IES20010693A2 - Pharmaceutical composition containing citalopram - Google Patents
Pharmaceutical composition containing citalopramInfo
- Publication number
- IES20010693A2 IES20010693A2 IE20010693A IES20010693A IES20010693A2 IE S20010693 A2 IES20010693 A2 IE S20010693A2 IE 20010693 A IE20010693 A IE 20010693A IE S20010693 A IES20010693 A IE S20010693A IE S20010693 A2 IES20010693 A2 IE S20010693A2
- Authority
- IE
- Ireland
- Prior art keywords
- citalopram
- crystals
- pharmaceutically acceptable
- acceptable salt
- particle size
- Prior art date
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 73
- 229960001653 citalopram Drugs 0.000 title claims abstract description 71
- 239000008194 pharmaceutical composition Substances 0.000 title description 3
- 239000013078 crystal Substances 0.000 claims abstract description 51
- 239000000203 mixture Substances 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 22
- 239000007892 solid unit dosage form Substances 0.000 claims abstract description 19
- 238000007907 direct compression Methods 0.000 claims abstract description 17
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 12
- 239000002775 capsule Substances 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 239000001828 Gelatine Substances 0.000 claims abstract description 6
- 229920000159 gelatin Polymers 0.000 claims abstract description 6
- 235000019322 gelatine Nutrition 0.000 claims abstract description 6
- 239000002245 particle Substances 0.000 claims description 40
- WIHMBLDNRMIGDW-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carbonitrile;hydron;bromide Chemical group [Br-].O1CC2=CC(C#N)=CC=C2C1(CCC[NH+](C)C)C1=CC=C(F)C=C1 WIHMBLDNRMIGDW-UHFFFAOYSA-N 0.000 claims description 28
- 229960000584 citalopram hydrobromide Drugs 0.000 claims description 28
- 239000004480 active ingredient Substances 0.000 claims description 15
- 239000011230 binding agent Substances 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 6
- 238000007906 compression Methods 0.000 claims description 5
- 230000006835 compression Effects 0.000 claims description 5
- 239000002552 dosage form Substances 0.000 claims description 5
- 238000011049 filling Methods 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000002585 base Substances 0.000 description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- 239000000945 filler Substances 0.000 description 12
- 238000005469 granulation Methods 0.000 description 9
- 230000003179 granulation Effects 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 238000009826 distribution Methods 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000005204 segregation Methods 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 238000007909 melt granulation Methods 0.000 description 3
- 238000010899 nucleation Methods 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 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 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical class [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 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 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004135 Bone phosphate Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001175 calcium sulphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Psychology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A solid unit dosage form comprising citalopram, which is prepared by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, or by filing of said mixture in a hard gelatine capsule. Large crystals of a pharmaceutical acceptable salt of citalopram and method for the manufacture of said large crystals.
Description
Pharmaceutical composition containing Citalopram The present invention relates to ft novel pharmaceutical composition containing citalopram, l-[3-(dimethylamino)propyl]-l-(4-fluorophenyl)-l,3-dihydro-5-isobajzofurancarbonitrjle.
Background of the Invention.
Citalopram is a well-known antidepressant drug that has the following structure: N CHa It is a selective, centrally active serotonin (5-hydraxytiyptaniine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities.
Citalopram was first disclosed in DE 2,657,013, corresponding to US 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 in crystalline form as the oxalate, the bydrobromide and the hydrochloride salt, respectively, Furthermore, the citalopram base was obtained as an oil (B.P. 175 C/0,03 mmHg). The publication also outlines the manufacture of tablets containing salts of citalopram. Citalopram is marketed as the hydrobromide and the hydrochloride, respectively.
Manufacture of crystalline citalopram base is disclosed in co-pending DK 2000 00402, This patent publication describes the preparation of crystalline citalopram base and the use of crystalline citalopram base as an intermediate in the purification of crude citalopram bydrobromide into pure citalopram hydrobromide. The publication also outlines the manufacture of tablets containing citalopram base.
