolinecarboxamide derivatives (I) are known from the aforementioned US patents. However, none of the above-mentioned patent specifications describe a method that makes it possible to provide 3-quinolinecarboxamide derivatives of the formula (I) susceptible to degradation in a pharmaceutical form, sufficiently stable or even suggesting any particular advantage of the use of the Saline form of a 3-quinolinecarboxamide derivative in pharmaceutical formulations.
BRIEF DESCRIPTION OF THE INVENTION According to the present invention, there is provided a solid, stable pharmaceutical formulation containing a salt of a 3-quinolinecarboxamide derivative of the formula (I) with a monovalent or multivalent cation and a process for preparing such a formulation. The process comprises forming a capsule or a tablet containing a salt of a 3-quinolinecarboxamide derivative and an alkaline reaction component, uniformly distributed, capable of neutralizing any dissociation proton of the excipients, thereby maintaining the 3-quinolinecarboxamide in the salt form of formula (II). Alternatively, the process comprises forming a capsule or a tablet containing a salt of a 3-quinolinecarboxamide derivative, sparingly soluble in water and a salt with a divalent metal cation, capable of decreasing the dissociation of a salt of the formula (II) in ions. The alkaline reaction component of this invention is typically sodium carbonate, and the salt with a divalent metal cation is typically calcium acetate. The solid formulation of the invention includes pharmaceutical excipients, such as solid carriers in powder form, binders, disintegrators and lubricating agents. The invention also provides a process for the manufacture of a crystalline salt of a 3-quinolinecarboxamide derivative of the formula (I) with a counterion, which is a multivalent metal cation. The present invention solves the problem faced by those derivatives that are susceptible to chemical degradation in a solid pharmaceutical formulation.
DESCRIPTION OF THE INVENTION Some 3-quinolinecarboxamide derivatives in the neutral form described in the above US patents are susceptible to chemical degradation in the solid state, and, in particular, when they are found in pharmaceutical formulations. A main object of the present invention is to overcome this stability problem. The solution offered by the present invention to the problem of stability is based on the surprising and unexpected finding that the salt form of a compound of the formula (I) has an improved chemical stability compared to the neutral form of such a compound.
Scheme of reaction 1. The formation of ketene.
The degradation of the compounds of the formula (I) was thoroy investigated. The present inventors have shown that the aniline portion of the compound of the formula (I) is removed unexpectedly and a strongly reactive ketene is formed. This ketene reacts rapidly, for example, with ROH compounds. - After storage without taking any special precautions, some 3-quinolinecarboxamide derivatives of the formula (I) are degraded at an unacceptable rate.
In storage under accelerated conditions, ie at 40 ° C and a relative humidity of 75%, the degradation of some 3-quinolinecarboxamide derivatives may exceed 2% over a period of 6 months (Table 1). Since the decomposition rate of the 3-quinolinecarboxamide derivatives of the formula (I) under normal storage conditions is lower, it is nevertheless desirable to obtain a physical form of a 3-quinolinecarboxamide derivative, which exhibits improved stability. Surprisingly and unexpectedly, it has now been found that the 3-quinolinecarboxamide derivatives of the formula (I) when converted to a salt form with a mono- or multivalent metal cation of the structural formula (II),
where n is an integer of 1, 2 or 3; An + is a mono- or multivalent metal cation, selected from Li +, Na +, K +, Mg2 +, Ca2 +, Mn2 +, Cu2 +, Zn2 +, Al3 + and Fe3 +; R is a linear or branched alkyl or alkenyl of 1 to 4 carbon atoms or an alkyl of 3 to 4 carbon atoms, cyclic; R5 is a linear or branched, saturated or unsaturated alkyl or alkenyl of 1 to 4 carbon atoms, an alkyl of 3 to 4 carbon atoms, an alkylthio of 1 to 4 carbon atoms, straight or branched, an alkylthio of 3 at 4 carbon atoms, cyclic, a linear or branched alkylsulfinyl of 1 to 4 carbon atoms, an alkylsulfinyl of 3 to 4 carbon atoms, cyclic, fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy; and R6 is hydrogen; or R5 and R6 taken together are methylenedioxy; R 'is hydrogen, a linear or branched, saturated or unsaturated alkyl or alkenyl of 1 to 4 carbon atoms or an alkyl of 3 to 4 carbon atoms, a linear or branched alkoxy of 1 to 4 carbon atoms, alkoxy of 3 to 4 carbon atoms, cyclic, fluoro, chloro, bromo or trifluoromethyl; and R "is hydrogen, fluorine or chlorine, with the proviso that R" is fluorine or chlorine only when R 'is fluorine or chlorine; said derivatives have an improved stability compared to the corresponding neutral form of the 3-quinolinecarboxamides of the formula (I). A preferred group of 3-quinolinecarboxamide salts of the formula (II) are those wherein A + is Li +, Na + and Ca2 +. Another preferred group of 3-quinolinecarboxamide salts of the formula (II) are those sparingly water soluble salts which include Ca +, Zn 2 + and