US20060229459A1 - Crystalline base of citalopram - Google Patents
Crystalline base of citalopram Download PDFInfo
- Publication number
- US20060229459A1 US20060229459A1 US11/425,308 US42530806A US2006229459A1 US 20060229459 A1 US20060229459 A1 US 20060229459A1 US 42530806 A US42530806 A US 42530806A US 2006229459 A1 US2006229459 A1 US 2006229459A1
- Authority
- US
- United States
- Prior art keywords
- citalopram
- base
- salt
- hydrochloride
- hydrobromide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 title claims abstract description 126
- 229960001653 citalopram Drugs 0.000 title claims abstract description 125
- 150000003839 salts Chemical class 0.000 claims abstract description 48
- 239000000203 mixture Substances 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 37
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 239000002671 adjuvant Substances 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 239000008187 granular material Substances 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 6
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 239000012535 impurity Substances 0.000 claims description 5
- 150000002825 nitriles Chemical group 0.000 claims description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- 238000007906 compression Methods 0.000 claims description 4
- 230000006835 compression Effects 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 230000001376 precipitating effect Effects 0.000 claims description 4
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 238000007907 direct compression Methods 0.000 claims description 3
- 239000000155 melt Substances 0.000 claims description 3
- WIHMBLDNRMIGDW-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carbonitrile;hydron;bromide Chemical compound [Br-].O1CC2=CC(C#N)=CC=C2C1(CCC[NH+](C)C)C1=CC=C(F)C=C1 WIHMBLDNRMIGDW-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- XAJMJYPAJNLKIS-UHFFFAOYSA-N [5-(4-bromophenyl)furan-2-yl]methanamine Chemical compound O1C(CN)=CC=C1C1=CC=C(Br)C=C1 XAJMJYPAJNLKIS-UHFFFAOYSA-N 0.000 claims description 2
- 229960000584 citalopram hydrobromide Drugs 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
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- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
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- 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 1
- 238000009472 formulation Methods 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 7
- 239000000935 antidepressant agent Substances 0.000 abstract description 5
- WSEQXVZVJXJVFP-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile Chemical compound O1CC2=CC(C#N)=CC=C2C1(CCCN(C)C)C1=CC=C(F)C=C1 WSEQXVZVJXJVFP-UHFFFAOYSA-N 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- 239000002585 base Substances 0.000 description 47
- 239000003826 tablet Substances 0.000 description 26
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- 239000012458 free base Substances 0.000 description 9
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000011701 zinc Substances 0.000 description 8
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 150000002148 esters Chemical group 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 7
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 6
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- 239000003085 diluting agent Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 229910006124 SOCl2 Inorganic materials 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
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- 229910019213 POCl3 Inorganic materials 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
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- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 4
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
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- 229940035423 ethyl ether Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000002608 ionic liquid Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 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
- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01M—PROCESSES OR MEANS, e.g. BATTERIES, FOR THE DIRECT CONVERSION OF CHEMICAL ENERGY INTO ELECTRICAL ENERGY
- H01M8/00—Fuel cells; Manufacture thereof
- H01M8/04—Auxiliary arrangements, e.g. for control of pressure or for circulation of fluids
- H01M8/04082—Arrangements for control of reactant parameters, e.g. pressure or concentration
- H01M8/04089—Arrangements for control of reactant parameters, e.g. pressure or concentration of gaseous reactants
- H01M8/04119—Arrangements for control of reactant parameters, e.g. pressure or concentration of gaseous reactants with simultaneous supply or evacuation of electrolyte; Humidifying or dehumidifying
- H01M8/04156—Arrangements for control of reactant parameters, e.g. pressure or concentration of gaseous reactants with simultaneous supply or evacuation of electrolyte; Humidifying or dehumidifying with product water removal
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01M—PROCESSES OR MEANS, e.g. BATTERIES, FOR THE DIRECT CONVERSION OF CHEMICAL ENERGY INTO ELECTRICAL ENERGY
- H01M8/00—Fuel cells; Manufacture thereof
- H01M8/04—Auxiliary arrangements, e.g. for control of pressure or for circulation of fluids
- H01M8/04082—Arrangements for control of reactant parameters, e.g. pressure or concentration
- H01M8/04089—Arrangements for control of reactant parameters, e.g. pressure or concentration of gaseous reactants
- H01M8/04119—Arrangements for control of reactant parameters, e.g. pressure or concentration of gaseous reactants with simultaneous supply or evacuation of electrolyte; Humidifying or dehumidifying
- H01M8/04156—Arrangements for control of reactant parameters, e.g. pressure or concentration of gaseous reactants with simultaneous supply or evacuation of electrolyte; Humidifying or dehumidifying with product water removal
- H01M8/04171—Arrangements for control of reactant parameters, e.g. pressure or concentration of gaseous reactants with simultaneous supply or evacuation of electrolyte; Humidifying or dehumidifying with product water removal using adsorbents, wicks or hydrophilic material
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01M—PROCESSES OR MEANS, e.g. BATTERIES, FOR THE DIRECT CONVERSION OF CHEMICAL ENERGY INTO ELECTRICAL ENERGY
- H01M8/00—Fuel cells; Manufacture thereof
- H01M8/04—Auxiliary arrangements, e.g. for control of pressure or for circulation of fluids
- H01M8/04082—Arrangements for control of reactant parameters, e.g. pressure or concentration
- H01M8/04186—Arrangements for control of reactant parameters, e.g. pressure or concentration of liquid-charged or electrolyte-charged reactants
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01M—PROCESSES OR MEANS, e.g. BATTERIES, FOR THE DIRECT CONVERSION OF CHEMICAL ENERGY INTO ELECTRICAL ENERGY
- H01M8/00—Fuel cells; Manufacture thereof
- H01M8/10—Fuel cells with solid electrolytes
- H01M8/1009—Fuel cells with solid electrolytes with one of the reactants being liquid, solid or liquid-charged
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01M—PROCESSES OR MEANS, e.g. BATTERIES, FOR THE DIRECT CONVERSION OF CHEMICAL ENERGY INTO ELECTRICAL ENERGY
- H01M8/00—Fuel cells; Manufacture thereof
- H01M8/10—Fuel cells with solid electrolytes
- H01M8/1009—Fuel cells with solid electrolytes with one of the reactants being liquid, solid or liquid-charged
- H01M8/1011—Direct alcohol fuel cells [DAFC], e.g. direct methanol fuel cells [DMFC]
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01M—PROCESSES OR MEANS, e.g. BATTERIES, FOR THE DIRECT CONVERSION OF CHEMICAL ENERGY INTO ELECTRICAL ENERGY
- H01M8/00—Fuel cells; Manufacture thereof
- H01M8/24—Grouping of fuel cells, e.g. stacking of fuel cells
- H01M8/241—Grouping of fuel cells, e.g. stacking of fuel cells with solid or matrix-supported electrolytes
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01M—PROCESSES OR MEANS, e.g. BATTERIES, FOR THE DIRECT CONVERSION OF CHEMICAL ENERGY INTO ELECTRICAL ENERGY
- H01M8/00—Fuel cells; Manufacture thereof
- H01M8/24—Grouping of fuel cells, e.g. stacking of fuel cells
- H01M8/2455—Grouping of fuel cells, e.g. stacking of fuel cells with liquid, solid or electrolyte-charged reactants
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
- Y02E60/00—Enabling technologies; Technologies with a potential or indirect contribution to GHG emissions mitigation
- Y02E60/30—Hydrogen technology
- Y02E60/50—Fuel cells
Definitions
- the present invention relates to the crystalline base of the well known antidepressant drug citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile, formulations of said base, a process for the preparation of purified salts of citalopram, such as the hydrobromide, using the base, the salts obtained by said process and formulations containing such salts.