OPEN TO PUBLIC INSPECTION UNDER SECTION 28 AND RULE 2 JNL No. OF ,10(01)1 ch. ΙΕΟ 1 06 93 Citdopram is marketed in a number of countries as a tablet prepared by compression of granulated citalopram hydrobromide, lactose and other excipients.
It is well recognised that preparation of tablets with a reproducible composition requires that all the dry ingredients have good flow properties. In cases, where the active ingredient has good flow properties, tablets can be prepared by direct compression of the ingredients. However, in many cases the particle size of the active substance is small, the active substance is cohesive or has poor flow properties.
Further, active substances with a small particle size mixed with excipients having a larger particle size will typically segregate or de-mix during the tabletting process.
The problem of small particle size and poor flowability, is conventionally solved by enlarging the particle size of the active substance, usually by granulation of the active ingredient either alone or in combination with a filler and/or other conventional tablet ingredients.
One such granulation method is the "wet" granulation process. Using this method, the dry solids (active ingredients, filler, binder etc.) are blended and moistened with water or another wetting agent (e.g. an alcohol) and agglomerates or granules are built up of the moistened solids. Wet massing is continued until a desired homogenous particle size has been achieved whereupon the granulated product is dried.
An alternative to the wet granulation method is the melt granulation, which is also known as the "thermal plastic" granulation process, where a low melting solid is used as the granulation agent. Initially, the dry solids are blended and heated until the binder melts. As the binder is liquefied and spreads over the surface of the particles, the particles will adhere to each other and form granules. The binder solidifies upon cooling forming a dry granular product.
Wet granulation as well as melt granulation are energy intensive unit operations requiring complicated and expensive equipment as well as technical skill. 330 AU 0 R 95 The process used for the preparation of citalopram hydrobromide results in a product with a very small particle size around 2-20 pm that as many other particulate products with a small particle size, has very poor flow properties. Thus, in order to achieve appropriate dosing of the citalopram during tabletting, it was considered necessary to make a granulate of citalopram with larger particle size and improved flow properties, The citalopram tablet that is marketed is a tablet made from granulated citalopram hydrobromide with various excipients.
In view of the fact that direct compression is much simpler and cheaper than the processes involving granulation there is a desire for a process for direct compression of citalopram hydrobromide.
The obstacles that hitherto have hindered direct compression of citalopram tablets have now been circumvented after extensive laboratory research.
It has been found that larger particles, i.e. particles of a size comparable to the size of the filler, may be prepared by a new and inventive crystallisation process and that these particles are useful for the manufacture of directly compressed tablets. Accurate dosing in capsules may also be with such large particles.
It has also been found, that tablets with surprisingly small variation in the content of citalopram may be prepared by direct compression of citalopram hydrobromide having a significantly smaller particle size than the filler. Accurate dosing in capsules may also be achieved despite the small particle size of citalopram.
Objects of the Invention It is the object of the present invention to provide a novel pharmaceutical unit dosage form containing citalopram with a suitable large particle size, wherein said unit dosage form may be prepared by direct compression.
A second object of the invention is to provide a capsule containing citalopram. 330 AU A third object of the invention is to provide large crystals of a pharmaceutically acceptable salt of citalopram suitable for use in direct compression.
A fourth object of the invention is to provide a method for manufacture of large crystals of a pharmaceutically acceptable salt of citalopram.
Summary of the Invention The invention then, inter alia, comprises the following alone or in combination; A solid unit dosage form comprising citalopram prepared by direct compression ofa mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, or by tilling of said mixture in a hard gelatine J 5 capsule.
Crystals of a pharmaceutically acceptable salt of citalopram suitable for use in a solid unit dosage form with a median particle size of at least 40 pm.
A method for the manufacture of crystals of a pharmaceutically acceptable salt of citalopram having a median particle size of at least 40 pm and suitable for use in a solid unit dosage form wherein a solution of a pharmaceutically acceptable salt of citalopram in a suitable solvent system at a first temperature is first cooled down to a second temperature then seeded by addition of crystals of said citalopram salt followed by a holding time at eaid second temperature and a controlled cooling down to a third temperature whereupon said crystals are isolated by conventional solid/liquid separation techniques.
