WO2010059259A1 - Process for recovering florfenicol from pharmaceutical compositions - Google Patents
Process for recovering florfenicol from pharmaceutical compositions Download PDFInfo
- Publication number
- WO2010059259A1 WO2010059259A1 PCT/US2009/033205 US2009033205W WO2010059259A1 WO 2010059259 A1 WO2010059259 A1 WO 2010059259A1 US 2009033205 W US2009033205 W US 2009033205W WO 2010059259 A1 WO2010059259 A1 WO 2010059259A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- florfenicol
- mixture
- analog
- solvent
- pharmaceutical composition
- Prior art date
Links
- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 title claims abstract description 508
- 229960003760 florfenicol Drugs 0.000 title claims abstract description 292
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 115
- 238000000034 method Methods 0.000 title claims abstract description 85
- 230000008569 process Effects 0.000 title claims description 60
- 238000004519 manufacturing process Methods 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims description 216
- 239000002904 solvent Substances 0.000 claims description 187
- 239000000126 substance Substances 0.000 claims description 127
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 84
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 63
- 239000002552 dosage form Substances 0.000 claims description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 56
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 50
- 238000004587 chromatography analysis Methods 0.000 claims description 38
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 36
- 238000004090 dissolution Methods 0.000 claims description 36
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- 125000005843 halogen group Chemical group 0.000 claims description 32
- -1 methylthio, methylsulfoxy, methylsulfonyl Chemical group 0.000 claims description 32
- 238000011084 recovery Methods 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
- 238000001914 filtration Methods 0.000 claims description 22
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 21
- 238000001816 cooling Methods 0.000 claims description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 17
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 16
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 16
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
- 230000009471 action Effects 0.000 claims description 13
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 13
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- 125000001188 haloalkyl group Chemical group 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 11
- 238000009835 boiling Methods 0.000 claims description 11
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 10
- 238000005119 centrifugation Methods 0.000 claims description 10
- 238000001704 evaporation Methods 0.000 claims description 9
- 230000008020 evaporation Effects 0.000 claims description 9
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 9
- 238000000638 solvent extraction Methods 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 125000005347 halocycloalkyl group Chemical group 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 238000001953 recrystallisation Methods 0.000 claims description 7
- KPSSIOMAKSHJJG-UHFFFAOYSA-N neopentyl alcohol Chemical compound CC(C)(C)CO KPSSIOMAKSHJJG-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 238000011109 contamination Methods 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 239000006201 parenteral dosage form Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- 239000006211 transdermal dosage form Substances 0.000 claims description 4
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
- 239000000443 aerosol Substances 0.000 claims description 3
- 239000007943 implant Substances 0.000 claims description 3
- 239000008297 liquid dosage form Substances 0.000 claims description 3
- 239000008184 oral solid dosage form Substances 0.000 claims description 3
- 238000005192 partition Methods 0.000 claims description 3
- 239000006208 topical dosage form Substances 0.000 claims description 3
- 229940127557 pharmaceutical product Drugs 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 238000013268 sustained release Methods 0.000 claims 1
- 239000012730 sustained-release form Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 42
- 229940126534 drug product Drugs 0.000 description 20
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 10
- 239000000872 buffer Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 229940060568 nuflor Drugs 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- 230000036541 health Effects 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 238000010979 pH adjustment Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- RVDLSEQLTZKBDJ-CPTGAEDZSA-N 2,2-dichloro-n-[(1r,2s)-3-fluoro-1-hydroxy-1-(4-methylsulfonylphenyl)propan-2-yl]acetamide;(2r,3r,4r,5s)-6-(methylamino)hexane-1,2,3,4,5-pentol;2-[2-methyl-3-(trifluoromethyl)anilino]pyridine-3-carboxylic acid Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.C1=CC=C(C(F)(F)F)C(C)=C1NC1=NC=CC=C1C(O)=O.CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 RVDLSEQLTZKBDJ-CPTGAEDZSA-N 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 229940033088 resflor Drugs 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 230000001476 alcoholic effect Effects 0.000 description 4
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 4
- 229910052729 chemical element Inorganic materials 0.000 description 4
- 239000006184 cosolvent Substances 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000001376 precipitating effect Effects 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 3
- MYKLQMNSFPAPLZ-UHFFFAOYSA-N 2,5-dimethylcyclohexa-2,5-diene-1,4-dione Chemical compound CC1=CC(=O)C(C)=CC1=O MYKLQMNSFPAPLZ-UHFFFAOYSA-N 0.000 description 3
- QMXBURPYNWBMJR-UHFFFAOYSA-N 6-methoxy-2,6-dimethylheptanal Chemical compound COC(C)(C)CCCC(C)C=O QMXBURPYNWBMJR-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- 230000005526 G1 to G0 transition Effects 0.000 description 3
- DBXNUXBLKRLWFA-UHFFFAOYSA-N N-(2-acetamido)-2-aminoethanesulfonic acid Chemical compound NC(=O)CNCCS(O)(=O)=O DBXNUXBLKRLWFA-UHFFFAOYSA-N 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 239000006177 biological buffer Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical group F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 description 3
- 238000001640 fractional crystallisation Methods 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000010826 pharmaceutical waste Substances 0.000 description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
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- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical group F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 2
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- JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical compound OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 description 2
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- 125000001246 bromo group Chemical group Br* 0.000 description 2
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- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
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- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
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- 238000001121 post-column derivatisation Methods 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000045 pyrolysis gas chromatography Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- HRQDCDQDOPSGBR-UHFFFAOYSA-M sodium;octane-1-sulfonate Chemical compound [Na+].CCCCCCCCS([O-])(=O)=O HRQDCDQDOPSGBR-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- XYKWNRUXCOIMFZ-UHFFFAOYSA-N tepoxalin Chemical compound C1=CC(OC)=CC=C1N1C(C=2C=CC(Cl)=CC=2)=CC(CCC(=O)N(C)O)=N1 XYKWNRUXCOIMFZ-UHFFFAOYSA-N 0.000 description 1
- 229950009638 tepoxalin Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 238000001323 two-dimensional chromatography Methods 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
- 229960002300 zeranol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
Definitions
- the present invention relates generally to a new process for recovering florfenicol and florfenicol analogs from pharmaceutical compositions.
- Florfenicol is also known as 2,2-dichloro-N-[(lS,2R)-l-(fluoromethyl)-2-hydroxy-2-[4- (methylsulfonyl)phenyl]ethyl]-acetamide or [R-(R*,S*)]-2,2-dichloro-N-[l - (fluoromethyl)-2-hydroxy-2-[4-(methylsulfonyl)phenyl]ethyl]acetamide. [4] Florfenicol is the active pharmaceutical ingredient in numerous drug products.
- Drug products containing florfenicol are discussed in, for example, US4235892, US5082863, IT1233873, US2004/242546, JP59112913, US2003/036564, US2003/0068339, CN1459282, KR2003/097739, WO2004/014340, KR439853, US6787568, US2005/014828, CN1660079, KR2005/ 102309, KR2005/102310, KR2005/103357, WO2006/067138, US2006/223889, KR2006/105826, CN1947699, CN1961881, CN1965816, CN1969834, CN1985812, IN2003CH01036, CN10155534, PL192847, KR748251, KR748252, CNlOl 129347, CN101152169, and FR2910323.
- Florfenicol prodrugs in drug products are discussed in, for example, US 7153842, and US2005/01428. And uses of florfenicol in combination with other active pharmaceutical ingredients in drug products are discussed in, for example, US2003/0216447, US2004/198704, US6790867, US2006/122159, CN1582909, CN1660079, CN1861084, CN1915229, CN1939306, CN1931175, KR2004/020086, and KR2004/104169. All the references cited in this paragraph are incorporated by reference into this patent.
- florfenicol is an expensive active pharmaceutical ingredient
- the recovered florfenicol is reused to make new drug product. This reduces the need for (and, therefore, the expense associated with) destroying unusable drug product containing florfenicol, and makes otherwise unusable florfenicol available for use.
- the present invention is directed to a process for recovering florfenicol or florfenicol analogs from a pharmaceutical composition
- a process for recovering florfenicol or florfenicol analogs from a pharmaceutical composition comprising:
- the present invention is directed to a process for preparing a pharmaceutical dosage form comprising: (a) obtaining a pharmaceutical composition comprising florfenicol or florfenicol analogs, and at least one auxiliary substance; (b) recovering the florfenicol or florfenicol analogs from the pharmaceutical composition by preferential dissolution; and (c) formulating the recovered florfenicol or florfenicol analogs into a pharmaceutical dosage form comprising the florfenicol or florfenicol analogs, and at least one auxiliary substance.