- Citalopram is a well-known antidepressant drug that has now been on the market for some years and has the following structure:
- Citalopram was first disclosed in DE 2,657,013, corresponding to U.S. Pat. No. 4,136,193. This patent publication describes the preparation of citalopram by one method and outlines a further method, which may be used for preparing citalopram.
- the citalopram prepared was isolated as the oxalate, the hydrobromide and the hydrochloride salt, respectively.
- the citalopram base was obtained as an oil (B.P. 175 C/0.03 mmHg).
- Citalopram is marketed as the hydrobromide and the hydrochloride, respectively.
- citalopram has been prepared by:
- citalopram processes for the preparation of citalopram comprise exchange of the 5-bromo group of 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuranbromide with 5-cyano followed by alkylation with a 3-(N,N-dimethylamino)propyl-halogenide (DE 2,657,013 and WO 9819511).
- the base of citalopram may be obtained as a very nice and pure crystalline product, which may easily be handled and conveniently be formulated into tablets and other pharmaceutical forms. Furthermore, it has surprisingly been found that a very good and efficient purification of citalopram may be obtained during manufacture of citalopram (e.g. of the hydrobromide or the hydrochloride salt) by crystallising the base, and thereafter optionally forming a salt from the base.
- manufacture of citalopram e.g. of the hydrobromide or the hydrochloride salt
- This purification process is particularly useful for removing intermediates which are structurally closely related to citalopram, in particular compounds which only differ from citalopram by the substituent situated in position 5 on the isobenzofuran ring, and intermediates which have physical/chemical properties which are close to those of citalopram, e.g.
- the present invention provides the crystalline base of the compound
- the invention provides a process for the manufacture of a salt of citalopram, preferably the hydrobromide or hydrochloride in which the free base of citalopram is precipitated in crystalline form, optionally re-crystallised one or more times and then transferred to a pharmaceutically acceptable salt of citalopram.
- the invention relates to the pure crystalline salt, preferably the hydrobromide or hydrochloride prepared by the process of the invention.
- the invention relates to a process for the manufacture of a salt of citalopram characterised in that the base of citalopram is set free and precipitated in crystalline form, optionally re-crystallised one or more times, and then transferred into a salt thereof.
- the invention relates to a process for the manufacture of a salt of citalopram characterised in that the base of citalopram is set free from a crude salt or crude mixture of citalopram.
- the present invention relates to a process for the manufacture of citalopram base or a salt of citalopram characterised in that one or more impurities of the formula wherein Z is halogen, —O—SO 2 —(CF 2 ) n —CF 3 , where n is 0-8, —CHO, —NHR 1 , —COOR 2 , —CONR 2 R 3 wherein R 2 and R 3 are selected from hydrogen, alkyl, optionally substituted aryl or aralkyl and R 1 is hydrogen or alkylcarbonyl, are removed from a crude mixture of citalopram or from a crude salt of citalopram, by precipitating citalopram base in crystalline form, optionally re-crystallising said base one or more times and/or transferring said base into a salt thereof.
- The-crude-mixture of citalopram containing the-compound of formula II as an impurity may be prepared by subjecting a compound of formula H to a cyanide exchange reaction with a cyanide source, or by subjecting 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuranhalogenide, in particular the bromide, to a cyanide exchange reaction followed by alkylation with a 3-(N,N-dimethylamino)propyl-halogenide.
- Z is halogen, in particular bromide or chloride.
- the salt prepared is the hydrobromide or hydrochloride salt of citalopram.
- the crude salt may be any convenient salt, such as the hydrobromide, hydrochloride, sulphate, oxalate, phosphate, nitrate or any other convenient salt.
- Other salts are salts of organic acids.
- the crude salt is the sulphate, the hydrobromide or the hydrochloride salt.
- the invention also relates to a hydrochloride or hydrobromide salt of citalopram prepared by the processes of the invention.
- the invention relates to a hydrochloride or hydrobromide salt of citalopram having a purity of more than 99.8% w/w, preferably more than 99.9% w/w.
- a pharmaceutical formulation of the free base of citalopram, or a hydrobromide or hydrochloride prepared from said base is provided.
- the formulation is for oral administration.
- the formulations according to the invention may be prepared by direct compression of citalopram in admixture with conventional adjuvants or diluents.
- a wet granulate or a melt granulate of citalopram optionally in admixture with conventional adjuvants or diluents may be used for compression of tablets.
- the pharmaceutical composition of the invention contains the racemic mixture of citalopram base, citalopram hydrochloride or citalopram hydrobromide.
- the crystalline base of citalopram is preferably more than 99.8% w/w pure, most preferably more than 99.9% w/w pure (peak area).
- the melting point is preferably a range within 90-93° C., most preferably 91-92° C. (DSC; onset, open capsule) or it is between 92 and 94° C., preferably 92.5 and 93.5° C. (DSC; onset, closed capsule).
- the crystalline base of citalopram is preferably in racemic form.
- crude salt and “crude mixture” refer to the fact that the salt and the mixture, respectively, comprise impurities, in particular impurities of formula II, which must be removed or which it is desired to remove.
- the crude salt may be a salt separated directly from the reaction mixture, or the crude reaction mixture may have been subjected to some initial purification, e.g. one re-crystallisation, and /or treatment with activated carbon or silica gel, and the salt formed subsequently by treatment with an acid using methods known in the art.
- the salt may be isolated by precipitation or it may exist in a solvent, e.g. in the mixture resulting directly from the synthesis of the salt.
- the crude mixture comprising citalopram may be obtained directly from the synthesis of the compound according to any of the above mentioned processes or it may have been subjected to some initial or simultaneous purification, e.g. one re-crystallisation, treatment with activated carbon or silica gel.
- the base of citalopram may be set free from the crude salt by dissolving the crude salt in a mixture of water and an organic solvent and then adding a base.
- the organic solvent may be toluene, ethyl acetate or any other suitable solvent and the base may be any convenient base, preferably NaOH or NH 3 .
- the base of citalopram may, if necessary, be set free from a crude mixture containing citalopram by treatment with a base.
- Crude mixtures containing citalopram base may be subjected to further purification and extraction, before the base is precipitated in crystalline form.
- the base of citalopram may be isolated by separation of the organic phase, evaporation of the solvent in order to obtain the base most probably as an oil and then crystallisation of the base from an aprotic solvent, such as an alkane, including n-heptane, hexane and isooctane, and high and low boiling petroleum ethers and substituted aromates, incl toluene and xylenes.
- Crystalline citalopram base may be re-crystallised from the same solvents.
- the pharmaceutically acceptable salt of citalopram such as the hydrobromide or hydrochloride
- the base may be reacted with either the calculated amount of acid in a water miscible solvent, such as acetone or ethanol, with subsequent isolation of the salt by concentration and cooling, or with an excess of the acid in a water immiscible solvent, such as ethylether, ethylacetate or dichloromethane, with the salt separating spontaneously.