The direct compression of citalopram, a filler and other pharmaceutically acceptable excipients into tablets has the great advantage, that the granulation and a drying step is avoided. Further, as the granulation step is avoided, it is no longer necessary to add a binding agent. 330 AU ΙΕΟ 1 08 9S As used herein, direct compression means that the solid unit dosage form is prepared by compression of a simple mixture of the active ingredient and excipients, without the active ingredient having been subjected to an intermediate granulation process in order to embed it in a larger particle and improve its fluidity properties.
As used herein, binder means an agent, which is used in wet or melt granulation processes and acts as a binder in the granulated product.
As used herein, particle size distribution means the distribution of equivalent spherical diameters as determined by laser diffraction at 1 bar dispersive pressure in a Sympatec Helos equipment Median particle size, correspondingly, means the median of said particle size distribution.
As used herein, refluxing temperature means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
Thus in one embodiment of the invention, the present invention relates to a tablet prepared by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, bi another embodiment, the present invention relates to a capsule prepared by filling a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients in a hard gelatine capsule.
In one embodiment, the present invention relates to a solid unit dosage form comprising citalopram in crystals with a median particle size below 20 pm.
In another embodiment, the present invention relates to a solid unit dosage form comprising citalopram in crystals with a median particle size of at least 40 pm, preferably in the range of 40 - 200 pm, even more preferred 45 - 150 pm and most preferred 50-100 pm. 330 AU Flow, segregation and demixing properties and, hence, the suitability of the citalopram crystals for direct compression depend, besides the median particle size, on the particle side distribution.
Preferably, the solid unit dosage forms according to the invention do not contain a binder.
The solid unit dosage form according to the invention may contain 2-60 % w/w active ingredient calculated as citalopram base, preferably 10-40 % w/w active ingredient KJ calculated as citalopram base, and more preferred 15-25 % w/w active ingredient calculated as ciralopram base. Suitably, the solid unit dosage form of the invention contains 20 % w/w active ingredient calculated as citalopram base.
In particular, the present invention relates to a solid unit dosage form wherein the active ingredient is citalopram hydrobromidc, or citalopram hydrochloride. Preferably the active ingredient contained in the solid unit dosage form of the invention is citalopram hydrobromide.
The solid unit dosage form according to the invention may contain a filler selected from lactose, or other sugars e.g, sorbitol, mannitol, dextrose and sucrose, calcium phosphates (dibasic, tribasic, hydrous and anhydrous), starch, modified starches, microcrystalline cellulose, calcium sulphate and/or calcium carbonate. In a preferred embodiment, the solid unit dosage form of the invention does not contain lactose.
Suitably the filler is a microcrystalline cellulose such as ProSolY SMCC90 manufactured by Penwest Pharmaceuticals or Avicel PH 200 manufactured by FMC Corporation.
Besides the active ingredient and filler, the solid pharmaceutical unit dosage forms may include various other conventional excipients such as disintegrants, and optionally minor amounts of lubricants, colorants, and sweeteners. 330 AU 11=(11 OS 9* Lubricants used according to the invention may suitably be on© or more of the following metallic stearates (magnesium, calcium, sodium), stearic add, wax, hydrogenated vegetable oil, talc and colloidal silica.
Suitably the lubricant is magnesium stearate or calcium stearate Disintegrants include sodium starch glycolate, croscarmellose, crospovidone, low substituted hydroxypropylcellulose, modified cornstarch, prcgclatizined starch and natural starch.
The solid, pharmaceutical unit dosage form of the invention may be prepared by conventional methods using a tablet press with forced feed capability.
The filled, hard gelatine capsule of the invention may be prepared by conventional methods using a capsule filler suitable for powder filling.
In one embodiment of the present invention the crystals of a pharmaceutically acceptable salt of citalopram have a median particle size in the range of 40 - 200 pm, preferably 45 -150 pm and even more preferred 50 -120 pm.
In a preferred embodiment of the present invention the crystals are of citalopram hydrobromide or citalopram hydrochloride, preferably citalopram hydrobromide.