Fe 3+ salts. A salt of the formula (II) of a 3-quinolinecarboxamide is prepared by reacting a 3-quinolinecarboxamide of the formula (I) with a mono- or multivalent metal salt. Examples of such salts and reaction conditions are given below. In general, the aqueous solubility of salts of the formula (II) is higher for the salts with monovalent cations, for example a sodium or potassium salt, than for the salts of multivalent cations, for example a calcium, zinc salt , copper (II) or iron (III). As an example, the sodium salts are readily soluble in water, but have a limited solubility in less polar solvents, for example chloroform. On the other hand, an iron (III) salt is almost insoluble in water but has a high solubility in chloroform and a low solubility in methanol. When only aqueous solvent is used for the precipitation of a multivalent salt, for example, a calcium salt of the formula (II), an amorphous precipitate can be formed due to the very low solubility in water. However, by increasing the temperature and adding an organic solvent miscible with water, for example, ethanol, in which the salt has a slightly higher but still limited solubility, a crystalline compound can be precipitated. Preferably, mixtures of water and ethanol, containing 10 to 95% ethanol are used to secure crystalline compounds. In such mixtures, the particle size of the precipitate depends on the reaction temperature, the higher the temperature the larger crystals are produced. The reaction temperature can vary from 0 ° C to the reflux temperature. Alternatively, a crystalline salt can be prepared from an amorphous salt by mixing with a solvent in which the crystalline compound has a limited solubility as demonstrated in EXAMPLES 4 and 7. The storage stability of a compound of the formula (II) It is greatly improved. This is evident from a comparison of the compound N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-l-methyl-2-oxo-3-quinolinecarboxamide (hereinafter referred to as the compound A) with the sodium salt of N-ethyl-N-phenyl-5-chloro-l, 2-dihydro-4-hydroxy-l-methyl-2-oxo-3-quinolinecarboxamide (hereinafter referred to as compound A of sodium). While at 40 ° C and a relative humidity of 75%, less than 0.01% of compound A of sodium in the solid state, is converted to degradation products over a period of 24 months, 0.31% of compound A is degraded over a period of 6 months. Another example of a 3-quinolinecarboxamide derivative susceptible to degradation is N-ethyl-N-phenyl-5-ethyl-l, 2-dihydro-4-hydroxy-l-methyl-2-oxo-3-quinolinecarboxamide (from hereinafter referred to as compound B), see Table 1.
Table 1. Stability of -3-quinolinecarboxamide derivatives. Storage conditions: + 40 ° C / 75% RH.
"Quantitative degradation as the percentage of increase of related substances after 6 months of storage 2" Shelf life "denotes how long the" compound can be stored under the given conditions without degradation exceeding 0.5%. 3 The same result is obtained after 24 months of storage.
Generally, any tendency of instability is exacerbated when a compound of formula (II) is formulated with various excipients. This is verified by the results of a compatibility study comparing compound A with sodium compound A shown in Table 2. This is clear, because the salt form is preferred as a drug substance in any binary mixture of the compound.
Table 2. Compatibility studies comparing compound A with sodium compound A. Samples are binary samples (1: 1) of excipient and test substance. Storage conditions: + 40 ° C / 75% RH.
1 Degradation quantified as the percentage of increase of related substances after 6 months of storage.
The sodium salt when formulated in a solid pharmaceutical formulation, however, still degrades at an unacceptable rate with a level of degradation products exceeding 5% in 6 months when stored at + 40 ° C and at a relative humidity of 75% (Table 3). Such a level is considered problematic. An acceptable limit of degradation, under these conditions, is judged to be less than 0.5% degradation after 6 months of storage. This limit is considered indicative of a shelf life of 3 years at room temperature. On the other hand, a solid, conventional pharmaceutical formulation with an alkaline reaction component also shows an unacceptable rate of degradation. The crucial step is to obtain a uniform distribution of the salt of the formula (II), the alkaline reaction component and all the pharmaceutical excipients at a molecular level.
Table 3. Stability data of different formulations of sodium compound A.
1 Degradation quantified as the percentage of increase of related substances after 6 months of storage. 2"Shelf life" denotes how long the formulation can be stored under given conditions, without degradation exceeding 0.5%. 3 Compositions: Compound A sodium 1 mg, sodium hydroxide 0.112 mg, water for injection up to 1 ml, pH adjusted to 7.5. 4 Composition: Sodium Compound 0.3 mg (0.19%), 49.8% microcrystalline cellulose, 48.5% lactose monohydrate, 0.5% sodium croscarmellose, 1% sodium stearyl fumarate. 5 Composition: Sodium Compound 0.3 mg (0.19%), 66% pregelatinized starch, 29.8% mannitol, 3.0% sodium carbonate, 1.0% sodium stearyl fumarate. s Composition: According to EXAMPLE 10. 7 Formation of related substances after 2 months of storage.