- a water miscible solvent such as acetone or ethanol
- a water immiscible solvent such as ethylether, ethylacetate or dichloromethane
- the hydrobromide or hydrochloride of citalopram obtained by the method of the invention has a very high purity, preferably more than 99.8% pure, most preferably more than 99.9% purity.
- Other salts of citalopram e.g. the oxalate, may also be obtained in a very pure form by this process.
- the conversion to a cyano group may be carried out by reaction with a cyanide source, for example KCN, NaCN, CuCN, Zn(CN) 2 or (R 4 ) 4 NCN where R 4 indicates four groups which may be the same or different and are selected from hydrogen and straight chain or branched alkyl, in the presence of a palladium catalyst and a catalytic amount of Cu + or Zn 2+ , or with Zn(CN) 2 in the presence of a palladium catalyst.
- a cyanide source for example KCN, NaCN, CuCN, Zn(CN) 2 or (R 4 ) 4 NCN where R 4 indicates four groups which may be the same or different and are selected from hydrogen and straight chain or branched alkyl, in the presence of a palladium catalyst and a catalytic amount of Cu + or Zn 2+ , or with Zn(CN) 2 in the presence of a palladium catalyst.
- the cyanide source is used in a stoichiometric amount or in excess, preferably 1-2 equivalents are used pr. equivalent starting material.
- R 4 N + may conveniently be (Bu) 4 N + .
- the cyanide compound is preferably NaCN or KCN or Zn(CN) 2 .
- the palladium catalyst may be any suitable Pd(0) or Pd(II) containing catalyst, such as Pd(PPh 3 ) 4 , Pd 2 (dba) 3 , Pd(PPh) 2 Cl 2 , etc.
- Pd catalyst is conveniently used in an amount of 1-10, preferably 2-6, most preferably about 4-5 mol %.
- Catalytic amounts of Cu + and Zn 2+ means substoichiometric amounts such as 0.1-5, preferably 1-3%. Conveniently, about 1 ⁇ 2 eq. is used per eq. Pd. Any convenient source of Cu + and Zn ++ may be used. Cu + is preferably used in the form of CuI and Zn 2+ is conveniently used as the Zn(CN) 2 salt.
- the conversion to a cyano group may also be carried out by reaction with Cu(CN) without catalyst.
- the reaction is performed at elevated temperature.
- reaction is performed in an ionic liquid of the general formula (5) 4 N + , X, wherein R 5 are alkyl-groups or two of the R 5 groups together form a ring and X ⁇ is the counterion.
- (R 5 ) 4 N + X ⁇ represents
- reaction is conducted with apolar solvents such as benzene, xylene or mesitylene and under the influence of microwaves by using i.e. Synthewave 1000TM by Prolabo.
- apolar solvents such as benzene, xylene or mesitylene
- the reaction is performed without added solvent.
- the temperature ranges are dependent upon the reaction type. If no catalyst is present, preferred temperatures are in the range of 100-200° C. However, when the reaction is conducted under the influence of microwaves, the temperature in the reaction mixture may raise to above 300° C. More preferred temperature ranges are between 120-170° C. The most preferred range is 130-150° C. If catalyst is present, the preferred temperature range is between 0 and 100° C. More preferred are temperature ranges of 40-90° C. Most preferred temperature ranges are between 60-90° C.
- reaction conditions are conventional conditions for such reactions and may easily be determined by a person skilled in the art.
- the conversion to a cyano group may also be carried out by reaction with a cyanide source, for example KCN, NaCN, CuCN, Zn(CN) 2 or (R 4 ) 4 NCN where (R 4 ) 4 indicates four groups which may be the same or different and are selected from hydrogen and straight chain or branched alkyl, in the presence of a nickel catalyst.
- a cyanide source for example KCN, NaCN, CuCN, Zn(CN) 2 or (R 4 ) 4 NCN where (R 4 ) 4 indicates four groups which may be the same or different and are selected from hydrogen and straight chain or branched alkyl, in the presence of a nickel catalyst.
- the nickel catalyst may be any suitable Ni(0) or Ni(II) containing complex which acts as a catalyst, such as Ni(PPh 3 ) 3 , ( ⁇ -aryl)-Ni(PPh 3 ) 2 Cl, etc.
- the nickel catalysts and their preparation are described in WO 96/11906, EP-A-613720 or EP-A-384392.
- the reaction is carried out in the presence of a catalytic amount of Cu + or Zn 2+ .
- a Nickel(0) complex is prepared in situ before the cyanation reaction by reduction of a Nickel(II) precursor such as NiCl 2 or NiBr 2 by a metal, such as zinc, magnesium or manganese in the presence of excess of complex ligands, preferably triphenylphosphin.
- a Nickel(II) precursor such as NiCl 2 or NiBr 2
- a metal such as zinc, magnesium or manganese
- Ni-catalyst is conveniently used in an amount of 0.5-10, preferably 2-6, most preferably about 4-5 mol %.
- Catalytic amounts of Cu + and Zn 2+ mean substoichiometric amounts such as 0.1-5, preferably 1-3%. Any convenient source of Cu + and Zn 2+ may be used.
- Cu + is preferably used in the form of CuI and Zn 2+ is conveniently used as the Zn(CN) 2 salt or formed in situ by reduction of a Nickel (II) compounds using zinc.
- Ni catalysts are i.e. Ni (0), Pd(0) or Pd(II) catalysts as described by Sakakibara et. al. in Bull. Chem. Soc. Jpn., 61, 1985-1990, (1988).
- Preferred catalysts are Ni(PPh 3 ) 3 or Pd(PPh 3 ) 4 , or Pd(PPh) 2 Cl 2 .
- the reactions may be performed in any convenient solvent as described in Sakakibara et. al. in Bull. Chem. Soc. Jpn., 61, 1985-1990, (1988).
- Preferred solvents are acetonitrile, ethylacetate, THF, DMF or NMP.
- the conversion to a cyano group may be carried out by conversion of the formyl group to an oxime or similar group by reaction with a reagent R 6 —V—NH 2 wherein R 6 is hydrogen, optionally substituted allyl, aryl or heteroaryl and V is O, N or S, followed by dehydration with a common dehydrating agent, for example thionylchloride, acetic anhydride/pyridine, pyridine/HCl or phosphor pentachloride.
- Preferred reagents R 6 —V—NH 2 are hydroxylamine and compounds wherein R 6 is alkyl or aryl and V is N or O.
- the conversion to a cyano group may be carried out via the corresponding acid chloride, ester or amide.
- the acid chloride is conveniently obtained by treatment of the acid with POCl 3 , PCl 5 or SOCl 2 neat or in a suitable solvent, such as toluene or toluene comprising a catalytic amount of N,N-dimethylformamide.
- the ester is obtained by treatment of the acid with an alcohol, in the presence of an acid, preferably a mineral acid or a Lewis acid, such as HCl, H 2 SO 4 , POCl 3 , PCl 5 or SOCl 2 .
- the ester may be obtained from the acid chloride by reaction with an alcohol.
- the ester or the acid chloride is then converted to an amide or by amidation with ammonia or an alkylamine, preferably t-butyl amine.
- the conversion to amide may also be obtained by reaction of the ester with ammonia or an alkylamine under pressure and heating.