- the present invention is directed to a process for purifying florfenicol or florfenicol analogs comprising:
- the purified recovered florfenicol or florfenicol analogs are reformulated into a new dosage form.
- the present invention is directed to a process for recovering florfenicol or florfenicol analogs from a pharmaceutical composition comprising: (a) obtaining a pharmaceutical composition comprising florfenicol or florfenicol analogs, and at least one auxiliary substance; and (b) recovering the florfenicol or florfenicol analogs from the pharmaceutical composition by chromatography.
- the present invention is directed to a process for preparing a pharmaceutical dosage form comprising:
- the present invention is directed to a process for purifying florfenicol or florfenicol analogs comprising:
- the purified recovered florfenicol or florfenicol analogs are reformulated into a new dosage form.
- the recovery of florfenicol or a florfenicol analog comprises a preferential dissolution of florfenicol or a florfenicol analog relative to the dissolution of at least one auxiliary substance.
- the recovery of the florfenicol or a florfenicol analog comprises a preferential dissolution of at least one auxiliary substance relative to florfenicol or a florfenicol analog.
- the recovery of florfenicol or a florfenicol analog comprises partitioning of at least one auxiliary substance in a first solvent from florfenicol or a florfenicol analog in a second solvent,
- this invention is directed to a method of conducting a pharmaceutical business comprising offering an incentive to a patient or healthcare provider to return an unused portion of a pharmaceutical dosage form.
- this invention is directed to a method of conducting a pharmaceutical business comprising: (a) obtaining an unused portion of a pharmaceutical dosage form from a patient or healthcare provider; and (b) recovering the active pharmaceutical ingredient from the unused portion of the pharmaceutical dosage form.
- this invention is directed to a method of conducting a pharmaceutical business comprising: (a) preparing a pharmaceutical dosage form comprising an active pharmaceutical ingredient, and at least one auxiliary substance;
- an incentive such as, for example, a monetary payment or rebate
- a patient or healthcare provider to obtain the unused portion of the pharmaceutical dosage form.
- the present invention is directed to a method of preventing the contamination of the environment (such as, for example, water supplies and landfills) comprising: (a) offering an incentive to a patient or healthcare provider to return an unused portion of a pharmaceutical dosage form; and (b) obtaining the unused portion of the pharmaceutical dosage form from the patient or healthcare provider.
- a method of preventing the contamination of the environment comprising: (a) offering an incentive to a patient or healthcare provider to return an unused portion of a pharmaceutical dosage form; and (b) obtaining the unused portion of the pharmaceutical dosage form from the patient or healthcare provider.
- the pharmaceutical dosage form generally will not be disposed of in a manner such that the active pharmaceutical ingredient can eventually contaminate water supplies or otherwise pollute the environment (such as, for example, in landfills).
- the present invention is directed to a process for recovering a compound of Formula II (or a pharmaceutically acceptable salt thereof) from a pharmaceutical composition by preferential dissolution of the auxiliary substances (such as, for example, pharmaceutically acceptable excipients or active pharmaceutical ingredients other than compounds of Formula II) relative to the dissolution of the active pharmaceutical ingredient.
- auxiliary substances such as, for example, pharmaceutically acceptable excipients or active pharmaceutical ingredients other than compounds of Formula II
- R 1 is hydrogen, methylthio, methylsulfoxy, methylsulfonyl, fluoromethylthio, fluoromethylsulfoxy, fluoromethylsulfonyl, nitro, fluoro, bromo, chloro, acetyl, benzyl, phenyl, halo-substituted phenyl, C 1 ⁇ alkyl, Ci- 6 haloalkyl, C 3-S cycloalkyl, C2.6 alkenyl, C 2-6 alkynyl, Ci- 6 alkoxy, Ci -6 arylalkyl, C 2-6 arylalkenyl, or C 3 -g heterocyclyl.
- R 2 , R 3 , and R 4 are independently hydrogen, halo, Ci -6 alkyl, C 1 ⁇ haloalkyl, C 3-8 cycloalkyl, C 2 -6 alkenyl, C 2-6 alkynyl, Ci -6 alkoxy, Ci-e arylalkyl, C 2 -6 arylalkenyl, benzyl, phenyl, C 3 -8 heterocyclyl, or C 1 ⁇ phenylalkyl.
- the phenyl may be substituted by one or two halo, C 3- g heterocyclyl, Cj -6 alkyl, or C 1 ⁇ alkoxy.
- each of R 2 and R 3 are hydrogen, and R 4 is fluoro.
- R 5 is hydrogen, C 1-6 alkyl, C 1 . 6 haloalkyl, C 3-8 halocycloalkyl, C 3 - 8 cycloalkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C ]-6 alkoxy, C 1-6 arylalkyl, C 2 - 6 arylalkenyl, benzyl, phenyl, or C 1-6 phenylalkyl.
- the phenyl may be substituted by one or two halo, C 3 .g heterocyclyl, C 1-6 alkyl, or C 1-6 alkoxy.
- R 5 is CH 2 Cl, CHCl 2 , CCl 3 , CH 2 Br, CHBr 2 , CBr 3 , CH 2 F, CHF 2 , or CF 3 .
- the recovery of florfenicol or a florfenicol analog from a pharmaceutical composition comprises: (a) obtaining a pharmaceutical composition comprising florfenicol or a florfenicol analog, and at least one auxiliary substance; (b) adding a solvent to the pharmaceutical composition that preferentially dissolves the auxiliary substances relative to the florfenicol or florfenicol analog to form a mixture;
- the recovery of florfenicol or a florfenicol analog from a pharmaceutical composition comprises:
- the solvent may, for example, be selected from the group consisting of water, methanol, ethanol, isopropanol, propanol, butanol, t-butanol, pentanol, neo-pentanol, methylene chloride, chloroform, carbon tetrachloride, 1,2 -dichloroethane, ethyl acetate, acetone, tetrahydrofuran, ether, dimethylsulfoxide, N, N-dimethylformamide, trifluoroethanol, and combinations thereof); (c) facilitating the dissolution of the auxiliary substances relative to the florfenicol or florfenicol analog in the mixture by performing at least one action selected from the group consisting of: heating the mixture up to, and including, the boiling
- the invention is directed to a process for recovering a compound of Formula II from a pharmaceutical composition by preferential dissolution of the compound of Formula II relative to the dissolution of the auxiliary substances.
- the recovery of florfenicol or a florfenicol analog from a pharmaceutical composition comprises: (a) obtaining a pharmaceutical composition comprising florfenicol or a florfenicol analog, and at least one auxiliary substance; (b) adding a solvent to the pharmaceutical composition (this is also meant to encompass adding the pharmaceutical composition to the solvent in all embodiments herein) that preferentially dissolves the florfenicol or florfenicol analog relative to the auxiliary substances to form a mixture;
- the recovery of florfenicol or a florfenicol analog from a pharmaceutical composition comprises: (a) obtaining a pharmaceutical composition comprising florfenicol or a florfenicol analog, and at least one auxiliary substance;
- the solvent may, for example, be selected from the group consisting of water, methanol, acetone, dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 2-pyrrolidone, trifluoroethanol, and combinations thereof;
- the invention includes a process for recovering a compound of Formula II from a pharmaceutical composition by partitioning of the auxiliary substances in one solvent or solvent system from the compound of Formula II in a different solvent or solvent system.
- the recovery offlorfenicol or a florfenicol analog from a pharmaceutical composition comprises:
- the recovery of florfenicol or a florfenicol analog from a pharmaceutical composition comprises:
- the florfenicol-dissolving solvent may, for example, be selected from the group consisting of water, methanol, acetone, dimethylsulfoxide, dimethylformamide, trifluoroethanol, and combinations thereof);
- the recovery of florfenicol or a florfenicol analog comprises dissolving the pharmaceutical composition in a suitable solvent or solvent system, injecting the dissolved pharmaceutical composition onto a chromatography column, separating florfenicol and/or florfenicol analogs from each other (if more than one is present) and at least one auxiliary substance by elution through the chromatography column with a suitable mobile phase, and collecting and isolating the separated florfenicol or florfenicol analog(s).
- the florfenicol or florfenicol analogue is optionally dried and/or purified.
- the drying of the florfenicol or florfenicol analog is at a temperature of from about 50 0 C to about 100 0 C, and the optional purifying is by recrystallization or by further chromatography.
- a compound of Formula III (or a pharmaceutically acceptable salt thereof) is recovered from a pharmaceutical composition.
- Formula III has the following structure:
- R 1 , R 4 , and R 5 are as previously defined.
- R 1 is CH 3 S O 2
- R 4 and R5 are as previously defined.
- R4 is F
- Rj and R 5 are as previously defined.