In yet another embodiment of the present invention crystals of a pharmaceutically acceptable salt of citalopram having a median particle size of at least 40 pm and suitable for use in a solid unit dosage form are crystallised from a solution of a pharmaceutically acceptable salt of citalopram in a suitable solvent system. Said solvent system may comprise one or more alcohols and optionally water, preferably the solvent system is a mixture of methanol and water, wherein the methanohwater weight ratio preferably is in the range of 5:1 to 50:1; even more preferred 10:1 to 30:1 and most preferred 15:1 to 25:1. Said pharmaceutically acceptable salt of citalopram is preferably dissolved in the solvent system at a temperature in the range between 50 °C and the refluxing temperature of the solvent system, preferably between 60 °C and 330 AU !E0 1 0 6 95 the refluxing temperature and more preferred between 64 °C and the refluxing temperature. The amounts of pharmaceutically acceptable salt of citalopram and solvent used are preferably corresponding to a solvenfcsolute weight ratio in the range of 0.5:1 to 5:1, more preferred 0.7:1 to 2:1 and most preferred 0.9:1 to 1.5:1. The solution of a pharmaceutically acceptable salt of citalopram is cooled down to a temperature, the seeding temperature, in the range of 20-40 "C, preferably 25-35 °C, whereupon it is seeded with citalopram crystals and kept at said seeding temperature for a holding time for crystal growth in the range of 30 minutes to 7 days, preferably 1 hour to 4 days and more preferred 12 to 36 hours. After said holding time, the crystallisation batch is gradually cooled down in a controlled way from the seeding temperature to the temperature at which the crystals will be isolated from the mother liquor wherein said gradual cooling down is done over a time span in the range of 5 minutes to 6 hours, preferably 15 minutes to 4 hours and more preferred 30 minutes to 2 hours. The crystals of said pharmaceutically acceptable salt of citalopram are preferably isolated from the mother liquor at a temperature in the range of 0-20 °C, more preferred 5-15 "C, using conventional separation techniques, e.g. filtration.
The small crystals of a pharmaceutically acceptable salt of citalopram used in one embodiment of the invention may be produced according to methods described in US 4,136,193.
The crystals of citalopram base used in one embodiment of the invention may be produced according to methods described in NL patent No. 1016435, In the following, the invention is illustrated by way of examples. However, the examples are merely intended to illustrate the invention and should not be construed as limiting. 330 AU ΙΡβ 106 93 Example 1 Crystallisation of citalopram hydrobromide into Urge crystals Citalopram hydrobromide (200 g) is dissolved in a mixture of methanol (200 g) and water (20 g) at 69 °C. The solution is cooled down to 30 ’C, seeded with citalopram hydrobromide crystals and kept at 30 °C for 24 hours, whereupon it is cooled down to 10 °C within 1 hour. The crystals are isolated by filtration, washed with cold methanol and dried. The particle size distribution for the resulting crystals is listed in table 1.
Example 2 Crystallisation of citalopram hydrobromide into large crystals Citalopram hydrobromide (12.0 kg) is dissolved in a mixture of methanol (12.5 kg) and water (1.2 kg) at reflux. The solution is cooled down to 30 °C, seeded with citalopram hydrobromide crystals (27 g) and kept at 30 °C for 16 hours, whereupon it is cooled down to 10 °C within 1 hour. The crystals are isolated by filtration, washed with cold (10 °C) methanol (3.5 kg) and dried. The particle size distribution for the resulting ciystals is listed in table 1.
Example 3 Crystallisation of citalopram hydrobromide into small crystals Citalopram hydrobromide (200 kg) is dissolved in a mixture of methanol (170 L) and acetone (680 L) at 56 °C. The solution is cooled down to 15 °C, seeded with citalopram hydrobromide crystals (50 g), hexane (1600 L) is gradually added within 60 minutes, whereupon the suspension is left standing with moderate stirring and cooling for 8 hours. The crystals are isolated by filtration, washed first with a cold (10 °C) mixture of acetone (50 L) and hexane then with cold (10 °C) hexane (220 L) and dried. The particle size distribution for the resulting crystals is listed in table I. 330 AU fl=0 1 0δ 93 Example 4 Crystallisation of citalopram as the free base.