- the amide group is then converted to a cyano group by dehydration.
- the dehydrating agent may be any suitable dehydrating agent, and the optimal agent may easily be determined by a person skilled in the art. Examples of suitable dehydrating agents are SOCl 2 , POCl 3 and PCl 5 , preferably SOCl 2 .
- the carboxylic acid is reacted with an alcohol, preferably ethanol, in the presence of POCl 3 , in order to obtain the corresponding ester, which is then reacted with ammonia thereby giving the corresponding amide, which in turn is reacted with SOCl 2 in toluene comprising a catalytic amount of N,N-dimethylformamide.
- a compound where Z is —COOH may be reacted with chlorosulfonyl isocyanate in order to form the nitrile, or treated with a dehydrating agent and a sulfonamide.
- the compounds of formula (II) may be prepared as described in DE 2,657,013, WO 0011926 and WO 0013648, WO 9819513, WO 9819512 and WO 9900548.
- halogen means chloro, bromo or iodo.
- alkyl refers to a branched or unbranched alkyl group, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, and 2-methyl-1-propyl.
- aryl refers to a carbocyclic aromatic group, in particular phenyl.
- Aralkyl refers to an arylalkyl group wherein aryl and alkyl is as defined above.
- the aryl and aralkyl groups may optionally be substituted, e.g. with alkyl groups, forming for example tolyl.
- compositions of the invention may be administered in any suitable way and in any suitable form, for example orally in the form of tablets, capsules, powders or syrups, or parenterally in the form of usual sterile solutions for injection.
- pharmaceutical compositions of the invention are administered orally.
- the pharmaceutical formulations of the invention may be prepared by conventional methods in the art.
- tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine.
- adjuvants or diluents comprise: Corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive colourings, aroma, preservatives etc. may be used provided that they are compatible with the active ingredients.
- the formulations according to the invention may be prepared by direct compression of citalopram in admixture with conventional adjuvants or diluents.
- a wet granulate or a melt granulate of citalopram optionally in admixture with conventional adjuvants or diluents may be used for compression of tablets.
- Solutions for injections may be prepared by solving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilisation of the solution and filling in suitable ampoules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
- the base of citalopram has been found to be crystalline with stable and nice white crystals and it has been found that the base may easily be crystallised in a very pure form. So for example more than 99.8% w/w pure citalopram base was obtained by crystallisation from up to 95% pure hydrobromide without further purification. Accordingly, the process of the invention for preparing salts of citalopram has been found to give the salts as very pure products of pharmaceutically acceptable quality. Accordingly, the yield may be improved substantially during the manufacture of citalopram.
- the crystalline citalopram base may be formulated into very good and stable solid formulations with good release properties.
- the batch size was 200 g and the granulation was performed in a small-scale laboratory high shear mixer (Micromixer).
- Citalopram base was sieved through a sieve aperture of 0.3 mm.
- the ingredients of the intragranular phase (1-4 in Table 1) were mixed at 600 rpm.
- 25 ml of purified water (5) was added in 30 sec and granulation terminated after a total processing time of 3 min.
- the granulate was wet sieved through a 0.7 mm sieve aperture and dried at 40° C. in 30 minutes to equilibrium relative humidity of 32%.
- the dried granulate was finally sieved through a 0.7 mm sieve aperture.
- Tablets were produced on a single punch tabletting machine Korsch EK0. The characteristics of the tables are shown in Table 2. TABLE 2 Tablet characteristics. Parameter Values Tablet strength, mg 20 Nominal tablet weight, mg 125 Tablet diameter, mm 7 Tablet shape Film coating (special doomed) Mean disintegration time, min 1.77 Mean crushing strength, N 69.1 Mean tablet weight, mg 125.4 RSD tablet weight, % 0.42 Friability, % 0.3
- the tablets produced had satisfactory technical properties.
- the batch size was 200 g.
- Citalopram base was sieved through a sieve aperture of 0.3 mm.
- the granulation was performed in a small-scale laboratory high shear mixer (Micromixer)
- the ingredients of the intra-granular phase (1-3 in Table 3) were mixed at 1200 rpm.
- Tablets were produced on a single punch tabletting machine Korsch EK0. The characteristics of the tables are shown in Table 4. TABLE 4 Tablet characteristics. Parameter Values Tablet strength, 20 mg 20 Nominal tablet weight, mg 125 Tablet diameter, mm 7 Tablet shape Film coating, Special doomed Mean disintegration time, min 1.0 Mean crushing strength, N 55.5 Mean tablet weight, mg 125.6 RSD tablet weight, % 0.5 Friability, % 0.4
- the tablets produced had satisfactory technical properties.
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Abstract
The present invention relates to the crystalline base of the well known antidepressant drug citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile, formulations of said base, a process for the preparation of purified salts of citalopram, such as the hydrobromide, using the base, the salts obtained by said process and formulations containing such salts.
Description
- This application is a continuation of International Application No. PCT/DK01/00137, filed Feb. 28, 2001. The prior application is hereby incorporated by reference, in its entirety.
- The present invention relates to the crystalline base of the well known antidepressant drug citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile, formulations of said base, a process for the preparation of purified salts of citalopram, such as the hydrobromide, using the base, the salts obtained by said process and formulations containing such salts.
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- It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities. The antidepressant activity of the compound has been reported in several publications, eg. J. Hyttel, Prog. Neuro-Psychopharmacol. & Biol. Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand, 1987, 75, 478-486. The compound has further been disclosed to show effects in the treatment of dementia and cerebrovascular disorders, EP-A-474580.
- Citalopram was first disclosed in DE 2,657,013, corresponding to U.S. Pat. No. 4,136,193. This patent publication describes the preparation of citalopram by one method and outlines a further method, which may be used for preparing citalopram. The citalopram prepared was isolated as the oxalate, the hydrobromide and the hydrochloride salt, respectively. Furthermore, the citalopram base was obtained as an oil (B.P. 175 C/0.03 mmHg). Citalopram is marketed as the hydrobromide and the hydrochloride, respectively.
- A number of processes for the preparation of citalopram have been disclosed. In many of these, the last step of the process is a conversion of a group different from cyano in the 5 position of the direct analogue of citalopram to a 5-cyano group. So citalopram has been prepared by:
- Exchange of 5-halogen, or 5-CF3—(CF2)n—SO2—O—, with cyano (DE 2,657,013 and co-pending WO 0011926 and WO 0013648).
- Conversion of a 5-amido or 5-ester group to a 5-cyano group (WO 9819513)
- Conversion of a 5-amino group to a 5-cyano group (WO 9819512)
- Conversion of a 5-formyl group to a 5-cyano group (WO 9900548)
- Conversion of a 5-oxazolinyl or 5-thiazolinyl group to a 5-cyano group (WO 0023431)
- Other processes for the preparation of citalopram comprise exchange of the 5-bromo group of 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuranbromide with 5-cyano followed by alkylation with a 3-(N,N-dimethylamino)propyl-halogenide (DE 2,657,013 and WO 9819511).
- Many of the processes mentioned above have the disadvantage that it is difficult to separate the intermediates formed during the process (the intermediates mentioned above or earlier intermediates) from the end product and, accordingly, extensive purification procedures involving loss of citalopram are required in order to obtain the necessary quality of the end product.