- R 5 is CHCI 2
- Ri and R 4 are as previously defined.
- R 1 is CH 3 SO 2
- R 4 is F
- R 5 is as previously defined.
- R 1 is CH3SO2
- R5 is CHCl 2
- R 4 is as previously defined.
- R5 is CHCl 2
- R 4 is F
- R 1 is as previously defined.
- florfenicol is recovered from a pharmaceutical composition.
- the recovery of the compounds of Formulas I-III from pharmaceutical compositions eliminates the expense associated with destroying unusable compositions.
- the recovered compounds of Formulas I-III are reused in the manufacture of new pharmaceutical dosage forms thereby saving additional expense by eliminating the need to manufacture such compounds (such as, for example, florfenicol).
- the recovery of compounds of Formulas I-III eliminates the need to dispose of this pharmaceutical waste. This, in turn, may reduce contamination of the environment.
- the present invention generally has the advantage of being an efficient, and economical process for recovering, and salvaging florfenicol from pharmaceutical compositions.
- the present invention encompasses situations wherein there is one auxiliary substance, as well as situations wherein there are more than one auxiliary substances, and it may be necessary to repeat the processes disclosed herein (in part or in full) to separate the florfenicol or florfenicol analog from the auxiliary substances.
- a disclosed process may preferentially dissolve one auxiliary substance (such as, for example, an excipient) relative to another auxiliary substance, such as, for example, an additional active pharmaceutical ingredient. This may result in the precipitation of the florfenicol or florfenicol analog in addition to the precipitation of the other auxiliary substances such as, for example, an additional active pharmaceutical ingredient.
- the resulting precipitate is then subjected to the same or different recovery process as disclosed herein, one or more times, to recover the florfenicol or florfenicol analog.
- some embodiments of the present invention include the additional step of determining the solubilities of some or all of the ingredients of the pharmaceutical composition. By determining the solubilities of ingredients in the composition, the necessary solvent or solvent systems can then be selected to preferentially dissolve, preferentially not dissolve, or partition a particular ingredient.
- florfenicol or a florfenicol analog is recovered from one pharmaceutical composition, and utilized in the manufacture of the same or a different pharmaceutical composition.
- florfenicol or a florfenicol analog is recovered from a transdermal dosage form, and then incorporated into a transdermal or solid oral dosage form.
- the unusable, and newly manufactured pharmaceutical compositions are independently selected from the group consisting of parenteral dosage forms, topical dosage forms, oral solid dosage forms, liquid dosage forms, granular dosage forms, suspension dosage forms, aerosol dosage forms, transdermal dosage forms, sustained or controlled released dosage forms, implant dosage forms, and powder dosage forms.
- chlorfenicol analog means a compound of Formula II that is other than florfenicol.
- the term “florfenicol analog” also encompasses salts of the compounds of Formula II, including salts of florfenicol. In general, such salts are preferably pharmaceutically acceptable.
- auxiliary substance means any ingredient other than the active pharmaceutical ingredient intended to be recovered. Such ingredients may include, for example, excipients or additional active pharmaceutical ingredients. In some embodiments, the processes disclosed in this patent is utilized to recover two or more active pharmaceutical ingredients from a pharmaceutical composition. Such embodiments may necessitate the repetition of some or all of the disclosed steps one or more times.
- impurity means an ingredient other than the active pharmaceutical ingredient intended to be recovered, and auxiliary substances. Impurities may include, for example, elemental material or degradation products such as dimers, hydroxylated compounds, ketones, oxides, aldol adducts, semiquinones, free radical peroxides, ether-linked adducts, and dehydrogenated compounds.
- excipients means all pharmacologically inactive substances (such as solvents, carriers, buffers, fillers, dispersants, colorants, preservatives, anti-microbial agents, anti-oxidant agents, and any other substance that is not an impurity) in a pharmaceutical composition other than the active pharmaceutical ingredient(s).
- the term "active pharmaceutical ingredient” is a pharmacologically active substance responsible for pharmacological activity of the drug product.
- pharmaceutical composition is synonymous with the term “drug product”, and means a combination of one or more active pharmaceutical ingredients with one or more excipient.
- the pharmaceutical composition can be a final pharmaceutical dosage form or an intermediate in the manufacture of a pharmaceutical dosage form.
- a “pharmaceutical dosage form” can be in the form of, for example, parenteral dosage forms, topical dosage forms, oral solid dosage forms, liquid dosage forms, granular dosage forms, suspension dosage forms, aerosol dosage forms, transdermal dosage forms, sustained or controlled released dosage forms, implant dosage forms, or powder dosage forms.
- the intermediate can be any composition utilized during the production of the dosage form, such as, for example, a free flowing powder from a tablet press or a solution of active pharmaceutical ingredient to be processed into a suitable parenteral dosage form.
- the term "patient” is defined as any subject who receives medical or veterinary attention, care, or treatment, and includes both humans, and animals.
- the term "healthcare provider” is defined as an organization or person who delivers health care to any patient.
- a “healthcare provider” may be, for example, a hospital, research laboratory, medical or clinical laboratory, physician, physician assistant, support staff, a nurse, pharmacist, therapist, psychologist, dentist, optometrist, psychiatrist, clinical psychologist, clinical social worker, psychiatric nurse, friend, family member, veterinarian, animal owner, or animal caregiver.
- chromatography means a technique for separating mixtures of components by passing the component mixture dissolved in a suitable mobile phase through a stationary phase that separates the compound or compounds of interest such that they can be isolated.
- acetyl means a CH 3 CO- radical.
- alcoholic solvent includes Ci-io monoalcohols (such as, for example, methanol, ethanol, and mixtures thereof), C 2 - 10 dialcohols (such as, for example, ethylene glycol), and Ci-I 0 trialcohols (such as, for example, glycerin).
- Ci-io monoalcohols such as, for example, methanol, ethanol, and mixtures thereof
- C 2 - 10 dialcohols such as, for example, ethylene glycol
- Ci-I 0 trialcohols such as, for example, glycerin
- the term “alcoholic solvent” also includes such alcohols mixed with any suitable co-solvent (/. e. , a second solvent added to the original solvent, generally in small concentrations, to form a mixture that has greatly enhanced solvent powers due to synergism).
- Such co-solvents include solvents that are miscible with the alcoholic solvent, such as, for example, C 4 - io alkanes, aromatic solvents (such as benzene, toluene, and xylenes), halobenzenes (such as, for example, chlorobenzene), ethers (such as, for example, diethylether, tert-butylmethylether, isopropylether, and tetrahydrofuran), and mixtures of any of the above co -solvents.
- solvents that are miscible with the alcoholic solvent such as, for example, C 4 - io alkanes, aromatic solvents (such as benzene, toluene, and xylenes), halobenzenes (such as, for example, chlorobenzene), ethers (such as, for example, diethylether, tert-butylmethylether, isopropylether, and tetra
- the phrase "adding one or more solvents to a pharmaceutical composition” also means adding a pharmaceutical composition to a solvent(s) and vice versa.
- the term "purity” means that the active pharmaceutical ingredient is free or substantially free of auxiliary substances and/or free or substantially free of impurities such as, for example, degradation products or other non-auxiliary-substance impurities.
- the purity for each is independently at least about 90%, at least about 95%, at least about 97%, or at least about 99%. In some embodiments, the purity is at least about 99% with respect to auxiliary substances, and at least about 97% with respect to impurities.
- obtaining a pharmaceutical composition means collecting pharmaceutical dosage forms to subject them to the processes disclosed herein.
- the collecting can be from, for example, manufacturing tailings, or rejected or expired batches of product.
- alkyl means a saturated straight or branched hydrocarbon, such as methyl, ethyl, propyl, or sec-butyl. Alternatively, the number of carbons in an alkyl can be specified. For example, "Ci -6 alkyl” means an “alkyl” containing from 1 to 6 carbon atoms.
- Example alkenyls include, without limitation, ethenyl, 1-propenyl, isopropenyl, 2-butenyl, 1,3-butadienyl, 3- ⁇ entenyl, 2-hexenyl, and the like.
- C 2 ⁇ alkynyl means an unsaturated branched or unbranched hydrocarbon having at least one triple carbon-carbon ( — C ⁇ C — ) bond, and containing from 2 to 6 carbon atoms.
- Example alkynyls include, without limitation, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl ⁇ 2-penten-4-ynyl, and the like.
- C ⁇ alkoxy means an alkyl-O- group. Examples alkoxy groups include, without limitation, methoxy, ethoxy, propoxy (including w-propoxy and isopropoxy), f-butoxy, and the like.
- C 1-6 arylalkyl means a C 1-6 alkyl substituted by an aryl that is any radical derived from an aromatic hydrocarbon by the removal of a hydrogen atom.