Citalopram hydrobromide (101 g) is suspended in water (500 mL) and toluene (500 mL). NaOH (60 mL, 5 N (aq)) is added and die mixture (pH>10) is stirred for 15 min before the phases are separated. The organic phase is washed with water (2 xlOO 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 to heated to 70 °C. On cooling, crystals forms. The white crystals of citalopram base are filtered off and dried at ambient temperature over night in vacuo.
Table 1: Particle size distribution (Sympatec Helos) for citalopram hydrobromide crystals and ProSolv SCMC90 Quantile w Example 1 (pm) Example 2 (pm) Example 3 (pm) ProSolv SCMC90 (gm) 95 465.43 549.42 96.96 279.94 90 342.89 352.23 72.27 231.66 50 96.87 52.70 14.04 114.17 10 16.54 11.97 1.19 32.10 5 8.23 6.67 0.82 20.56 Example 5 Tablet prepared by direct compression of small citalopram hydrobromide crystals.
Tablet ingredients: Citalopram, HBr ProSolv SMCC90 Magnesium stearate 5800 g (20%w/w) 23055 g (19.5% w/w) 145 g (0.5%w/w) 330 AU Citalopram hydrobromide crystals from example 3 and ProSolv SMCC90 were blended at 7 ipm for 10 min in a 100 litre Bohle PTM 200 mixer. Magnesium stearate was added and blending continued for 3 min. kg of the resulting mixture was tabletted (125.000 tablets/hour) on a 30 station Fette P 120O/IC tablet press fitted with oblong, embossed, scored 5,5 x 8 mm punches. Tablet core weight was set to 125 mg. The nominal yield was 200.000 tablets. The tablet press was run until the mixture level was just above the forced feeder, i.e. the tabletting was continued as long as possible in order to identify io possible segregation tendencies in the last quantities of mixture.
Tablet properties: Diametrical crushing strength; 70 N Disintegration time: 30 seconds Friability: NA Weight variation: 0.84% relative standard deviation (measured on 20 tablets) Punch adhesion: None observed Citalopram content in the composition during compression, Tablets were sampled throughout the compression in order to measure segregation tendency. Since there is a significant size difference between the active ingredient, citalopram hydrobromide, and the inert filler, ProSolv SMCC90, as seen in table 1, it would be expected that the unequally sized components would segregate, i.e. de-mix, during transfer from blending vessel to tablet press hopper or sitting in the tablet press hopper during tabletting· Sampling was performed 50 times at regular intervals during tabletting, corresponding to sampling at every 4000 tablets produced. Two tablets were withdrawn for each sample, 330 AU IE 0 1 06 93 The tablets were assayed by a validated method using UV-absarption in an aqueous solution, thus analysing in total 100 tablets. The relative standard deviation in citalopram content was 1.6% The variability in tablet strength is surprisingly low in view of the small particle size of citalopram hydrobromide as compared to the inert filler.
One possible explanation for this surprising and beneficial result may be that the tendency to segregation between small citalopram crystals and larger filler particles is uniquely balanced by the poor flow properties of the small crystals, Example 6 Tablet prepared by direct compression of large citalopram hydrobromide crystals.
Tablet ingredients: Citalopram, HBr ProSolv SMCC90 Magnesium stearate (20%w/w) (79.5 %w/w) (0.5%w/w) Citalopram hydrobromide crystals from example 2 and ProSolv SMCC90 were blended. Magnesium stearate was added and blending continued.
Tablets (125 mg nominel weight) were produced.
The tablets had satisfactory technical properties. 330 AU ¢0 1 06 93 Example 6 Tablet prepared by direct compression of citalopram crystals.
Tablet ingredients: Citalopram base ProSolv SMCC90 Magnesium stearate (16 % w/w) (83.3% w/w) (0.7 % w/w) Citalopram base crystals from example 4 were sieved through sieve aperture of 0.3 mm and mixed with ProSolv SMCC90 for 3 minutes in a Turbula mixer. Magnesium stearate was added and blending continued for 30 seconds.