- It has now been found that the base of citalopram may be obtained as a very nice and pure crystalline product, which may easily be handled and conveniently be formulated into tablets and other pharmaceutical forms. Furthermore, it has surprisingly been found that a very good and efficient purification of citalopram may be obtained during manufacture of citalopram (e.g. of the hydrobromide or the hydrochloride salt) by crystallising the base, and thereafter optionally forming a salt from the base.
- This purification process is particularly useful for removing intermediates which are structurally closely related to citalopram, in particular compounds which only differ from citalopram by the substituent situated in position 5 on the isobenzofuran ring, and intermediates which have physical/chemical properties which are close to those of citalopram, e.g. the 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-isobenzofurans having halogen (in particular bromide and chloride), an -amide or an ester in position 5 of the isobenzofuran ring, or 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuranbromide, or -chloride.
-
- In a second aspect, the invention provides a process for the manufacture of a salt of citalopram, preferably the hydrobromide or hydrochloride in which the free base of citalopram is precipitated in crystalline form, optionally re-crystallised one or more times and then transferred to a pharmaceutically acceptable salt of citalopram.
- In a further aspect, the invention relates to the pure crystalline salt, preferably the hydrobromide or hydrochloride prepared by the process of the invention.
- In particular, the invention relates to a process for the manufacture of a salt of citalopram characterised in that the base of citalopram is set free and precipitated in crystalline form, optionally re-crystallised one or more times, and then transferred into a salt thereof.
- In particular, the invention relates to a process for the manufacture of a salt of citalopram characterised in that the base of citalopram is set free from a crude salt or crude mixture of citalopram.
- More particularly, the present invention relates to a process for the manufacture of citalopram base or a salt of citalopram characterised in that one or more impurities of the formula
wherein Z is halogen, —O—SO2—(CF2)n—CF3, where n is 0-8, —CHO, —NHR1, —COOR2, —CONR2R3 wherein R2 and R3 are selected from hydrogen, alkyl, optionally substituted aryl or aralkyl and R1 is hydrogen or alkylcarbonyl, are removed from a crude mixture of citalopram or from a crude salt of citalopram, by precipitating citalopram base in crystalline form, optionally re-crystallising said base one or more times and/or transferring said base into a salt thereof. - The-crude-mixture of citalopram containing the-compound of formula II as an impurity may be prepared by subjecting a compound of formula H to a cyanide exchange reaction with a cyanide source, or by subjecting 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuranhalogenide, in particular the bromide, to a cyanide exchange reaction followed by alkylation with a 3-(N,N-dimethylamino)propyl-halogenide.
- In a particular embodiment of the invention, Z is halogen, in particular bromide or chloride.
- In a particularly preferred embodiment of the invention, the salt prepared is the hydrobromide or hydrochloride salt of citalopram.
- The crude salt may be any convenient salt, such as the hydrobromide, hydrochloride, sulphate, oxalate, phosphate, nitrate or any other convenient salt. Other salts are salts of organic acids.
- In a preferred embodiment of the invention, the crude salt is the sulphate, the hydrobromide or the hydrochloride salt.
- The invention also relates to a hydrochloride or hydrobromide salt of citalopram prepared by the processes of the invention. In particular, the invention relates to a hydrochloride or hydrobromide salt of citalopram having a purity of more than 99.8% w/w, preferably more than 99.9% w/w.
- In yet another aspect, a pharmaceutical formulation of the free base of citalopram, or a hydrobromide or hydrochloride prepared from said base, is provided. Preferably the formulation is for oral administration.
- The formulations according to the invention may be prepared by direct compression of citalopram in admixture with conventional adjuvants or diluents. Alternatively, a wet granulate or a melt granulate of citalopram, optionally in admixture with conventional adjuvants or diluents may be used for compression of tablets.
- In particular, the pharmaceutical composition of the invention contains the racemic mixture of citalopram base, citalopram hydrochloride or citalopram hydrobromide.
- The crystalline base of citalopram is preferably more than 99.8% w/w pure, most preferably more than 99.9% w/w pure (peak area). The melting point is preferably a range within 90-93° C., most preferably 91-92° C. (DSC; onset, open capsule) or it is between 92 and 94° C., preferably 92.5 and 93.5° C. (DSC; onset, closed capsule). The crystalline base of citalopram is preferably in racemic form.
- The terms “crude salt” and “crude mixture” refer to the fact that the salt and the mixture, respectively, comprise impurities, in particular impurities of formula II, which must be removed or which it is desired to remove.
- The crude salt may be a salt separated directly from the reaction mixture, or the crude reaction mixture may have been subjected to some initial purification, e.g. one re-crystallisation, and /or treatment with activated carbon or silica gel, and the salt formed subsequently by treatment with an acid using methods known in the art. The salt may be isolated by precipitation or it may exist in a solvent, e.g. in the mixture resulting directly from the synthesis of the salt.
- Similarly, the crude mixture comprising citalopram may be obtained directly from the synthesis of the compound according to any of the above mentioned processes or it may have been subjected to some initial or simultaneous purification, e.g. one re-crystallisation, treatment with activated carbon or silica gel.
- The base of citalopram may be set free from the crude salt by dissolving the crude salt in a mixture of water and an organic solvent and then adding a base. The organic solvent may be toluene, ethyl acetate or any other suitable solvent and the base may be any convenient base, preferably NaOH or NH3. Likewise, the base of citalopram may, if necessary, be set free from a crude mixture containing citalopram by treatment with a base.
- Crude mixtures containing citalopram base may be subjected to further purification and extraction, before the base is precipitated in crystalline form. The base of citalopram may be isolated by separation of the organic phase, evaporation of the solvent in order to obtain the base most probably as an oil and then crystallisation of the base from an aprotic solvent, such as an alkane, including n-heptane, hexane and isooctane, and high and low boiling petroleum ethers and substituted aromates, incl toluene and xylenes. Crystalline citalopram base may be re-crystallised from the same solvents.
- The pharmaceutically acceptable salt of citalopram, such as the hydrobromide or hydrochloride, may be prepared by methods known in the art. So, the base may be reacted with either the calculated amount of acid in a water miscible solvent, such as acetone or ethanol, with subsequent isolation of the salt by concentration and cooling, or with an excess of the acid in a water immiscible solvent, such as ethylether, ethylacetate or dichloromethane, with the salt separating spontaneously. The hydrobromide or hydrochloride of citalopram obtained by the method of the invention has a very high purity, preferably more than 99.8% pure, most preferably more than 99.9% purity. Other salts of citalopram, e.g. the oxalate, may also be obtained in a very pure form by this process.
- The cyanide exchange reactions mentioned above may be carried out as described in the patent applications mentioned above.
- In particular, when Z is halogen, or CF3—(CF2)n—SO2—O— wherein n is an integer in the range 0-8, incl., the conversion to a cyano group may be carried out by reaction with a cyanide source, for example KCN, NaCN, CuCN, Zn(CN)2 or (R4)4NCN where R4 indicates four groups which may be the same or different and are selected from hydrogen and straight chain or branched alkyl, in the presence of a palladium catalyst and a catalytic amount of Cu+ or Zn2+, or with Zn(CN)2 in the presence of a palladium catalyst.