- the aryl is optionally substituted by halo or Ci- ⁇ alkyl.
- C 2-6 arylalkenyl means a C 2 . 6 alkenyl substituted by an aryl that is any radical derived from an aromatic hydrocarbon by the removal of a hydrogen atom.
- the aryl is optionally substituted by halo or Ci -6 alkyl.
- bromo means the chemical element bromine.
- benzyl means the univalent radical C 6 HsCH 2 - , formally derived from toluene (i.e., methylbenzene).
- chloro means the chemical element chorine.
- C 3 - S cycloalkyl means a saturated cyclic hydrocarbon (/. e. , a cyclized alkyl group) containing from 3 to 8 carbon atoms.
- Example cycloalkyls include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
- C 3 .g halocycloalkyl means a C 3 -s cycloalkyl substituted by one or more halo. When there is more than one halo, the halo may be the same or different.
- the C 3 - 8 halocycloalkyl is "C 3-8 monohalocycloalkyl," i.e., C 3 -g cycloalkyl substituted by one halo.
- the C 3 - 8 halocycloalkyl is "C 3-S dihalocycloalkyl," i.e., C 3 -g cycloalkyl substituted by two halo.
- the C 3 - 8 halocycloalkyl is "C 3-8 trihalocycloalkyl," i.e. , C 3 - S cycloalkyl substituted by three halo.
- C2-10 dialcohol means an alcohol containing two hydroxyls, and from 2 to 10 carbon atoms.
- fluoro means the chemical element fluorine.
- fluoromethylsulfonyl means a CH 2 FSO 2 - radical.
- fluoromethylsulfoxy means a CH 2 F S O- radical.
- fluoromethylthio means a CH 2 FS- radical.
- halo means fluoro, chloro, bromo, or iodo.
- Ci. 6 haloalkyl means a C 1 ⁇ alkyl wherein one or more hydrogens are replaced by halo. When there is more than one halo, the halo may be the same or different.
- the d- 6 haloalkyl is "Ci -6 monohaloalkyl," i.e., C 1 -6 alkyl substituted by one halo.
- the C ⁇ s haloalkyl is "C 1-6 dihaloalkyl,” i.e., C!- 6 alkyl substituted by two halo.
- the C 1 ⁇ haloalkyl is "Ci-etrihaloalkyl," i.e., C 1 - O alkyl substituted by three halo.
- halo substituted phenyl means a phenyl substituted by halo.
- C 3 . 8 heterocyclyl means a ring system radical wherein one or more of the ring-forming carbon atoms is replaced by a heteroatom, such as an oxygen, nitrogen, or sulfur atom, which include mono- or polycyclic (i.e., having 2 or more fused rings) ring systems as well as spiro ring systems.
- the ring system can contain from 3 to 8 carbon atoms, and can be aromatic or non-aromatic.
- iodo means the chemical element iodine.
- methylsulfonyl means a CH 3 SO 2 - radical.
- methylsulfoxy means a CH 3 SO- radical.
- methylthio means a CH 3 S- radical.
- C ⁇ - ]0 monoalcohol means an alcohol containing one hydroxyl, and from 1 to 10 carbon atoms.
- nitro means a -NO 2 radical.
- phenyl means the monovalent radical C 6 H 5 - of benzene, which is the aromatic hydrocarbon C 6 H 6 .
- Cn 5 phenylalkyl means a C 1 ⁇ alkyl substituted by phenyl.
- C no trialcohol means an alcohol containing three hydroxyls, and from 1 to 10 carbon atoms.
- pharmaceutically acceptable is used adjectivally to mean that the modified noun is appropriate for use in a pharmaceutical product.
- it characterizes the salt as not being deleterious to the intended recipient to the extent that the deleterious effect(s) outweighs the benefit(s) of the salt.
- a given chemical formula or name shall encompass all stereo, and optical isomers, and racemates thereof, as well as mixtures in different proportions of the separate enantiomers, where such isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof, and solvates thereof such as for instance, hydrates.
- Isomers can be separated using conventional techniques, such as, for example, chromatography or fractional crystallization.
- the enantiomers can be isolated by separation of a racemic mixture, for example, by fractional crystallization, resolution or high-performance (or -pressure) liquid chromatography (HPLC).
- the diastereomers can be isolated by separation of isomer mixtures, for instance, by fractional crystallization, HPLC, or flash chromatography.
- the stereoisomers also can be made by chiral synthesis from chiral starting materials under conditions which will not cause racemization or epimerization, or by derivatization, with a chiral reagent.
- the starting materials, and conditions will be within the understanding of one skilled in the art. All stereoisomers are included within the scope of the invention.
- a given chemical formula or name shall encompass all prodrugs.
- Prodrugs include but are not limited to, agents converted by esterase or DOPA decarboxylase to active agents, esters of active agents, and agents which are demethylated, dephosphorylated, deacetylated, or dehydrolyzed to active agents.
- a given chemical formula or name shall also encompass all metabolites, such as, for example, hydroxylated metabolites.
- Ri is hydrogen, methylthio, methylsulfoxy, methylsulfonyl, fluoromethylthio, fluoromethylsulfoxy, fluoromethylsulfonyl, nitro, fluoro, bromo, chloro, acetyl, benzyl, phenyl, halo substituted phenyl, Ci -6 alkyl, Ci -6 haloalkyl,
- C 3-S cycloalkyl C 2-6 alkenyl, C 2 . 6 alkynyl, Ci. 6 alkoxy, Ci. 6 arylalkyl, C 2 . 6 arylalkenyl, or C 3-S heterocyclyl;
- R 2 , R 3 , and R 4 are independently hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 3 .g cycloalkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, C 1-6 alkoxy, C 1-6 arylalkyl, C 2-6 arylalkenyl, benzyl, phenyl, C 3 .g heterocyclyl, or Ci- 6 phenylalkyl.
- the phenyl may be substituted by one or two halo, C 3 .g heterocyclyl, Ci. 6 alkyl, or C 1-6 alkoxy.
- each of R 2 and R 3 are hydrogen, and R 4 is fluoro;
- Rs is hydrogen, Ci. 6 alkyl, C 1-6 haloalkyl, C 3 .g halocycloalkyl, C 3 . 8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, Ci -6 arylalkyl, C 2-6 arylalkenyl, benzyl, phenyl, or Ci- 6 phenylalkyl.
- the phenyl may be substituted by one or two halo, C 3- g heterocyclyl, Ci -6 alkyl, or Ci -6 alkoxy.
- R 5 is CH 2 Cl, CHCl 2 , CCl 3 , CH 2 Br, CHBr 2 , CBr 3 , CH 2 F, CHF 2 , or CF 3 .
- the compounds corresponding thereto are useful active pharmaceutical ingredients for the preparation of pharmaceutical dosage forms. [951 In some embodiments, the compound of Formula II is the compound of
- the compound of Formula III is the compound of Formula IV:
- the compound of Formula III is the compound of
- R 5 is as previously defined.
- the compound of Formula III is the compound of Formula VI:
- R 4 is as previously defined.
- the compound of Formula III is the compound of Formula VII:
- the compound of Formula III is the compound of Formula VIII:
- R 1 is as previously defined.
- the compound of Formula III is the compound of
- R 1 and R 4 are as previously defined.
- the compound is florfenicol.
- One preferred process corresponding to the invention includes the following: a) Adding one or more solvents to a pharmaceutical composition containing the compound of Formula Il such that the auxiliary substances of the pharmaceutical composition are preferentially dissolved, and the compound of Formula II is preferentially undissolved.
- the pharmaceutical composition is placed into a reaction vessel, and the one or more solvents are added.
- reaction vessel shall be understood to mean a container known to those of ordinary skill which is capable of holding the reactants, and allowing the recovery to proceed to completion. The size, and type of vessel will, of course, depend upon the size of the batch, and the specific reactants selected.
- a non limiting list of dissolving solvents are water, methanol, ethanol, isopropanol, propanol, butanol, t-butanol, pentanol, neo-pentanol, methylene chloride, chloroform, carbon tetrachloride, 1,2 -dichloroethane, ethyl acetate, acetone, tetrahydrofuran, ether, dimethylsulfoxide, N, N-dimethylformamide, trifluoroethanol, or combinations thereof.
- the auxiliary-substance-dissolving solvent is water, ethanol, isopropanol, propanol, butanol, t-butanol, pentanol, neo-pentanol, and combinations thereof.
- the auxiliary-substance-dissolving solvent is water.
- the volume ratio of solvent to pharmaceutical composition is from about 1 :1 to about 20:1.
- the volume ratio of solvent (such as, for example, water) to drug product is from about 5: 1 to about 10:1.