The present invention provides compositions of a salt form of a 3-quinolinecarboxamide derivative, such compositions show improved storage stability which allows the development of new pharmaceutical formulations of a 3-quinolinecarboxamide with improved stability over the long term, for example, at least 3 years, storage at room temperature. Here, the expression "a 3-quinolinecarboxamide derivative susceptible to degradation" should
• mean a substance with a reactivity index > 1.0
(See EXAMPLES, Investigating degradation speed later). Mechanistic studies of ketene degradation have shown that the degradation involves an intramolecular transfer of the enol proton at position 4 of the quinoline ring to the nitrogen atom of the 3-quinolinecarboxamide portion (Reaction Scheme 1). It is considered that a stable dosage form of a compound of the formula (I) would be obtained if the compound is converted to the salt form of the formula (II). However, in spite of the improved chemical stability of the salt in the solid state, an acceptable degree of instability in the conventional solid dosage forms of the salts of the formula (II) still remains. The reason for the instability of the salts of the formula (II) in conventional solid dosage forms is now believed to be linked to the exchange of the counterion for a proton combined with the conformation of the salt in the solid state. X-ray studies of the sodium salt of compound A showed that the conformation of the solid salt is such that the exocyclic carbonyl group becomes curved from the enolate oxygen atom at position 4. This leads to an open path between the Nitrogen atom of the 3-quinolinecarboxamide portion and the enolate sodium atom in the 4 position. Without wishing to be bound to any theory of action, it is believed that this conformational property of the salts of the formula (II) results in the unacceptable rate of degradation in conventional solid dosage forms, once the counterion of the salt is exchanged with a proton obtained from the excipients. From what was said above regarding the properties of the stability of the 3-quinolinecarboxamide derivatives, it is evident that a stable dosage form of a compound of the formula (I) is obtained when the compound is present and remains in the salt form of formula (II). For clinical use, a salt of the formula (II) of the present invention, for example, the active ingredient, is suitably formulated into solid pharmaceutical formulations for the oral administration mode. The stringent prevention of any conversion of the salt to the neutral form could lead to improved stability of the salts during manufacture, and during the storage of the pharmaceutical formulation. Examples of such formulations are tablets and capsules. Commonly, the amount of active ingredient is from about 0.01 to 10% by weight of the formulation, preferably from about 0.1 to 2% by weight of the formulation. The pharmaceutical compositions of the present invention contain a salt of the formula (II) in combination with at least one component that inhibits the degradation of the active ingredient, and the pharmaceutical excipients. These compositions are an object of this invention.
In one embodiment of the present invention, the composition comprises an alkaline reaction component, which neutralizes the protons. The amount of the alkaline reaction component depends on the property of the alkaline reaction component and is from about 0.1 to 99% by weight of the formulation, preferably from about 1 to 20%. The pH of a specific composition is determined by the addition of 2 g of the composition, 4 g of deionized water, and subsequently measuring the pH of the resulting suspension. The pH should preferably be greater than 8. Suitable alkaline reaction components are selected from sodium, potassium, calcium and aluminum salts of acetic acid, carbonic acid, citric acid, phosphoric acid, sulfuric acid, or other weak organic or inorganic acids , adequate. In another embodiment, the composition comprises a salt with a divalent metal cation, preferably calcium acetate, and a calcium salt of the formula (II). Any other salt with a divalent metal cation, suitable in view of the intended application of the composition, can be used, for example, zinc and manganese salts. The amount of such salt is from about 1 to 99% by weight of the formulation, depending on the salt chosen. It is believed that the addition of salt containing a divalent metal cation to the pharmaceutical composition would decrease the dissociation of the salt of the formula (II) into ions. A salt of the formula (II) having a divalent metal counterion has limited solubility. Accordingly, protonation of the anion of the salt of formula (II) is suppressed, which results in increased stability. The pharmaceutical compositions and formulations containing the compounds of the formula (II), described above, are manufactured as described hereinafter. In the preparation of the pharmaceutical formulations in the form of dosage units for oral administration, the compound (II) is mixed with a salt with a divalent metal cation or an alkaline reaction component and with conventional pharmaceutical excipients. Suitable excipients may be chosen, but without restriction, between solid carriers in powder, for example, mannitol, microcrystalline cellulose, calcium acid phosphate, calcium sulfate, and starch; binders, for example, polyvinylpyrrolidone, starch and hydroxypropylmethylcellulose; disintegrators, for example, sodium croscamellose, sodium starch glycolate and polyvinylpyrrolidone, as well as lubricating agents, for example, magnesium stearate, sodium stearyl fumarate, talc and hydrogenated vegetable oil such as Sterotex NF. The mixture is then processed into tablets or granules for capsules.
According to one aspect, the present invention provides a method of preparing a tablet, comprising as an active ingredient a 3-quinolinecarboxamide derivative of improved chemical stability, wherein a tablet core containing a salt of the formula is manufactured (II) and an alkaline reaction component, or a salt with a divalent metal cation, as well as suitable pharmaceutical excipients. The crucial step is to achieve a tablet core with a uniform distribution, at the molecular level, of the alkaline reaction component, in order to neutralize all the protons that diffuse from the pharmaceutical excipients, or from the salt with a divalent metal cation. , in order to suppress the ion dissociation of the salt of the formula (II). The manufacturing methods of a tablet of the invention are the following: a) a tablet core containing a salt of the formula (II) is manufactured by spraying a solution of calcium acetate onto a mixture of the calcium salt of the formula (II) and the pharmaceutical excipients, granulation of the mixture until adequate consistency, dehydration, and subsequently compression of the granulate; or b) a tablet core containing a salt of the formula (II) sparingly soluble in water is manufactured by spraying a solution of an alkaline reaction component onto a mixture of the pharmaceutical excipients, granulating the mixture to the appropriate consistency , dehydration, mixing with a crystalline salt of the formula (II) sparingly soluble in water, and subsequently compressing the final mixture; or c) a tablet core containing a lithium, sodium or potassium salt of the formula (II) is manufactured by spraying a solution of the salt of the formula