- The cyanide source is used in a stoichiometric amount or in excess, preferably 1-2 equivalents are used pr. equivalent starting material. R4N+ may conveniently be (Bu)4N+. The cyanide compound is preferably NaCN or KCN or Zn(CN)2.
- The palladium catalyst may be any suitable Pd(0) or Pd(II) containing catalyst, such as Pd(PPh3)4, Pd2(dba)3, Pd(PPh)2Cl2, etc. The Pd catalyst is conveniently used in an amount of 1-10, preferably 2-6, most preferably about 4-5 mol %.
- Catalytic amounts of Cu+ and Zn2+, respectively, means substoichiometric amounts such as 0.1-5, preferably 1-3%. Conveniently, about ½ eq. is used per eq. Pd. Any convenient source of Cu+ and Zn++ may be used. Cu+ is preferably used in the form of CuI and Zn2+ is conveniently used as the Zn(CN)2 salt.
- When Z is Br or I, the conversion to a cyano group may also be carried out by reaction with Cu(CN) without catalyst. In a preferred embodiment, the reaction is performed at elevated temperature.
-
- In another particular aspect the reaction is conducted with apolar solvents such as benzene, xylene or mesitylene and under the influence of microwaves by using i.e. Synthewave 1000™ by Prolabo. In a particular aspect, the reaction is performed without added solvent.
- The temperature ranges are dependent upon the reaction type. If no catalyst is present, preferred temperatures are in the range of 100-200° C. However, when the reaction is conducted under the influence of microwaves, the temperature in the reaction mixture may raise to above 300° C. More preferred temperature ranges are between 120-170° C. The most preferred range is 130-150° C. If catalyst is present, the preferred temperature range is between 0 and 100° C. More preferred are temperature ranges of 40-90° C. Most preferred temperature ranges are between 60-90° C.
- Other reaction conditions, solvents, etc. are conventional conditions for such reactions and may easily be determined by a person skilled in the art.
- When Z is Cl or Br, the conversion to a cyano group may also be carried out by reaction with a cyanide source, for example KCN, NaCN, CuCN, Zn(CN)2 or (R4)4NCN where (R4)4 indicates four groups which may be the same or different and are selected from hydrogen and straight chain or branched alkyl, in the presence of a nickel catalyst.
- The nickel catalyst may be any suitable Ni(0) or Ni(II) containing complex which acts as a catalyst, such as Ni(PPh3)3, (σ-aryl)-Ni(PPh3)2Cl, etc. The nickel catalysts and their preparation are described in WO 96/11906, EP-A-613720 or EP-A-384392.
- In one embodiment of the invention, the reaction is carried out in the presence of a catalytic amount of Cu+ or Zn2+.
- In a particularly preferred embodiment, a Nickel(0) complex is prepared in situ before the cyanation reaction by reduction of a Nickel(II) precursor such as NiCl2 or NiBr2 by a metal, such as zinc, magnesium or manganese in the presence of excess of complex ligands, preferably triphenylphosphin.
- The Ni-catalyst is conveniently used in an amount of 0.5-10, preferably 2-6, most preferably about 4-5 mol %.
- Catalytic amounts of Cu+ and Zn2+, respectively, mean substoichiometric amounts such as 0.1-5, preferably 1-3%. Any convenient source of Cu+ and Zn2+ may be used. Cu+ is preferably used in the form of CuI and Zn2+ is conveniently used as the Zn(CN)2 salt or formed in situ by reduction of a Nickel (II) compounds using zinc.
- The Ni catalysts are i.e. Ni (0), Pd(0) or Pd(II) catalysts as described by Sakakibara et. al. in Bull. Chem. Soc. Jpn., 61, 1985-1990, (1988). Preferred catalysts are Ni(PPh3)3 or Pd(PPh3)4, or Pd(PPh)2Cl2.
- The reactions may be performed in any convenient solvent as described in Sakakibara et. al. in Bull. Chem. Soc. Jpn., 61, 1985-1990, (1988). Preferred solvents are acetonitrile, ethylacetate, THF, DMF or NMP.
- When Z is CHO, the conversion to a cyano group may be carried out by conversion of the formyl group to an oxime or similar group by reaction with a reagent R6—V—NH2 wherein R6 is hydrogen, optionally substituted allyl, aryl or heteroaryl and V is O, N or S, followed by dehydration with a common dehydrating agent, for example thionylchloride, acetic anhydride/pyridine, pyridine/HCl or phosphor pentachloride. Preferred reagents R6—V—NH2 are hydroxylamine and compounds wherein R6 is alkyl or aryl and V is N or O.
- When Z is —COOH, the conversion to a cyano group may be carried out via the corresponding acid chloride, ester or amide.
- The acid chloride is conveniently obtained by treatment of the acid with POCl3, PCl5 or SOCl2 neat or in a suitable solvent, such as toluene or toluene comprising a catalytic amount of N,N-dimethylformamide. The ester is obtained by treatment of the acid with an alcohol, in the presence of an acid, preferably a mineral acid or a Lewis acid, such as HCl, H2SO4, POCl3, PCl5 or SOCl2. Alternatively, the ester may be obtained from the acid chloride by reaction with an alcohol. The ester or the acid chloride is then converted to an amide or by amidation with ammonia or an alkylamine, preferably t-butyl amine.
- The conversion to amide may also be obtained by reaction of the ester with ammonia or an alkylamine under pressure and heating.
- The amide group is then converted to a cyano group by dehydration. The dehydrating agent may be any suitable dehydrating agent, and the optimal agent may easily be determined by a person skilled in the art. Examples of suitable dehydrating agents are SOCl2, POCl3 and PCl5, preferably SOCl2.
- In a particularly preferred embodiment, the carboxylic acid is reacted with an alcohol, preferably ethanol, in the presence of POCl3, in order to obtain the corresponding ester, which is then reacted with ammonia thereby giving the corresponding amide, which in turn is reacted with SOCl2 in toluene comprising a catalytic amount of N,N-dimethylformamide.
- Alternatively, a compound where Z is —COOH may be reacted with chlorosulfonyl isocyanate in order to form the nitrile, or treated with a dehydrating agent and a sulfonamide.
- When Z is —NHR1, where R1 is hydrogen, the conversion into cyano is preferably performed by diazotation and followed by reaction with CN−. Most preferably NaNO2 and CuCN and/or NaCN are used. When R1 is alkylcarbonyl, it is initially subjected to hydrolysis thereby obtaining the corresponding compound wherein R1 is H which is the converted as described above. The hydrolysis may be performed either in acidic or basic environment.
- The compounds of formula (II) may be prepared as described in DE 2,657,013, WO 0011926 and WO 0013648, WO 9819513, WO 9819512 and WO 9900548.
- Throughout this specification and claims, halogen means chloro, bromo or iodo.
- The term alkyl refers to a branched or unbranched alkyl group, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, and 2-methyl-1-propyl.
- The term aryl refers to a carbocyclic aromatic group, in particular phenyl. Aralkyl refers to an arylalkyl group wherein aryl and alkyl is as defined above. The aryl and aralkyl groups may optionally be substituted, e.g. with alkyl groups, forming for example tolyl.
- The pharmaceutical compositions of the invention may be administered in any suitable way and in any suitable form, for example orally in the form of tablets, capsules, powders or syrups, or parenterally in the form of usual sterile solutions for injection. Preferably the pharmaceutical compositions of the invention are administered orally.