- the solvent can be added to the reaction vessel over any suitable time, such as, for example, over about 24 hours, over about 12 hours, or over about 3 hour.
- water is added over about 6 hours, Heating, cooling, adjusting the pH, adjusting the volume, adding one or more additional solvents, separating and/or removing different solvent phases, stirring, or agitating the mixture to facilitate the further dissolution of the auxiliary substances, and the insolubility of the compound of Formula II.
- the mixture is heated up to the boiling point of the utilized solvent or solvents (or the boiling point of the mixture).
- the mixture is cooled to a temperature of less than about 25 0 C, such as from about
- the temperature of the mixture is maintained at a temperature of from about -15°C to about 3O 0 C or from about -20 0 C to about 25 0 C.
- the pH is adjusted with a base to a pH of, for example, greater than about 8, such as from about 8 to about 12 or from about 9 to about 11.
- the pH is adjusted with an acid to a pH of less than about 5, such as to a pH of about 1.
- a non-limiting list of reagents suitable for the basic pH adjustment includes inorganic bases such as NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , KHCO 3 , or organic bases such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, and combinations thereof.
- a non-limiting list of reagents suitable for the acidic pH adjustment includes inorganic acids such as HCI, H 2 SO4, HNO 3 , H 3 PO4, organic acids such as methanesulfonic acid, acetic acid, trifluoroacetic acid, and combinations thereof.
- the pH is adjusted to a neutral pH which is defined as a pH of from about 6 to about 8, by the addition of a base, an acid, or a buffer.
- a neutral pH which is defined as a pH of from about 6 to about 8, by the addition of a base, an acid, or a buffer.
- a non-limiting list of buffers includes biological buffers such as tri s(hydroxymethyl)methylam ine, 2- ⁇ [tris(hydroxymefhyl)methyl] amino ⁇ ethanesulfonic acid, piperazine-N,N'-bis(2-ethanesulfonic acid),
- N-(2-acetamido)-2-aminoethanesulfonic acid and commercial buffers such as a combination of potassium dihydrogen phosphate, and disodium hydrogen phosphate.
- the volume of the mixture can be reduced by, for example, distillation of the solvent or solvents or by separation of the phases should a phase spit occur.
- the volume can be increased by addition of more solvent or of a co-solvent that further enhances the solubility of the auxiliary substances. Stirring or agitation can also enhance the solubility of the auxiliary substances. In some embodiments, the mixture is stirred or agitated for up to about 24 hours. In other embodiments, the mixture is stirred or agitated for from about 1 hour to about 10 hours. Isolating the undissohed solids of the compound of Formula JI, from the mixture (by, for example, filtration), and optionally washing with one or more solvents to further remove soluble auxiliary substances. In some embodiments, the undissolved compound of Formula II is isolated by centrifugation or filtration.
- the isolated compound of Formula II is then washed with the same or different auxiliary-substance-dissolving solvent to further remove soluble auxiliary substances.
- auxiliary-substance-dissolving solvent e.g. water, methanol, ethanol, isopropanol, propanol, butanol, t-butanol, pentanol, neo-pentanol, methylene chloride, chloroform, carbon tetrachloride, 1,2 -dichloroethane, ethyl acetate, acetone, tetrahydrofuran, ether, dimethylsulfoxide, N, N-dimethylformamide, trifluoroethanol, and combinations thereof.
- the auxiliary-substance-excipient-dissolving solvent is water, ethanol, isopropanol, propanol, butanol, t-butanol, pentanol, neo-pentanol, or combinations thereof. In some preferred embodiments, the auxiliary-substance-dissolving solvent is water.
- the volume of wash solvent used will depend on the relative solubility of the auxiliary substances, and the insolubility of the compound of Formula II.
- the volume-to-weight ratio of wash solvent to the compound of Formula II is from about 0.1:1 to about 10:1 or from about 0.1:1 to about 3:1. In other embodiments, the ratio is from about 1 to about 5:1 or from about 1 to about 1.5:1.
- drying the crude recovered compound of Formula II In some embodiments, the crude recovered compound of Formula II is used directly. In other embodiments, the crude recovered compound of Formula II is dried at, for example, a temperature of from about 50°C to about 100 0 C.
- the crude recovered compound of Formula II is dried at a temperature of from about 70 0 C to about 9O 0 C. The drying is performed for a suitable time (such as, for example, from about 1 to about 24 hours) to obtain a desired moisture content. In preferred embodiments, the moisture content is less than about 5%, or less than about 1%.
- purifying the crude recovered compound of Formula II by, for example, recrystallization or chromatography, to produce the purified compound of Formula II.
- purifying the compound of Formula II involves using an alcoholic solvent such as a Ci. ioalkyl monoalcohol, a Ci- io alkyl dialcohol, or a C 1 .
- C M O monoalcohols includes methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, t-butanol, pentanol, and a mixture thereof.
- a non-limiting list OfC 1 - I0 dialcohols includes ethylene glycol, propylene glycol, butylene glycol, and a mixture thereof.
- a non-limiting example of a C j.io trialcohol is glycerin.
- the Ci -1O monoalcohol for the purification comprises isopropanol.
- the Ci. io dialcohol of the purification comprises propylene glycol.
- the C 1 ⁇ 10 trialcohol of the purification comprises glycerin.
- the purification comprises using a mixture of alcohol and water.
- the mixture comprises methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, t-butanol, pentanol, ethylene glycol, propylene glycol, butylene glycol, glycerin, or a mixture thereof.
- the alcohol such as isopropanol
- water are present in a ratio from about 1:5 to about 5:1 (for example, about 1:1).
- the alcohol comprises isopropanol, and the ratio of the isopropanol to water mixture is about 1:1.
- the compound of Formula II, and the about 1:1 isopropanol, and water mixture have a weight-to-volume ratio of from about 1:1 and about 10:1. In some embodiments, the weight-to-volume ratio of the compound of Formula II to the isopropanol/water mixture is about 1 :4.6.
- the compound of Formula II is dissolved in a mixture of about 1:1 isopropanol and water mixture such that the volume ratio of the compound of Formula II to the isopropanol/water mixture of about 1 :4.6.
- the resulting mixture is heated to reflux.
- the resultant solution is clarified by filtration with active carbon and a filter, then cooled to a temperature of from about 10°C to about 3O 0 C to obtain crystallized compound of Formula II that is pure.
- the terms "pure” or “purified” means reduced levels of impurities, and improved color compared to un-purified compound.
- the compound of Formula II is obtained to a purity level of at least about 90%, at least about 95%, at least about 97%, or at least about 99%.
- the solution is cooled to a temperature of from about 20 0 C to about 25 0 C to crystallize the purified compound of Formula II from the solution.
- the purified compound of Formula II is isolated by filtration, and washed with 1 : 1 isopropanol, and water.
- the volume-to-weight wash ratio of the isopropanol/water mixture to the compound of Formula II is from about 0.25 to about 1.5: 1.
- the wash ratio is from about 0.6 to about 0.7: 1.
- the purified compound of Formula II is then dried at a temperature of from about 60 to about 90 0 C. In some embodiments, the purified compound of Formula II is dried at a temperature of from about 75 to about 85°C. The drying is continued for about 24 hours. In some embodiments, the drying is continued until the moisture content of the purified compound of Formula II is less than about 2%. In some embodiments, the drying is continued until the moisture content is less than about 0.5%. In preferred embodiments, the purified compound of Formula II crystallized from the solution is Florfenicol.
- Another preferred process corresponding to the invention includes the following: a) Adding one or more solvents to a pharmaceutical composition containing the compound of Formula II such that the compound of Formula II is preferentially dissolved, and the auxiliary substances are preferentially undissolved.
- the pharmaceutical composition is placed into a reaction vessel, and the solvent or solvents are added as disclosed above in section A.
- a non limiting list of dissolving solvents for the compound of Formula II include water, methanol, acetone, dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 2-pyrrolidone, trifluoroethanol, and combinations thereof.
- the dissolving solvent for the compound of Formula II is water, methanol, acetone, and combinations thereof. In some preferred embodiments, the dissolving solvent for the compound of Formula II is methanol. In some embodiments, the volume ratio of solvent to pharmaceutical composition is from about 1:1 to about 20:1. In some embodiments, the volume ratio of methanol to drug product is from about 2:1 to about 8:1.
- the solvent can be added to the reaction vessel over any suitable time, such as, for example, over about 24 hours, over about 12 hours, or over about 3 hour. In some embodiments, methanol is added over about 6 hours.