(II) and an alkaline reaction component on a mixture of the pharmaceutical excipients, granulation of the mixture to appropriate consistency, dehydration, and then compression of the granulate; and d) a lubricating agent can optionally be added to the granulate before compression; and e) optionally a coating layer is added to the core, using conventional pharmaceutical coating excipients. A preferred method of manufacturing a tablet of the invention is: f) a tablet core containing a sodium salt of the formula (II) is made by spraying a solution of the sodium salt of the formula (II) and an alkaline reaction component on a mixture of the pharmaceutical excipients, granulation of the mixture to appropriate consistency, dehydration, and then compression of the granulate. Optionally, a lubricating agent can be added to the granulate, before compression, and optionally a coating layer is added to the core using conventional pharmaceutical coating excipients. . According to another aspect, the present invention provides a method of preparing a capsule comprising as an active ingredient, a 3-quinolinecarboxamide derivative with improved chemical stability. The manufacturing methods of a capsule of the invention are the following: g) a mixture containing a calcium salt of the formula (II) is manufactured by spraying a solution of calcium acetate on a mixture of the calcium salt of the formula (II) and the pharmaceutical excipients, granulation of the mixture to appropriate consistency, and subsequently the dehydration of the granulate; oh) a mixture containing a salt of the formula (II) sparingly soluble in water is manufactured by spraying a solution of an alkaline reaction component onto a mixture of the pharmaceutical excipients, granulating the mixture to an appropriate consistency, dehydrating the granulated, and mixed with a crystalline salt of the formula (II) sparingly soluble in water; or i) a mixture containing a lithium, sodium or potassium salt of the formula (II), more preferably a sodium salt, is made by spraying a solution of the salt of the formula (II) and a component of alkaline reaction on a mixture of the pharmaceutical excipients, granulation of the mixture to the appropriate consistency, and then dehydration of the granulate; j) optionally a lubricating agent is added to the mixture; and k) the final mixture is filled into hard gelatin capsules. An alternative method of preparing a salt of the formula (II), which has to be readily soluble in water, is to dissolve the corresponding compound of the formula (I) in the neutral form of a solution of an alkaline reaction component such as sodium carbonate, thereby producing the salt of formula (II) in itself, and subsequently following the methods described above.
EXAMPLES The following examples are given with the intention of illustrating the invention, without limiting the scope thereof.
EXAMPLE 1 Investigation of degradation rate The rate of degradation, hereinafter referred to as the reactivity index, of the compound of formula (I) was determined in solution. Roquinimex (Merck Index 12th Edition; No. 8418; Linomide®, LS2616, N-methyl-N-phenyl-1, 2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide) was selected as a reference compound with the reactivity index defined at 1.0. A medium of 0.01 M hydrochloric acid, 1% in n-propanol, was selected. The reaction temperature was in the range of 45 to 60 ° C. The 3-quinolinecarboxamide derivative of the formula (I) was added to the solution of n-propanol. The reaction transfers the compound to an n-propyl ester. The reaction was stopped after 0, 2 and 4 hours, and the analysis was carried out by means of HPLC with UV detection. The disappearance of the 3-quinolinecarboxamide derivative was used for the evaluation of the reactivity index, but an alternative for the formation of the n-propyl ester can be used. A reactivity index of 1.0 corresponds to a degradation rate of 13% per hour at 60 ° C, a reactivity index of 2.0 corresponds to a degradation rate of 26% per hour, etc. The reactivity indexes of some compounds of the formula (I) are shown in Table 1.
Table 4. Reactivity index of compounds of the formula (I)
Compound A is N-ethyl-N-phenyl-5-chloro-l, 2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide; Compound B is N-ethyl-N-phenyl-5-ethyl-l, 2-dihydro-4-hydroxy-l-methyl-2-oxo-3-quinolinecarboxamide; Compound C is N-methyl-N- (2,4-difluorophenyl) -5-chloro-l, 2-dihydro-4-hydroxy-l-methyl-2-oxo-3-quinolinecarboxamide; Compound D is N-methyl-N- (4-trifluorophenyl) -1,2-dihydro-1,5-dimethyl-4-hydroxy-l-methyl-2-oxo-3-quinolinecarboxamide;
Compound E is N-ethyl-N-phenyl-5,6-methylenedioxy-l, 2-dihydro-4-hydroxy-l-methyl-2-oxo-3-quinolinecarboxamide; Compound F is N-ethyl-N-phenyl-5-methylthio-l, 2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide. The following detailed Examples 2 to 7 serve to illustrate the process for manufacturing the compounds of the formula (II), which are used in the pharmaceutical formulations according to the present invention.
EXAMPLE 2 Sodium salt of N-ethyl-N-f-enyl-5-chloro-l, 2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide. N-ethyl-N-phenyl-5-chloro-l, 2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide (28 mmol, 10.00 g) was suspended in 99.5% ethanol (150 ml. ) and 5M aqueous sodium hydroxide solution (28.4 mmol, 5.68 mL) was added. The reaction mixture was stirred for 30 minutes at room temperature. The resulting crystalline precipitate was isolated by filtration, washed rapidly 2 times with cold ethanol (2 x 150 ml), and dried in vacuo over P2Os to obtain the title compound (9.5 g, 90% yield). Analysis calculated for C? 9H? EClN203Na: C, 60.2; H, 4.26; N, 7.40. Found C, 60.4; H, 4.20; N, 7.32. The solubility in water at room temperature was 138 mg / ml.
EXAMPLE 3 Calcium salt of N-ethyl-N-f-enyl-5-chloro-l, 2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide. N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-l-methyl-2-oxo-3-quinolinecarboxamide (2.63 mmol, 1.0 g) was dissolved in a mixture of ethanol (10.5 ml) ) and water (5.3 ml).