- The pharmaceutical formulations of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: Corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive colourings, aroma, preservatives etc. may be used provided that they are compatible with the active ingredients.
- In particular, the formulations according to the invention may be prepared by direct compression of citalopram in admixture with conventional adjuvants or diluents. Alternatively, a wet granulate or a melt granulate of citalopram, optionally in admixture with conventional adjuvants or diluents may be used for compression of tablets.
- Solutions for injections may be prepared by solving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilisation of the solution and filling in suitable ampoules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
- According to the present invention, the base of citalopram has been found to be crystalline with stable and nice white crystals and it has been found that the base may easily be crystallised in a very pure form. So for example more than 99.8% w/w pure citalopram base was obtained by crystallisation from up to 95% pure hydrobromide without further purification. Accordingly, the process of the invention for preparing salts of citalopram has been found to give the salts as very pure products of pharmaceutically acceptable quality. Accordingly, the yield may be improved substantially during the manufacture of citalopram.
- Finally, it has been found that the crystalline citalopram base may be formulated into very good and stable solid formulations with good release properties.
- The invention is further illustrated by the following examples.
- 1-(3-Dimethylaminopropyl)-1-(4′-fluorophenyl)-1,3-dihydrobenzofuran-5-carbonitrile hydrobromide (101 grams, 0.25 mole) prepared from 1-(3-Dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuranbromide, is suspended in water (500 ml) and toluene (500 ml). NaOH (60 ml, 5 N (aq)) is added and the mixture (pH>10) is stirred for 15 min. before the phases are separated. The organic phase is washed with water (2×100 ml) and filtered through a pad of filter help. The volatiles are removed in vacuo and the title compound is obtained as an oil. n-Heptane (400 ml) is added and the mixture is heated to 70° C. On cooling, crystals form. The white crystals of the title compound are filtered off and dried at ambient temperature over night in vacuo.
- Yield: 75.4 grams (93%). DSC(onset, open capsule): 91.3-91.8° C. DSC (onset, closed capsule): 92.8° C.
- Purity: (>99.8% (peak area)).
- Anal. calcd. for C20H21N2F1O1; C, 74.04; H, 6.54; N, 8.64. Found C, 74.01; H, 6.49; N, 8.59.
- 1H-NMR (DMSO-d6, 500 MHz): 1.21 (1H, m), 1.29 (1H, m), 2.02 (6H, s), 2.09-2.23 (4H, m), 5.15 (1H, d J=12.5 Hz), 5.22 (1H, d J=12.5 Hz), 7.16 (2H, t J=8.5 Hz), 7.60 (2H, dt J=8.5 Hz J=1.2 Hz), 7.76 (1H, d J=8.5 Hz), 7.79 (1H, d J=8.5 Hz), 7.80 (1H, s). 13C-NMR (DMSO-d6, 125 MHz): 21.8, 38.3, 45.0, 58.8, 71.0, 90.7, 110.5, 115.1 (d J=22 Hz), 118.8, 123.1, 125.1, 127.0 (d J=8 Hz), 132.0, 140.0 (d J=3 Hz), 140.5, 149.5, 161.3 (d J=245Hz).
- a) A crude mixture of Citalopram and sulphuric acid is made basic by adding NaOH and the citalopram base is extracted with toluene. The toluene is evaporated and the citalopram base obtained is dissolved in n-heptane at elevated temperature. The very pure free base of citalopram is precipitated by cooling.
- b) A crude mixture of Citalopram and sulphuric acid is made basic by adding NaOH and the citalopram base is extracted with toluene. The toluene is evaporated and the citalopram base obtained is dissolved in methanol. The mixture is treated with activated carbon and filtrated and the solvent is evaporated. The purified free base is dissolved in n-heptane at elevated temperature. Then the very pure free base of citalopram is precipitated by cooling.
- c) A crude mixture of Citalopram and sulphuric acid is made basic by adding NaOH and the citalopram base is extracted with toluene. The toluene phase is treated with silicagel, the toluene is evaporated and the citalopram base obtained is dissolved in n-heptane at elevated temperature. The very pure free base of citalopram is precipitated by cooling.
- d) A crude mixture of Citalopram and sulphuric acid is made basic by adding NaOH and the citalopram base is extracted with toluene. The toluene phase is treated with silicagel, the toluene is evaporated and the citalopram base obtained is dissolved in methanol. The mixture is treated with activated carbon and filtrated and the solvent is evaporated. The purified free base is dissolved in n-heptane at elevated temperature. Then the extremely pure free base of citalopram is precipitated by cooling.
- The batch size was 200 g and the granulation was performed in a small-scale laboratory high shear mixer (Micromixer).
- Citalopram base was sieved through a sieve aperture of 0.3 mm. The ingredients of the intragranular phase (1-4 in Table 1) were mixed at 600 rpm. 25 ml of purified water (5) was added in 30 sec and granulation terminated after a total processing time of 3 min. The granulate was wet sieved through a 0.7 mm sieve aperture and dried at 40° C. in 30 minutes to equilibrium relative humidity of 32%. The dried granulate was finally sieved through a 0.7 mm sieve aperture.
- The dried granulate was mixed for 3 minutes with the extragranular phase (6-7) in a Turbula mixer and finally mixed with the lubricant (8) for 30 sec.
TABLE 1 Composition of the tablets. Materials % 1 Citalopram (base) 16.00 2 Kollidon VA64 2.32 3 Lactose 350 mesh 38.98 4 Corn starch 20.00 5 Purified water 25 6 Avicel PH 200 (Microcrystalline cellulose) 20.00 7 Ac-Di-Sol (Croscarmelose sodium) 2.00 8 Magnesium stearate 0.7 - Tablets were produced on a single punch tabletting machine Korsch EK0. The characteristics of the tables are shown in Table 2.
TABLE 2 Tablet characteristics. Parameter Values Tablet strength, mg 20 Nominal tablet weight, mg 125 Tablet diameter, mm 7 Tablet shape Film coating (special doomed) Mean disintegration time, min 1.77 Mean crushing strength, N 69.1 Mean tablet weight, mg 125.4 RSD tablet weight, % 0.42 Friability, % 0.3 - The tablets produced had satisfactory technical properties.
- The batch size was 200 g. Citalopram base was sieved through a sieve aperture of 0.3 mm. The granulation was performed in a small-scale laboratory high shear mixer (Micromixer)
- The ingredients of the intra-granular phase (1-3 in Table 3) were mixed at 1200 rpm.
- The jacket temperature was 80° C. The granulation process was terminated after 3.5 min. The granulate was sieved through a sieve aperture of 1.0 mm and mixed with the extra-granular phase (4, 5) for 3 min. and with the lubricant (6) for 30 sec.
TABLE 3 Composition of the tablet. Materials % 1 Citalopram (base) 16.00 2 Polyethyleneglycol 6000 9.14 3 Lactose 350 mesh 38.98 4 Avicel PH 200 (Microcrystalline cellulose) 30.00 5 Kollidon CL (Cross-linked povidone) 4.00 6 Magnesium stearate 0.7 - Tablets were produced on a single punch tabletting machine Korsch EK0. The characteristics of the tables are shown in Table 4.