- the mixture is heated up to the boiling point of the solvent or solvents utilized (or the boiling point of the mixture). In some embodiments, the mixture is cooled to a temperature of less than about 25°C, such as from about -25°C to about 25 0 C, from about -15 0 C to about 15°C, or from about -5°C to about 5 0 C.
- the temperature of the mixture is maintained at from about -15°C to about 3O 0 C or from about -2O 0 C to about 25 0 C.
- the pH is adjusted with a base to a pH of greater than about 8, such as from about 8 to about 12 or from about 9 to about 11.
- the pH is adjusted with an acid to a pH of less than about 5, such as to a pH of about 1.
- a non-limiting list of reagents suitable for the basic pH adjustment includes inorganic bases such as NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , NaHCO 3 ,
- KHCO 3 or organic bases such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, and combinations thereof.
- a non-limiting list of reagents suitable for the acidic pH adjustment includes inorganic acids such as HCl, H 2 SO 4 , HNO 3 , H 3 PO 4 , organic acids such as methanesulfonic acid, acetic acid, trifluoroacetic acid, and combinations thereof.
- the pH is adjusted to a neutral pH which is defined as a pH of from about 6 to about 8, by the addition of a base, acid, or buffer.
- a non-limiting list of buffers includes biological buffers such as tris(hydroxymethyl)methylamine,
- N-(2-acetamido)-2-aminoethanesulfonic acid and commercial buffers such as a combination of potassium dihydrogen phosphate, and di sodium hydrogen phosphate.
- the volume of the mixture can be reduced by, for example, distillation of the solvent or solvents or by separation of the phases should a phase spit occur.
- the volume can be increased by, for example, addition of more solvent or of a co-solvent that further enhances the solubility of the compound of Formula II. Stirring or agitation can also enhance the solubility of the compound of Formula II.
- the mixture is stirred or agitated for up to about 24 hours.
- the mixture is stirred or agitated for from about 1 to about 10 hours.
- the undissolved auxiliary substances are isolated by centrifugation or filtration.
- the isolated auxiliary substances are then washed with the Formula-II-dissolving solvent or solvents or other solvents that further remove the soluble compound of Formula II.
- the Formula-II-dissolving solvent is selected from the list disclosed above. The volume of wash solvent used will depend on the relative solubility of the compound of Formula II, and the insolubility of the auxiliary substances.
- the volume-to-weight ratio of wash solvent to the auxiliary substances is from about 0.1:1 to about 10:1. In some embodiments, the ratio is from about 1 to about 3:1.
- Precipitating or crystallizing the compound of Formula II by, for example, reducing the volume of solvent with cooling to a temperature of from about -25°C to about 10°C or by cooling to a temperature of from about -25 0 C to about 10°C. In some embodiments, the cooling is to a temperature of from about -5°C to about 5 0 C.
- One preferred process corresponding to the invention includes the following: a) Adding at least two solvents to a pharmaceutical composition containing the compound of Formula II such that the auxiliary substances of the pharmaceutical composition are preferentially partitioned in one solvent (or solvent system), and the compound of Formula II is preferentially partitioned in another solvent (or solvent system).
- the pharmaceutical composition is placed into a reaction vessel as disclosed above in section A.
- auxiliary-substance-dissolving solvents may include, for example, those solvents disclosed above in section A.
- the solvents utilized to partition the compound of Formula II may, for example, be selected from those disclosed above in section B.
- the solvents are added to the pharmaceutical composition in the ratios, and over the time periods discussed above in sections A, and B. b) Heating, cooling, adjusting the pH, adjusting the volume, adding one or more additional solvents, stirring, or agitating the mixture to facilitate the further partitioning of the auxiliary substances, and the compound of Formula II in their respective solvent or solvent system.
- the mixture is heated up to the boiling point of the mixture.
- the mixture is cooled to a temperature of less than about 25°C, such as from about -25 0 C to about 25°C, from about -15 0 C to about 15 0 C, or from about -5 0 C to about 5°C.
- the temperature of the mixture is maintained at from about -15 0 C to about 30°C or from about -2O 0 C to about 25 0 C.
- the pH is adjusted with a base to a pH of greater than about 8, such as from about 8 to about 12 or from about 9 to about 11.
- the pH is adjusted with an acid to a pH of less than about 5, such as to a pH of about 1.
- a non-limiting list of reagents suitable for the basic pH adjustment includes inorganic bases such as NaOH, KOH, NaCO 2 , KCO 2 , NaHCO 3 , KHCO 3 , or organic bases such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, and combinations thereof.
- a non-limiting list of reagents suitable for the acidic pH adjustment includes inorganic acids such as HCl, H 2 SO 4 , HNO 3 , H 3 PO 4 , organic acids such as methanesulfonic acid, acetic acid, trifluoroacetic acid, and combinations thereof.
- the pH is adjusted to a neutral pH which is defined as a pH of from about 6 to about 8, by the addition of a base, acid, or buffer.
- a neutral pH which is defined as a pH of from about 6 to about 8, by the addition of a base, acid, or buffer.
- a non-limiting list of buffers includes biological buffers such as tris(hydroxymethyl)methylamine,
- N-(2-acetamido)-2-aminoethanesulfonic acid and commercial buffers such as a combination of potassium dihydrogen phosphate, and disodium hydrogen phosphate.
- the volume of the mixture may be reduced by, for example, distillation of the solvents or by separation of the phases should a phase spit occur.
- the volume may be increased by, for example, adding more solvent or of a co-solvent that further enhances the partitioning of the auxiliary substances, and the compound of Formula II. Stirring or agitation can also enhance the partitioning of the auxiliary substances, and the compound of Formula II.
- the mixture is stirred or agitated for up to about 24 hours.
- the mixture is stirred or agitated for about 1 to about 10 hours.
- further partitioning of the auxiliary substances, and the compound of Formula II by repetition of one or more of the steps disclosed above one or more times; d) Separating the at least one solvent containing the preferentially dissolved compound of Formula II from the mixture; e) Optionally repeating the immediate preceding steps one or more times on the solvent containing the partitioned compound of Formula II to remove further auxiliary substance; f) Optionally repeating the immediate preceding steps one or more times on the remaining mixture containing the partitioned auxiliary substance to remove further the compound of Formula II; g) Collecting the solvent or solvent system containing the partitioned compound of
- Section A h) Isolating the undissotved solids of the compound of Formula II, from the mixture as disclosed above in Section A, including any further washing to remove additional auxiliary substances; and i) If necessary, drying and/or purifying the crude recovered compound of Formula II as disclosed above in Section A.
- the florfenicol, florfenicol analogs or auxiliary substances may be recovered using chromatography.
- chromatography as described in the IUPAC Nomenclature for Chromatography, Pure & Appl. Chem., Vol. 65, No. 4, pp.819-872, 1993, the disclosure of which is hereby incorporated by reference, means a method of separation in which the components to be separated are distributed between two phases, one of which is stationary (stationary phase) while the other (the mobile phase) moves in a definite direction.
- Methods of chromatography which may be utilized in the present invention include, for example, frontal chromatography, displacement chromatography, elution chromatography, column chromatography (such as, for example, packed column and open-tubular chromatography), planar chromatography (such as, for example, paper chromatography (PC), thin layer chromatography (TLC)), gas-liquid chromatography (GLC), gas-solid chromatography (GSC), liquid-liquid chromatography (LLC), liquid-solid chromatography (LSC), gas chromatography (GC), liquid chromatography (LC) (such as, for example, high performance or pressure liquid chromatography (HPLC)), simulated moving bed chromatography (SMB), supercritical-fluid chromatography (SFC), adsorption chromatography, partition chromatography, ion-exchange chromatography (IC), exclusion chromatography, affinity chromatography, reversed-phase chromatography, simulated moving bed chromatography (SMBC), normal-phase chromatography, isocratic analysis
- recovering florfenicol or a florfenicol analog from a pharmaceutical composition comprises: (a) obtaining a pharmaceutical composition comprising florfenicol or a florfenicol analog, and at least one auxiliary substance;
- recovering florfenicol or florfenicol analog from a pharmaceutical composition comprises: (a) obtaining a pharmaceutical composition comprising florfenicol or florfenicol analog, and at least one auxiliary substance;
- the solvent or solvent system may, for example, be selected from the group consisting of water, methanol, acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, trifluoroethanol, and combinations thereof);
- a chromatography column containing a normal or reverse stationary phase such as, for example, silica, cyanosilica, amino silica, octylsilane, butylsilane, octadecylsilane, diisopropyloctadecylsilane, or diisobutyloctadecylsilane with a suitable mobile phase such as an organic solvent, water, a buffered water solution, or combinations thereof;
- a suitable mobile phase such as an organic solvent, water, a buffered water solution, or combinations thereof;
- a manufacturer obtains unused portions of pharmaceutical dosage forms from a patient or healthcare provider, and proceed to recover the active pharmaceutical ingredient contained therein. In some embodiments, the recovered active pharmaceutical ingredient is then recycled into new dosage forms.