Tablets were produced on a single punch tabletting machine Korsch ΕΚ0.
Tablet properties: Tablet strength, mg: 20 Nominel tablet weight, mg: 125 Tablet diameter, mm: 7 Tablet shape: Film coating, special doomed Diametrical crushing strength: 61.6 N Disintegration time, min: < 1 Friability: 0.1 % Mean tablet weight: 125.4 Weight variation: 0.22 % relative standard deviation The tablets produced had satisfactory technical properties.
Claims (5)
1. A solid unit dosage form comprising titalopram, characterised in that it is prepared by direct compression of a mixture of citalopram base or a pharmaceutically 5 acceptable salt thereof and pharmaceutically acceptable excipients, or by filling of said mixture in a hard gelatine capsule.
2. The solid unit dosage form according to claims 1-2, characterised in that the active ingredient is citalopram hydrobromide in the form of crystals with a median JO particle size below 20 pm, and in that it does not contain a binder.
3. The solid unit dosage form according to claims 1-2, characterised in that the active ingredient is citalopram hydrobromide in the form of crystals with a median particle size of at least 40 pm, preferably in the range of 40 - 200 pm, even more 15 preferred 45-150 pm and most preferred 50-100 pm, and in that it does not contain a binder.
4. Crystals of a pharmaceutically acceptable salt of citalopram suitable for use in a solid unit dosage fonn according to claim 1, characterised in that the median 20 particle size of the crystals is at least 40 pm.
5. Method for manufacture of crystals of a pharmaceutically acceptable salt of citalopram having a median particle size of at least 40 pm and suitable for use in a solid wait dosage form according to claim 1, characterised in that a solution of a 25 pharmaceutically acceptable salt of citalopram in a suitable solvent system at a first temperature is first cooled down to a second temperature then seeded by addition of crystals of said citalopram salt followed by a holding time at said second temperature and a controlled cooling down to a third temperature whereupon said crystals are isolated by conventional solid/liquid separation techniques. 330 AU ΙΕΟ 1 06 9 5 Abstract A solid unit dosage form comprising citalopram, which is prepared by direct 5 compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, or by filling of said mixture in a hard gelatine capsule. Large crystals of a pharmaceutical acceptable salt of citalopram and method for the manufacture of said large crystals.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DKPA200001202 | 2000-08-10 | ||
DKPA200001614 | 2000-10-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
IES20010693A2 true IES20010693A2 (en) | 2002-07-10 |
Family
ID=26068858
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE20010693A IES20010693A2 (en) | 2000-08-10 | 2001-07-24 | Pharmaceutical composition containing citalopram |
Country Status (34)
Country | Link |
---|---|
EP (1) | EP1318805A2 (en) |
JP (1) | JP2003531153A (en) |
KR (1) | KR20030024833A (en) |
CN (1) | CN1446089A (en) |
AR (1) | AR030095A1 (en) |
AT (1) | AT5744U1 (en) |
AU (2) | AU2001100198B4 (en) |
BE (1) | BE1013559A6 (en) |
BG (1) | BG107578A (en) |
BR (1) | BR0113250A (en) |
CA (1) | CA2353693C (en) |
CH (2) | CH694242A5 (en) |
CZ (1) | CZ2003397A3 (en) |
DE (2) | DE20113195U1 (en) |
EA (1) | EA200300247A1 (en) |
ES (1) | ES2172481B2 (en) |
FI (1) | FI5176U1 (en) |
FR (1) | FR2812811B1 (en) |