TABLE 4 Tablet characteristics. Parameter Values Tablet strength, 20 mg 20 Nominal tablet weight, mg 125 Tablet diameter, mm 7 Tablet shape Film coating, Special doomed Mean disintegration time, min 1.0 Mean crushing strength, N 55.5 Mean tablet weight, mg 125.6 RSD tablet weight, % 0.5 Friability, % 0.4 - The tablets produced had satisfactory technical properties.
Claims (20)
1. A process for the manufacture of a salt of citalopram, comprising the steps of:
(a) freeing citalopram base;
(b) precipitating the citalopram base in crystalline form;
(c) optionally recrystallising the citalopram base one or more times; and
(d) then transforming the citalopram base into a pharmaceutically acceptable citalopram salt.
2. The process of claim 1 , wherein the step of freeing the citalopram base comprises freeing the citalopram base from a crude salt or a crude mixture of citalopram.
3. A process for the manufacture of citalopram base or a salt of citalopram, wherein one or more impurities of the formula
wherein Z is halogen, —O—SO2—(CF2)n—CF3, where n is 0-8, —CHO, —NHR1, —COOR2, —CONR2R3 wherein R2 and R3 are selected from hydrogen, alkyl, optionally substituted aryl or aralkyl, and R1 is hydrogen or alkylcarbonyl, is removed from a crude mixture of citalopram or from a crude salt of citalopram, comprising the steps of
(a) precipitating citalopram base in crystalline form,
(b) optionally re-crystallising the citalopram base one or more times, and
(c) transforming the citalopram base into a pharmaceutically acceptable salt of citalopram.
4. The process of claim 3 wherein the crude mixture of citalopram or crude salt of citalopram is prepared by subjecting a compound of formula II to a cyanide exchange reaction with a cyanide source.
5. The process of claim 3 , wherein Z is halogen.
6. The process of claim 5 , wherein the halogen is bromide or chloride.
7. The process of claim 3 or 4 , further comprising the step of purifying the crude mixture of citalopram before the step of precipitating citalopram base in crystalline form.
8. The process of claim 3 or 4 , further comprising before step (a) the steps of purifying a crude mixture of citalopram, and then forming a crude salt of citalopram from said crude mixture.
9. The process of claim 3 or 4 , further comprising before step (a) the steps of freeing the citalopram base from a crude mixture of citalopram by treating a crude mixture of citalopram with a base, and optionally further purifying the citalopram base.
10. The process of claim 3 or 4 , wherein the citalopram base is transformed into the hydrobromide or the hydrochloride salt of citalopram.
11. The process of claim 2 or 3 , wherein the crude salt of citalopram is a hydrobromide, hydrochloride, sulphate, oxalate, phosphate or nitrate salt.
12. The process of claim 11 , wherein the crude salt of citalopram is a sulphate, hydrobromide or hydrochloride salt.
13. The crystalline base of citalopram, or a hydrochloride or hydrobromide salt of citalopram, prepared by the process of claim 1 or 3 .
14. The base, the hydrochloride or the hydrobromide salt of claim 13 , having a purity of more than 99.8% w/w.
15. The base, the hydrochloride or the hydrobromide salt of claim 13 , having a purity of more than 99.9% w/w.
16. A pharmaceutical composition comprising the hydrochloride or the hydrobromide salt of citalopram, or the crystalline base of citalopram, of claim 13 .
17. The pharmaceutical composition of claim 16 which is a tablet prepared by
a) direct compression of citalopram, optionally in admixture with pharmaceutically acceptable adjuvants;
b) by compression of a wet granulate of the citalopram, optionally in admixture with pharmaceutically acceptable adjuvants; or
c) by compression of a melt granulate of the citalopram, optionally in admixture with pharmaceutically acceptable adjuvants.
18. The pharmaceutical composition of claim 17 , comprising the racemic mixture of citalopram base, citalopram hydrochloride or citalopram hydrobromide.
19. A crystalline base of citalopram, or a hydrochloride or hydrobromide salt of citalopram, having a purity of more than 99.8% w/w.
20. A crystalline base of citalopram, or a hydrochloride or hydrobromide salt of citalopram, having a purity of more than 99.9% w/w.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/425,308 US20060229459A1 (en) | 2000-03-13 | 2006-06-20 | Crystalline base of citalopram |
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DKPA200000402 | 2000-03-13 | ||
DKPA200000402 | 2000-03-13 | ||
DKPCT/DK00/00183 | 2000-04-13 | ||
WOPCT/DK00/00183 | 2000-04-13 | ||
PCT/DK2001/000137 WO2001068627A1 (en) | 2000-03-13 | 2001-02-28 | Crystalline base of citalopram |
US10/090,336 US6824900B2 (en) | 2002-03-04 | 2002-03-04 | Method and apparatus for water management of a fuel cell system |
US10/245,824 US20030078442A1 (en) | 2000-03-13 | 2002-09-12 | Crystalline base of citalopram |
US10/750,049 US20040167210A1 (en) | 2000-03-13 | 2003-12-30 | Crystalline base of citalopram |
US11/425,308 US20060229459A1 (en) | 2000-03-13 | 2006-06-20 | Crystalline base of citalopram |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
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US10/090,336 Continuation US6824900B2 (en) | 2000-03-13 | 2002-03-04 | Method and apparatus for water management of a fuel cell system |
US10/750,049 Continuation US20040167210A1 (en) | 2000-03-13 | 2003-12-30 | Crystalline base of citalopram |
Publications (1)
Publication Number | Publication Date |
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US20060229459A1 true US20060229459A1 (en) | 2006-10-12 |
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Application Number | Title | Priority Date | Filing Date |
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US10/090,336 Expired - Fee Related US6824900B2 (en) | 2000-03-13 | 2002-03-04 | Method and apparatus for water management of a fuel cell system |
US10/379,815 Abandoned US20030215686A1 (en) | 2002-03-04 | 2003-03-04 | Method and apparatus for water management of a fuel cell system |
US11/425,308 Abandoned US20060229459A1 (en) | 2000-03-13 | 2006-06-20 | Crystalline base of citalopram |
US11/523,475 Abandoned US20070015032A1 (en) | 2002-03-04 | 2006-09-19 | Method and apparatus for water management of a fuel cell system |
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US10/090,336 Expired - Fee Related US6824900B2 (en) | 2000-03-13 | 2002-03-04 | Method and apparatus for water management of a fuel cell system |
US10/379,815 Abandoned US20030215686A1 (en) | 2002-03-04 | 2003-03-04 | Method and apparatus for water management of a fuel cell system |
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US11/523,475 Abandoned US20070015032A1 (en) | 2002-03-04 | 2006-09-19 | Method and apparatus for water management of a fuel cell system |
Country Status (3)
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US (4) | US6824900B2 (en) |
AU (1) | AU2003228279A1 (en) |
WO (1) | WO2003077345A1 (en) |
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- 2003-03-04 WO PCT/US2003/006740 patent/WO2003077345A1/en not_active Application Discontinuation
- 2003-03-04 US US10/379,815 patent/US20030215686A1/en not_active Abandoned
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WO2003077345A1 (en) | 2003-09-18 |
US20030215686A1 (en) | 2003-11-20 |
AU2003228279A1 (en) | 2003-09-22 |
US20030165720A1 (en) | 2003-09-04 |
US20070015032A1 (en) | 2007-01-18 |
US6824900B2 (en) | 2004-11-30 |
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