The solution was heated to 70 ° C and a solution of calcium acetate hydrated in water (1 M solution, 1.05 eq;
1. 38 mmol, 1.38 ml). The resulting suspension was stirred for 30 minutes, then cooled, and the crystals were isolated by filtration, washed with water, and dried in vacuo (966 mg, 98% yield). Analysis calculated for
C 38 H 32 Cl 2 N 4 Osca: C, 60.7; H, 4.29; N, 7.45. Found C,
60. 5; H, 4.34; N, 7.41. The solubility in water at room temperature was about 1.0 mg / ml. It is considered that the salt is sparingly soluble in water.
EXAMPLE 4 Iron (III) salt of N-ethyl-N-f-enyl-5-chloro-l, 2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide. N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide (5.0 g, 13.2 mmol) was dissolved in water (80 ml) at 40 ° C. ° C and chloroform (100 ml) was added. A solution of iron (III) sulphate pentahydrate (0.95 eq, 2.09 mmol, 1.023 g) dissolved in water (30 ml) is added. The biphasic system is stirred vigorously and the pH in the aqueous phase is adjusted to 8 with 1 M NaOH. The dark red organic phase is separated, dried with sodium sulfate, and the solvents are removed to obtain the title compound. as an amorphous, red crystalline mass (4.22 g, 85% yield). MS-ESI; m / z 1122 [MH] +. The crystalline mass is dissolved in methanol and red crystals are formed of the title compound. The crystals are filtered, washed with methanol, and dried under vacuum to obtain the title compound (3.96 g, 80% yield). Analysis calculated for C57H48Ns09Ci3Fe: C, 61.0; H, 4.31; N, 7.48. Found C, 62.7; H, 4.37; N, 7.27. The titri-metric determination of EDTA of iron (III) gave a content of 4.90% (the theoretical content is 4.97%). EXAMPLE 5 Lithium salt of N-ethyl-N-phenyl-5-ethyl-l, 2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide. N-Ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide (4.39 mmol, 1539 g) is suspended in methanol (7.5 ml) and add a solution of hydrated lithium hydroxide (1.05 eq, 4.61 mmol, 195 mg) dissolved in water. The mixture is stirred for 4 hours and ethyl acetate (30 ml) is added. After stirring for 1 hour, the crystals are filtered, washed with ethyl acetate, and dried under vacuum to obtain the title product (1.31 g, 84% yield). Analysis calculated for C21H21N203Li: C, 70.8; H, 5.94; N, 7.86. Found C, 70.5; H, 5.22; N, 8.01. The solubility in water at room temperature was 18 mg / ml. EXAMPLE 6 Calcium salt of N-ethyl-N-phenyl-5-ethyl-1, 2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide. N-ethyl-N-phenyl-5-ethyl-l, 2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide (5.0 g, 14.2 mmol) is dissolved in a mixture of 1 M NaOH ( 14.26 mmol, 14.26 ml) and ethanol (30 ml), and the pH is adjusted to 7.5. The solution is heated to 70 ° C and hydrated calcium acetate (1.05 eq, 7.5 mmol, 1335 g) in water (7 ml) is added dropwise for 5 minutes. The heating is continued and the mixture is stirred at room temperature for 1 hour, the crystals are filtered, washed with 1/1 ethanol / water, and dried under vacuum to obtain the title compound (5.16 g, 98% yield). ). Analysis calculated for C42H42N406Ca: C, 68.3; H, 5.73; N, 7.58. Found C, 68.4; H, 5.72; N, 7.63. The EDTA titriometric determination of calcium gave a content of 5.42% (the theoretical content is 5.42%). The solubility in water at room temperature was 0.3 mg / ml.
EXAMPLE 7 Zinc salt of N-ethyl-N-f-enyl-5-ethyl-l, 2-dihydro-4-hydroxy-l-ethyl-2-oxo-3-quinolinecarboxamide. N-Ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide (1.0 g, 2.85 mmol) is dissolved in a mixture of 1 M NaOH ( 2.95 mmol, 295 ml) and ethanol (6.0 ml). Chloroform (20 ml) and water (40 ml) are added, followed by the addition of zinc acetate dihydrate (3.0 mmol, 660 mg). The biphasic mixture is stirred vigorously for 10 minutes, the organic phase is separated and dried with sodium sulfate and the solvents are removed. The residue was recrystallized from methanol to obtain the title compound (823 mg, 76% yield). Analysis calculated for C42H42N4OsZn: C, 66.01; H, 5.54; N, 7.33. Found C, 65.4; H, 5.68; N, 7.29. The EDTA titriometric determination of zinc gave a content of 8.45% (the theoretical content is 8.56%). The solubility in water at room temperature was 0.3 mg / ml.
EXAMPLE 8 Description of Fabri cation. A pharmaceutical formulation according to the present invention was prepared, in the form of capsules, having the following composition: Granulate 0.17% Mannitol Excipients 96.8% Sodium Carbonate Solids 3.00% Sodium Compound A Fluid 1. 0.18% Granulation Sodium Carbonate1 0.03 % Water (13.3% of solid na2 excipients)
Capsules Final blend Granulated Compound A of 99.0% sodium 0.17% 1.00% Sodium stearyl fumarate
1 The compound given above can be replaced with another compound of the present invention. 2 Water is removed during dehydration.
The sodium compound A is dissolved in aqueous sodium carbonate and wet granulation together with mannitol and additional sodium carbonate. All the excipients required to fill the capsules except the lubricant, were present in the granulation stage. The resulting granulate is dehydrated in a conventional manner and passed through a sieve of suitable size. The dry granules are mixed perfectly with sodium stearyl fumarate and the obtained mixture is filled into capsules. The capsules contain adequate amounts of the active ingredient.