- the portions of pharmaceutical dosage forms that are unused may be due to any number of reasons, such as, for example, the medicine has expired or the patient has discontinued therapy due to intolerance, recovery from an ailment, or a change in dosage strength or drug therapy.
- an incentive is offered to the patient or healthcare provider to promote the return of the dosage form.
- the incentive is, for example, a monetary payment, a rebate, a coupon, merchandise, or a voucher for merchandise.
- the original manufacturer obtains the unused portion of pharmaceutical dosage forms, or a third party obtains the unused portion of pharmaceutical dosage forms.
- the third party then recovers the active pharmaceutical agent from the dosage forms, and utilizes the recovered agent for resale or in their own manufacturing processes.
- a clearinghouse is established which obtains unused portions of pharmaceutical active agents from multiple manufacturers, and sources.
- the original manufacturer or third party who obtains the unused portion of active pharmaceutical ingredient out-sources the recovery of the active pharmaceutical ingredient contained therein.
- the above disclosed methods are also utilized to decrease the disposal of unused portions of active pharmaceutical ingredients to reduce their disposal in, for example, drainage systems or landfills. This could potentially reduce the contamination of water sources (such as, for example streams, oceans, and groundwater) with pharmaceutical agents.
- water sources such as, for example streams, oceans, and groundwater
- the methods of conducting a pharmaceutical business can be applied to other active pharmaceutical ingredients, such as, for example, steroidal compounds (such as, for example, mometasone, betamethasone, or pharmaceutically acceptable salts thereof), antibiotics (such as, for example, moxifloxacin, ciprofloxacin, orbifloxacin, gentamicin, cephalonium, enraymicin, or pharmaceutically acceptable salts thereof), anthelmintics (such as, for example, netobimin, ivermectin, or pharmaceutically acceptable salts thereof), coccidiostats (such as, for example, diclazuril or pharmaceutically acceptable salts thereof), immunosuppressants (such as, for example, cyclosporine or pharmaceutically acceptable salts thereof), insecticides (such as, for example, emmacectin, indoxacarb, or pharmaceutically acceptable salts thereof), anabolics (such as, for example, steroidal compounds (such as, for example, mometasone,
- Nuflor® is an Intervet/Schering-Plough Animal Health drug product that contains 300 mg of florfenicol, 250 mg of N-methyl-2-pyrrolidone, 150 mg propylene glycol, and polyethylene glycol diluted to 1 mL.
- Example IA 1.5 L of water was added over about 4 hours to about 350 g of Nuflor ® solution while maintaining the temperature at less than 30 0 C. The resulting mixture was agitated for about 4 hours while continuing to maintain the temperature at less than 30 0 C. The resulting precipitated florfenicol was collected by filtration, and washed with 450 mL of water, then dried at about 75-85 0 C to a moisture content of less than about 1 % to yield about 124 g of crude florfenicol (Compound I) (92 %).
- Example IB Alternative Method for Recovery of Florfenicol from Nuflor ® .
- Nuflor about 100 mL
- acetonitrile about 300 mL
- the Florfenicol can be eluted with an about a 2 to 1 0.01 M sodium acetate solution in water, and acetonitrile adjusted to about pH 4.4 with glacial acetic acid while maintaining the temperature less than 3O 0 C.
- Florfenicol can be identified by ultra violet detection at 254 run. Fractions containing Florfenicol can be collected, and pooled together.
- the eluent containing any residual Florfenicol or any fractions containing impure Florfenicol can be recycled back through the column to further recover additional Florfenicol. Evaporation of the solvent in the pooled fractions, then drying at about 75-85°C can yield crude Florfenicol.
- Florfenicol (Compound I) (about 124 g, 0.3462 moles) was dissolved in water (about 285 mL), and isopropanol (about 285 mL) at reflux. Following addition of charcoal, the solution was clarified by filtration, and cooled to about 2O 0 C to about 25°C. The solids were filtered, washed with about 1 : 1 water/isopropanol (about 85 mL) then dried at about 80°C to a moisture content of about less than 0.5% to yield pure Florfenicol (Compound I). (114 g, 0.3185 moles, 92%).
- Nuflor Gold ® is an Intervet/Schering-Plough Animal Health drug product that contains 300 mg of florfenicol, 300 mg of 2-pyrrolidone, and triacetin diluted to 1 mL. 176.4 g of Nuflor Gold ® was added over about 1 hour to 1764 mL of water heated to about 60 0 C. The resulting mixture was stirred for about 1 hour then cooled to about 2O 0 C, and maintained at this temperature with stirring for an additional about 30 minutes.
- Example 4 Recovery of Florfenicol from Florfenicol Premix ® .
- Florfenicol Premix ® is an Intervet/Schering-Plough Animal Health drug product that contains 1- 25% by weight of florfenicol, rice hulls, and mineral oil. Methanol (about 400 mL) was added to 100 g of Florfenicol Premix ® 2% (containing 2% florfenicol), and stirred for about 1 hour. Insoluble excipients were filtered off, and washed with 100 mL of methanol. The methanol wash was combined with the methanol filtrate. Evaporation of the combined methanol yielded about 4 g of a solid.
- Example 5 Recovery of Florfenicol from Aquaflor ® .
- Aquaflor ® is an Intervet/Schering-Plough Animal Health drug product that contains 50% florfenicol, 47% lactose, and 3% povidone.
- About 150 g of Aquaflor ® was added over about 1 hour to about 750 mL of stirring water. The resulting mixture was heated to about 80°C, and stirred at this temperature for about 1 hour. The mixture was then cooled to about 20 0 C, and held at this temperature with stirring for about 30 minutes.
- the resulting precipitated florfenicol was collected by filtration, and washed with about 300 mL of water, then dried at about 60 0 C to a moisture content of less than about 1% to yield about 73 g of crude florfenicol (Compound I) (97%).
- Resflor ® is an Intervet/Schering-Plough Animal Health drug product that contains 300 mg florfenicol, 27.4 mg flunixin meglumine, 250 mg of N-methyl-2-pyrrolidinone or 2-pyrrolidinonem 10 mg of citric acid, 150 mg of propylene glycol, and polyethylene glycol in 1 mL.
- Example 6A About 300 g of Resflor ® was added over about 1 hour to a stirring solution of about 24 mL of concentrated ammonia in about 3 L of water heated to a temperature of about 50 0 C. Additional concentrated ammonia was added to ensure that the pH was about 9. The mixture was stirred, and cooled to room temperature. The resulting precipitated florfenicol was collected by filtration then dried at about 70 0 C to a moisture content of less than about 1% to yield about 73.5 g of crude florfenicol (Compound I) (100%).
- Example 6B Alternative Method for Recovery of Florfenicol from Resflor ® .
- Resflor about 100 mL
- acetonitrile about 300 mL
- the florfenicol can be separated by elution with an about 9 to 1 acetonitrile to 10 mM 1-octanesulfonic acid sodium salt solution in water while maintaining the temperature at less than 3O 0 C.
- Florfenicol can be identified by ultra violet detection at 275 run. Fractions containing florfenicol can be collected, and pooled together. If necessary, the eluent containing any residual florfenicol or any fractions containing impure florfenicol can be recycled back through the column to further recover additional florfenicol. Evaporation of the solvent in the pooled fractions containing florfenicol, then drying at about 75-85 0 C can yield crude florfenicol.
- Maxflor is Virbac Philippines, Inc.'s product containing 2% Florfenicol. Methanol (about 730 mL) was added to 182 g of Maxflor, and the resulting mixture stirred for about 1 hour at ambient room temperature. The insolubles were filtered off, and washed with methanol (about 180 mL). Evaporation of the combined methanol solutions produced 7.82 g of a yellow-brown solid. The solid was dissolved in isopropanol (about 20 mL), and water (about 16 mL) heated to about 80°C, and washed with hexane (about 16 mL) to remove mineral oil.
- Floron is KRKA's drug product containing 300 mg/mL Florfenicol in a solution of dimethyl sulfoxide, propylene glycol, and macrogol 400.
- USP Water about 500 mL was added over about 30 minutes to 100 mL of Floron with agitation while maintaining the temperature at less than about 30 0 C.
- the resulting mixture was agitated for about 1 hour while continuing to maintain the temperature at less than 3O 0 C.
- the resulting precipitated Florfenicol was collected by filtration, and washed with about 300 mL of USP water, then dried at about 75-85 0 C to a moisture content of less than about 1% to yield 28.1 g of crude Florfenicol (94%).