GB (1) | GB2368014B (en) |
GR (1) | GR1004193B (en) |
HR (1) | HRP20030054A2 (en) |
HU (1) | HUP0103071A3 (en) |
IE (1) | IES20010693A2 (en) |
IL (1) | IL154050A0 (en) |
IS (1) | IS6021A (en) |
IT (1) | ITMI20011637A1 (en) |
MX (1) | MXPA03000837A (en) |
NL (1) | NL1018741C1 (en) |
NO (1) | NO20013891L (en) |
NZ (1) | NZ523785A (en) |
PL (1) | PL359824A1 (en) |
SK (1) | SK2842003A3 (en) |
WO (1) | WO2001080619A2 (en) |
YU (1) | YU9003A (en) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2353693C (en) * | 2000-08-10 | 2003-07-22 | H. Lundbeck A/S | Pharmaceutical composition containing citalopram |
AU2001100195B4 (en) * | 2001-01-05 | 2001-12-20 | H Lundbeck As | Pharmaceutical composition containing citalopram. |
GB0206708D0 (en) * | 2002-03-21 | 2002-05-01 | Cipla Ltd | Pharmaceutical salts |
US6812355B2 (en) | 2002-10-22 | 2004-11-02 | Sekhsaria Chemicals Limited | Process for the manufacture of citalopram hydrobromide from 5-bromophthalide |
RS51092B (en) * | 2002-12-23 | 2010-10-31 | H. Lundbeck A/S. | Escitalopram hydrobromide and a method for the preparation thereof |
WO2004103361A2 (en) * | 2003-05-20 | 2004-12-02 | Ranbaxy Laboratories Limited | A pharmaceutical dosage form of citalopram |
HU227491B1 (en) * | 2003-11-25 | 2011-07-28 | Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag | Tablet containing citalopram hydrogen bromide |
WO2006038217A1 (en) * | 2004-10-05 | 2006-04-13 | Strides Acrolab Limited | An improved drug delivery system of citalopram hydrobromide and process for producing the same |
US7834201B2 (en) | 2005-06-22 | 2010-11-16 | H. Lundbeck A/S | Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base |
CN100353939C (en) * | 2006-01-05 | 2007-12-12 | 昆明积大制药有限公司 | Antidepressant composition containing citalopram and cyclodextrin |
GB2446847B (en) * | 2007-02-02 | 2012-02-22 | Ubiquisys Ltd | Location of Basestation |
CN106397248A (en) * | 2015-08-03 | 2017-02-15 | 深圳信立泰药业股份有限公司 | LCZ696 crystallized powder and a preparing method thereof |
EP4277661A1 (en) * | 2021-01-18 | 2023-11-22 | Anton Frenkel | Pharmaceutical dosage form |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1358915A (en) * | 1919-04-14 | 1920-11-16 | Amici Domenico | Aeroplane |
GB1358915A (en) * | 1971-09-13 | 1974-07-03 | Merck & Co Inc | Directly compressed tablet and composition therefor |
GB1526331A (en) | 1976-01-14 | 1978-09-27 | Kefalas As | Phthalanes |
GB8419963D0 (en) | 1984-08-06 | 1984-09-12 | Lundbeck & Co As H | Intermediate compound and method |
GB8814057D0 (en) * | 1988-06-14 | 1988-07-20 | Lundbeck & Co As H | New enantiomers & their isolation |
US5296507A (en) * | 1990-09-06 | 1994-03-22 | H.Lundbeck A/S | Treatment of cerbrovascular disorders |
EP0714663A3 (en) * | 1994-11-28 | 1997-01-15 | Lilly Co Eli | Potentiation of drug response by a serotonin 1A receptor antagonist |
GB9714841D0 (en) * | 1997-07-14 | 1997-09-17 | Smithkline Beecham Plc | Treatment method |
GB2357762B (en) * | 2000-03-13 | 2002-01-30 | Lundbeck & Co As H | Crystalline base of citalopram |
US6977306B2 (en) | 2000-05-02 | 2005-12-20 | Sumitomo Chemical Company, Limited | Citalopram hydrobromide crystal and method for crystallization thereof |
CA2353693C (en) * | 2000-08-10 | 2003-07-22 | H. Lundbeck A/S | Pharmaceutical composition containing citalopram |
-
2001
- 2001-07-24 CA CA002353693A patent/CA2353693C/en not_active Expired - Lifetime
- 2001-07-24 IE IE20010693A patent/IES20010693A2/en not_active IP Right Cessation