EXAMPLE 9 Manufacturing Description. A pharmaceutical formulation according to the present invention was prepared, in the form of capsules, having the following composition:
Granulated 0.18!
Solid Excipients Compound B of calcium1 0. 19% Mannitol 65. 0% Microcrystalline Cellulose 32. 0 Granulation fluid Calcium acetate 3. 00% Water (50.0% na2 solid excipients) x The compound given above can be replaced with another compound of the present invention. 2 Water is removed during dehydration.
A premix of compound A of calcium, mannitol and microcrystalline cellulose was prepared. The premix was wet granulated with an aqueous solution of calcium acetate. All the excipients required for the filling of the capsules were in the granulation stage. The resulting granulate was dried in a conventional manner and passed through a screen of suitable size. The dried granules were filled in capsules. The capsules contained adequate amounts of the active ingredient.
EXAMPLE 10 Manufacturing Description A pharmaceutical formulation according to the present invention was prepared, in the form of tablets, having the following composition:
Granulated 0.19%
Solid Excipients Mannitol 30.0% Pregelatinized Starch 66.8% Sodium Carbonate 2.84% Granulation Fluid Compound A sodium1 0.20% Sodium carbonate 0.20% Water (35.8% excipients na2 solids) Tablets Granule of compound A 93.1% sodium 0. 19% Sodium stearyl fumarate 0. 94 Coating suspension
Opadry 03B28796 White 6. 00
1 The compound given above can be replaced with another compound of the present invention. Water is removed during dehydration.
Sodium compound A is dissolved in aqueous sodium carbonate and wet granulated together with mannitol, pregelatinized starch and additional sodium carbonate. All the excipients required for the tablet formation, except the lubricant, were present in the granulation stage. The resulting granulate was dried in a conventional manner and passed through a screen of suitable size. The dried granules were mixed thoroughly with stearyl sodium fumarate and the obtained mixture was compressed into tablets. The tablets were covered with a film of Opadry 03B28796 White. The tablets contained adequate amounts of the active ingredient.
EXAMPLE 11 Manufacturing Description. A pharmaceutical formulation according to the present invention was prepared, in the form of tablets, having the following composition:
Granulated 0.18%
Solid Excipients Mannitol 32. 0% Microcrystalline Cellulose 65. 8% Compound granulation fluid A sodium1 0. 20% Sodium carbonate 0. 20% Sodium acid carbonate 1. 80% Water (50.0% of solid na2 excipients) Tablets
Compound granulate of 99.0% sodium 0.18% Sodium stearyl fumarate 1.00% 1 The compound given above can be replaced with another compound of the present invention. 2 Water is removed during dehydration.
The sodium compound A was dissolved in an aqueous solution of a sodium carbonate / sodium acid carbonate mixture and wet granulated together with mannitol and microcrystalline cellulose. All the excipients required for the tablet formation, except the lubricant, were present in the granulation stage. The resulting granulate was dried in a conventional manner and passed through a screen of suitable size. The dried granules were mixed perfectly with sodium stearyl fumarate and the obtained mixture was compressed into tablets. The tablets contained adequate amounts of the active ingredient.
EXAMPLE 12 Manufacturing Description A pharmaceutical formulation according to the present invention was prepared, in the form of tablets, having the following composition:
Granulated 0.18%
Solid Excipients Mannitol 48.5% Calcium sulphate dihydrate 48.3% Sodium carbonate 3.02% Granulation fluid Compound A sodium1 0.19% Sodium carbonate 0.01% Water (6.7% excipients na2 Solids)
Tablets Compound Granulate 99.0% sodium 0.18% Sodium stearyl fumarate 1.00% x The compound given above can be replaced with another compound of the present invention. 2 Water is removed during dehydration.
The sodium compound A is dissolved in aqueous sodium carbonate solution and wet granulated together with mannitol, calcium sulfate dihydrate and additional sodium carbonate. All excipients required for tabletting, except lubricant, were present in the granulation step and the resulting granules were dried in a conventional manner. The dried granules were mixed perfectly with sodium stearyl fumarate and the obtained mixture was compressed into tablets. The tablets contained adequate amounts of the active ingredient. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (8)
1. A solid, stable pharmaceutical composition, consisting essentially of an effective amount of a salt of the formula (II) characterized in that n is an integer of 1, 2 or 3; An + is a mono- or multivalent metal cation, selected from Li +, Na +, K +, Mg2 +, Ca2 +, Mn2 +, Cu2 +, Zn2 +, Al3 + and Fe3 +; R is a linear or branched alkyl or alkenyl of 1 to 4 carbon atoms or an alkyl of 3 to 4 carbon atoms, cyclic; R5 is a linear or branched, saturated or unsaturated alkyl or alkenyl of 1 to 4 carbon atoms, an alkyl of 3 to 4 carbon atoms, an alkylthio of 1 to 4 carbon atoms, straight or branched, an alkylthio of 3 at 4 carbon atoms, cyclic, a linear or branched alkylsulfinyl of 1 to 4 carbon atoms, an alkylsulfinyl of 3 to 4 carbon atoms, cyclic, fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy; and R6 is hydrogen; or R5 and R6 taken together are methylenedioxy; R 'is hydrogen, a linear or branched, saturated or unsaturated alkyl or alkenyl of 1 to 4 carbon atoms or an alkyl of 3 to 4 carbon atoms, a linear or branched alkoxy of 1 to 4 carbon atoms, alkoxy of 3 to 4 carbon atoms, cyclic, fluoro, chloro, bromo or trifluoromethyl; and R "is hydrogen, fluorine or chlorine, with the proviso that R" is fluorine or chlorine only when R 'is fluorine or chlorine; an alkaline reaction component maintains the pH preferably above 8, or a salt with a divalent metal cation; and at least one pharmaceutical excipient; wherein the salt of formula (II) is essentially stable during storage at room temperature for a period of at least 3 years.