- Nuflor Minidose ® is an Intervet/Schering-Plough Animal Health drug product that contains 400 mg of florfenicol, 45 mg of JV-methyl-2-pyrrolidinone, and diethylene glycol monoethyl diluted to ImL. 2 L of Nuflor Minidose ® was added over about 2 hours to 10 L of water maintained at about 65 0 C. The resulting mixture was agitated for about 2 hours during which time florfenicol precipitated from the mixture. The resulting suspension was then cooled to about 20 0 C, and agitated for about 30 minutes at 20 0 C.
- Florfenicol was collected by filtration, and washed with 10 L of water, then dried at about 60 0 C to a moisture content of less than about 1 % to yield about 748 g of crude florfenicol (Compound I) (94 %).
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MX2010006529A MX2010006529A (es) | 2008-11-20 | 2009-02-05 | Proceso para recuperar florfenicol de composiciones farmaceuticas. |
CN2009801025658A CN101998850B (zh) | 2008-11-20 | 2009-02-05 | 从药物组合物中回收氟苯尼考的方法 |
CA2708334A CA2708334A1 (en) | 2008-11-20 | 2009-02-05 | Process for recovering florfenicol from pharmaceutical compositions |
EP09789452A EP2358357A1 (de) | 2008-11-20 | 2009-02-05 | Verfahren zur wiedergewinnung von florfenicol aus pharmazeutischen zusammensetzungen |
AU2009318027A AU2009318027A1 (en) | 2008-11-20 | 2009-02-05 | Process for recovering florfenicol from pharmaceutical compositions |
IL206266A IL206266A0 (en) | 2008-11-20 | 2010-06-09 | Process for recovering florfenicol from pharmaceutical compositions |
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US (1) | US20090170954A1 (de) |
EP (1) | EP2358357A1 (de) |
CN (1) | CN101998850B (de) |
AU (1) | AU2009318027A1 (de) |
CA (1) | CA2708334A1 (de) |
IL (1) | IL206266A0 (de) |
MX (1) | MX2010006529A (de) |
PE (1) | PE20091171A1 (de) |
WO (1) | WO2010059259A1 (de) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200505425A (en) * | 2003-05-29 | 2005-02-16 | Schering Plough Ltd | Compositions and method for treating infection in cattle and swine |
WO2008076256A1 (en) * | 2006-12-13 | 2008-06-26 | Schering-Plough Ltd. | Water-soluble prodrugs of chloramphenicol, thiamphenicol, and analogs thereof |
US8314252B2 (en) * | 2008-07-30 | 2012-11-20 | Intervet Inc. | Process for preparing oxazoline-protected aminodiol compounds useful as intermediates to florfenicol |
JP2014513116A (ja) | 2011-05-02 | 2014-05-29 | ゾエティス・エルエルシー | 抗菌剤として有用な新規セファロスポリン |
CN104370782A (zh) * | 2014-11-29 | 2015-02-25 | 郑州后羿制药有限公司 | 一种氟苯尼考的精制方法 |
CN114166972A (zh) * | 2021-12-06 | 2022-03-11 | 天津市中升挑战生物科技有限公司 | 一种氟苯尼考的高效液相色谱检测方法 |
CN114460193B (zh) * | 2022-01-25 | 2023-06-13 | 杭州海关技术中心 | 超高效合相色谱法分离和测定氟苯尼考对映体的方法 |
Citations (2)
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WO2006136919A1 (en) * | 2005-06-20 | 2006-12-28 | Aurobindo Pharma Limited | An improved process for the preparation of florfenicol |
WO2007030385A2 (en) * | 2005-09-07 | 2007-03-15 | Schering-Plough Ltd. | A process for preparing oxazolidine protected aminodiol compounds useful as intermediates to florfenicol |
Family Cites Families (13)
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US4235892A (en) * | 1979-02-05 | 1980-11-25 | Schering Corporation, Patent Dept. | 1-Aryl-2-acylamido-3-fluoro-1-propanols, methods for their use as antibacterial agents and compositions useful therefor |
US5082863A (en) * | 1990-08-29 | 1992-01-21 | Schering Corporation | Pharmaceutical composition of florfenicol |
US6787568B1 (en) * | 2000-11-27 | 2004-09-07 | Phoenix Scientific, Inc. | Antibiotic/analgesic formulation and a method of making this formulation |
US20030036564A1 (en) * | 2001-08-08 | 2003-02-20 | Borchert Jeff N. | Control of lyme disease spirochete |
US20030068339A1 (en) * | 2001-10-02 | 2003-04-10 | Phoenix Scientific, Inc. | Veterinary florfenicol formulation that is syringeable under cold weather conditions |
EP1440270B1 (de) * | 2001-10-11 | 2006-07-05 | Straub Werke AG | Rohrkupplung und Verankerungsring |
US6790867B2 (en) * | 2002-05-20 | 2004-09-14 | Schering-Plough Animal Health Corporation | Compositions and method for treating infection in cattle and swine |
UA82359C2 (uk) * | 2003-04-03 | 2008-04-10 | Schering Plough Ltd | Композиція (варіанти) і спосіб лікування мікробних і паразитних інфекцій у великої рогатої худоби і інших тварин |
TW200505425A (en) * | 2003-05-29 | 2005-02-16 | Schering Plough Ltd | Compositions and method for treating infection in cattle and swine |
US7439268B2 (en) * | 2003-07-18 | 2008-10-21 | Idexx Laboratories | Compositions containing prodrugs of florfenicol and methods of use |
ES2266695T3 (es) * | 2003-07-31 | 2007-03-01 | Emdoka Bvba, Drug Registration And Marketing | Suspensiones acuosas inyectables para uso veterinario que contienen florfenicol. |
KR20060111605A (ko) * | 2003-12-23 | 2006-10-27 | 쉐링-프라우 리미티드 | 수용성이 개선된 플로르페니콜 전구약물 |
MX2007001811A (es) * | 2004-08-13 | 2007-03-26 | Schering Plough Ltd | Formulacion farmaceutica que comprende un antibiotico, un triazol y un corticoesteroide. |
-
2008
- 2008-12-12 PE PE2008002069A patent/PE20091171A1/es not_active Application Discontinuation
- 2008-12-12 US US12/333,695 patent/US20090170954A1/en not_active Abandoned
-
2009
- 2009-02-05 WO PCT/US2009/033205 patent/WO2010059259A1/en active Application Filing
- 2009-02-05 EP EP09789452A patent/EP2358357A1/de not_active Withdrawn
- 2009-02-05 AU AU2009318027A patent/AU2009318027A1/en not_active Abandoned
- 2009-02-05 CN CN2009801025658A patent/CN101998850B/zh not_active Expired - Fee Related
- 2009-02-05 CA CA2708334A patent/CA2708334A1/en not_active Abandoned
- 2009-02-05 MX MX2010006529A patent/MX2010006529A/es not_active Application Discontinuation
-
2010
- 2010-06-09 IL IL206266A patent/IL206266A0/en unknown
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WO2006136919A1 (en) * | 2005-06-20 | 2006-12-28 | Aurobindo Pharma Limited | An improved process for the preparation of florfenicol |
WO2007030385A2 (en) * | 2005-09-07 | 2007-03-15 | Schering-Plough Ltd. | A process for preparing oxazolidine protected aminodiol compounds useful as intermediates to florfenicol |
Non-Patent Citations (2)
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VUE C ET AL: "Liquid chromatographic determination of florfenicol in the plasma of multiple species of fish", JOURNAL OF CHROMATOGRAPHY B: BIOMEDICAL SCIENCES & APPLICATIONS, ELSEVIER, AMSTERDAM, NL, vol. 780, no. 1, 15 November 2002 (2002-11-15), pages 111 - 117, XP004385509, ISSN: 1570-0232 * |
YAMINI YADOLLAH ET AL: "Effects of different parameters on supercritical fluid extraction of steroid drugs, from spiked matrices and tablets.", TALANTA 12 NOV 2002, vol. 458, no. 5, 12 November 2002 (2002-11-12), pages 1003 - 1010, XP009113494, ISSN: 1873-3573 * |
Also Published As
Publication number | Publication date |
---|---|
PE20091171A1 (es) | 2009-08-03 |
US20090170954A1 (en) | 2009-07-02 |
IL206266A0 (en) | 2010-12-30 |
MX2010006529A (es) | 2010-09-03 |
AU2009318027A1 (en) | 2010-05-27 |
CN101998850B (zh) | 2013-10-23 |
CN101998850A (zh) | 2011-03-30 |
EP2358357A1 (de) | 2011-08-24 |
CA2708334A1 (en) | 2010-05-27 |
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