- 2001-07-24 IS IS6021A patent/IS6021A/en unknown
- 2001-07-26 HU HU0103071A patent/HUP0103071A3/en unknown
- 2001-07-26 AU AU2001100198A patent/AU2001100198B4/en not_active Expired
- 2001-07-27 IT IT2001MI001637A patent/ITMI20011637A1/en unknown
- 2001-07-30 MX MXPA03000837A patent/MXPA03000837A/en unknown
- 2001-07-30 CN CN01813752A patent/CN1446089A/en active Pending
- 2001-07-30 YU YU9003A patent/YU9003A/en unknown
- 2001-07-30 KR KR10-2003-7001683A patent/KR20030024833A/en not_active Application Discontinuation
- 2001-07-30 PL PL01359824A patent/PL359824A1/en not_active Application Discontinuation
- 2001-07-30 IL IL15405001A patent/IL154050A0/en unknown
- 2001-07-30 WO PCT/DK2001/000520 patent/WO2001080619A2/en not_active Application Discontinuation
- 2001-07-30 NZ NZ523785A patent/NZ523785A/en unknown
- 2001-07-30 JP JP2001577732A patent/JP2003531153A/en not_active Withdrawn
- 2001-07-30 EP EP01957768A patent/EP1318805A2/en not_active Withdrawn
- 2001-07-30 BR BR0113250-4A patent/BR0113250A/en not_active IP Right Cessation
- 2001-07-30 CZ CZ2003397A patent/CZ2003397A3/en unknown
- 2001-07-30 AU AU2001279591A patent/AU2001279591A1/en not_active Abandoned
- 2001-07-30 SK SK284-2003A patent/SK2842003A3/en not_active Application Discontinuation
- 2001-07-30 EA EA200300247A patent/EA200300247A1/en unknown
- 2001-07-31 GB GB0118579A patent/GB2368014B/en not_active Expired - Fee Related
- 2001-07-31 GR GR20010100377A patent/GR1004193B/en unknown
- 2001-07-31 AR ARP010103662A patent/AR030095A1/en not_active Application Discontinuation
- 2001-08-07 AT AT0062401U patent/AT5744U1/en not_active IP Right Cessation
- 2001-08-08 CH CH01469/01A patent/CH694242A5/en not_active IP Right Cessation
- 2001-08-08 CH CH01422/03A patent/CH694241A5/en not_active IP Right Cessation
- 2001-08-08 FR FR0110586A patent/FR2812811B1/en not_active Expired - Fee Related
- 2001-08-09 DE DE20113195U patent/DE20113195U1/en not_active Ceased
- 2001-08-09 NO NO20013891A patent/NO20013891L/en not_active Application Discontinuation
- 2001-08-09 ES ES200101877A patent/ES2172481B2/en not_active Expired - Fee Related
- 2001-08-09 FI FI20010303U patent/FI5176U1/en active
- 2001-08-09 DE DE10139115A patent/DE10139115A1/en not_active Ceased
- 2001-08-10 BE BE2001/0537A patent/BE1013559A6/en not_active IP Right Cessation
- 2001-08-10 NL NL1018741A patent/NL1018741C1/en not_active IP Right Cessation
-
2003
- 2003-01-27 HR HR20030054A patent/HRP20030054A2/en not_active Application Discontinuation
- 2003-02-21 BG BG107578A patent/BG107578A/en unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1414435B1 (en) | Crystalline composition containing escitalopram | |
AU2002355624A1 (en) | Crystalline composition containing escitalopram | |
AU2001100198B4 (en) | Pharmaceutical composition containing citalopram | |
US20030109577A1 (en) | Pharmaceutical composition containing citalopram | |
US20030232881A1 (en) | Crystals of pharmaceutically acceptable salts of citalopram, methods of crystallization, and pharmaceutical compositions comprising them | |
GB2376233A (en) | Crystals of a pharmaceutically acceptable salt of citalopram wherein the median particle size of the crystals is at least 40 microns | |
ZA200300561B (en) | Pharmaceutical composition containing citalopram. | |
CA2358356A1 (en) | Pharmaceutical composition containing citalopram |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Patent lapsed |