2. The solid pharmaceutical composition according to claim 1, characterized in that the salt of the formula (II) is a lithium or calcium salt of N-ethyl-N-phenyl-5-chloro-1,2-dihydro- 4-hydro? Il-methyl-2-oxo-3-quinolinecarboxamide or a lithium, calcium or zinc salt of N-ethyl-N-phenyl-5-ethyl-l, 2-dihydro-4-hydroxy-1 -methyl-2-oxo-3-quinolinecarboxamide.
3. The solid pharmaceutical composition according to claim 1 or 2, characterized in that the salt of formula (II) is present in an amount from 0.01 to 10% by weight of the composition, preferably from 0.1 to 2% by weight of the composition. . The solid pharmaceutical composition according to any of claims 1 to 3, characterized in that the alkaline reaction component is selected from sodium, potassium, calcium and aluminum salts of acetic acid, carbonic acid, citric acid and phosphoric acid. 5. The solid pharmaceutical composition according to any of claims 1 to 4, characterized in that the alkaline reaction component is present in an amount from 0.1 to 99% by weight of the composition, preferably from 1 to 20% by weight of the composition. 6. The solid pharmaceutical composition according to any of claims 1 to 3, characterized in that the salt with a divalent metal cation is calcium acetate. The solid pharmaceutical composition according to claim 6, characterized in that the calcium acetate is present in an amount of from 1 to 10% by weight of the composition. 8. The solid pharmaceutical composition according to any of claims 1 to 7, characterized in that the pharmaceutical excipient is selected from powdered solid carriers, binders, disintegrating agents and lubricating agents. 9. The solid pharmaceutical composition according to claim 8, characterized in that the solid carriers in powder form are selected from mannitol, microcrystalline cellulose, calcium hydrogen phosphate, calcium sulfate and starch. 10. The solid pharmaceutical composition according to claim 8 or 9, characterized in that the binders are selected from polyvinylpyrrolidone, starch and hydroxypropylmethylcellulose. 11. The solid pharmaceutical composition according to any of claims 8 to 10, characterized in that the disintegrators are selected from croscarmellose sodium, sodium starch glycolate and polyvinylpyrrolidone. 12. The solid pharmaceutical composition according to any of claims 8 to 11, characterized in that the lubricating agents are selected from magnesium stearate, sodium stearyl fumarate, talc and hydrogenated vegetable oil. 13. A process to stabilize a salt of the formula (II) characterized because n is 2 An + is Ca2 +; R is a linear or branched alkyl or alkenyl of 1 to 4 carbon atoms or an alkyl of 3 to 4 carbon atoms, cyclic; R5 is a linear or branched, saturated or unsaturated alkyl or alkenyl of 1 to 4 carbon atoms, an alkyl of 3 to 4 carbon atoms, an alkylthio of 1 to 4 carbon atoms, straight or branched, an alkylthio of 3 at 4 carbon atoms, cyclic, a linear or branched alkylsulfinyl of 1 to 4 carbon atoms, an alkylsulfinyl of 3 to 4 carbon atoms, cyclic, fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy; and R6 is hydrogen; or R5 and R6 taken together are methylenedioxy; R 'is hydrogen, a linear or branched, saturated or unsaturated alkyl or alkenyl of 1 to 4 carbon atoms, an alkyl of 3 to 4 carbon atoms, a linear or branched alkoxy of 1 to 4 carbon atoms, alkoxy of 3 to 4 carbon atoms, cyclic, fluoro, chloro, bromo or trifluoromethyl; and R "is hydrogen, fluorine or chlorine, with the proviso that R" is fluorine or chlorine only when R 'is fluorine or chlorine; by spraying a solution of calcium acetate onto a mixture of calcium salt of the formula (II) 1 and at least one pharmaceutical excipient, the process produces a salt of the formula (II) which is essentially stable in a solid pharmaceutical composition during storage at room temperature for a period of at least 3 years. 1
4. A process to stabilize a salt of the formula (II) characterized in that n is an integer of 2 or 3; An + is a multivalent metal cation, selected from Ca2 +, Zn2 + and Fe3 +; R is a linear or branched alkyl or alkenyl of 1 to 4 carbon atoms or an alkyl of 3 to 4 carbon atoms, cyclic; R5 is a linear or branched, saturated or unsaturated alkyl or alkenyl of 1 to 4 carbon atoms, an alkyl of 3 to 4 carbon atoms, an alkylthio of 1 to 4 carbon atoms, straight or branched, an alkylthio of 3 at 4 carbon atoms, cyclic, a linear or branched alkylsulfinyl of 1 to 4 carbon atoms, an alkylsulfinyl of 3 to 4 carbon atoms, cyclic, fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy; and R6 is hydrogen; or R5 and R6 taken together are methylenedioxy; R 'is hydrogen, a linear or branched, saturated or unsaturated alkyl or alkenyl of 1 to 4 carbon atoms, an alkyl of 3 to 4 carbon atoms, a linear or branched alkoxy of 1 to 4 carbon atoms, alkoxy of 3 to 4 carbon atoms, cyclic, fluoro, chloro, bromo or trifluoromethyl; and R "is hydrogen, fluorine or chlorine, with the proviso that R" is fluorine or chlorine only when R 'is fluorine or chlorine; by spraying a solution of an alkaline reaction component onto a pharmaceutical excipient or a mixture of pharmaceutical excipients, granulation to the appropriate consistency, dehydration of the granulate thus obtained and mixing the dehydrated granulate with the salt of the formula (II), the process produces a salt of formula (II) that is essentially stable in a solid pharmaceutical composition during storage at room temperature for a period of at least 3 years. 1
5. A process to stabilize a salt of the formula (II) characterized in that n is 1; An + is a monovalent metal cation, selected from Li + 'Na + and K +; R is a linear or branched alkyl or alkenyl of 1 to 4 carbon atoms or an alkyl of 3 to 4 carbon atoms, cyclic; R5 is a linear or branched, saturated or unsaturated alkyl or alkenyl of 1 to 4 carbon atoms, an alkyl of 3 to 4 carbon atoms, an alkylthio of 1 to 4 carbon atoms, straight or branched, an alkylthio of 3 at 4 carbon atoms, cyclic, an alkylsulfinyl having 1 to 4 carbon atoms, linear or branched, an alkylsulfinyl having 3 to 4 carbon atoms, cyclic, fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy, and R6 is hydrogen; or R5 and R6 taken together are methylenedioxy; R 'is hydrogen, a linear or branched, saturated or unsaturated alkyl or alkenyl of 1 to 4 carbon atoms, an alkyl of 3 to 4 carbon atoms, a linear or branched alkoxy of 1 to 4 carbon atoms, alkoxy of 3 to 4 carbon atoms, cyclic, fluoro, chloro, bromo or trifluoromethyl; and R "is hydrogen, fluorine or chlorine, with the proviso that R" is fluorine or chlorine only when R 'is fluorine or chlorine; by spraying a solution of the salt of the formula (II) and an alkaline reaction component on a pharmaceutical excipient or a mixture of pharmaceutical excipients, the process produces a salt of the formula (II) which is essentially stable in a pharmaceutical composition solid during storage at room temperature for a period of at least 3 years. 1
6. A process for the preparation of a crystalline salt of the formula (II) characterized in that n is an integer of 2 or 3; An + is a multivalent metal cation, selected from Mg2 +, Ca +, Mn2 +, Cu2 +, Zn2 +, Al3 + and Fe3 +; R is a linear or branched alkyl or alkenyl of 1 to 4 carbon atoms or an alkyl of 3 to 4 carbon atoms, cyclic; R5 is a linear or branched, saturated or unsaturated alkyl or alkenyl of 1 to 4 carbon atoms, an alkyl of 3 to 4 carbon atoms, an alkylthio of 1 to 4 carbon atoms, straight or branched, an alkylthio of 3 at 4 carbon atoms, cyclic, a linear or branched alkylsulfinyl of 1 to 4 carbon atoms, an alkylsulfinyl of 3 to 4 carbon atoms, cyclic, fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy; and R6 is hydrogen; or R5 and R6 taken together are methylenedioxy; R 'is hydrogen, a linear or branched, saturated or unsaturated alkyl or alkenyl of 1 to 4 carbon atoms, an alkyl of 3 to 4 carbon atoms, a linear or branched alkoxy of 1 to 4 carbon atoms, alkoxy of 3 to 4 carbon atoms, cyclic, fluoro, chloro, bromo or trifluoromethyl; and R "is hydrogen, fluorine or chlorine, with the proviso that R" is fluorine or chlorine only when R 'is fluorine or chlorine; by reaction of the neutral form or the sodium salt of a 3-quinolinecarboxamide derivative with a salt containing the multivalent metal cation in a liquid phase consisting of water and at least one organic solvent miscible with water, in whose liquid phase, the salt of formula (II) is sparingly soluble. 1
7. The process according to claim 16, characterized in that the liquid phase is a mixture of water and ethanol, containing from 10 to 95% ethanol. 1
8. A crystalline salt of the formula (II) characterized in that n is an integer of 2 or 3; Ap + is a multivalent metal cation, selected from Mg2 +, Ca2 +, Mn2 +, Cu2 +, Zn2 +, Al3 + and Fe3 +; R is a linear or branched alkyl or alkenyl of 1 to 4 carbon atoms or an alkyl of 3 to 4 carbon atoms, cyclic; R5 is a linear or branched, saturated or unsaturated alkyl or alkenyl of 1 to 4 carbon atoms, an alkyl of 3 to 4 carbon atoms, an alkylthio of 1 to 4 carbon atoms, straight or branched, an alkylthio of 3 at 4 carbon atoms, cyclic, a linear or branched alkylsulfinyl of 1 to 4 carbon atoms, an alkylsulfinyl of 3 to 4 carbon atoms, cyclic, fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy; and R6 is hydrogen; or R5 and R6 taken together are methylenedioxy; R 'is hydrogen, a linear or branched, saturated or unsaturated alkyl or alkenyl of 1 to 4 carbon atoms, an alkyl of 3 to 4 carbon atoms, a linear or branched alkoxy of 1 to 4 carbon atoms, alkoxy of 3 to 4 carbon atoms, cyclic, fluoro, chloro, bromo or trifluoromethyl; and R "is hydrogen, fluorine or chlorine, with the proviso that R" is fluorine or chlorine only when R 'is fluorine or chlorine.
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SE0400235-8 | 2004-02-06 |
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