EP1817307A2 - New pseudopolymorph of desloratadine formed with carbon dioxide - Google Patents
New pseudopolymorph of desloratadine formed with carbon dioxideInfo
- Publication number
- EP1817307A2 EP1817307A2 EP05763423A EP05763423A EP1817307A2 EP 1817307 A2 EP1817307 A2 EP 1817307A2 EP 05763423 A EP05763423 A EP 05763423A EP 05763423 A EP05763423 A EP 05763423A EP 1817307 A2 EP1817307 A2 EP 1817307A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- desloratadine
- formula
- carbon dioxide
- pseudopolymorph
- mixture
- 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.)
- Withdrawn
Links
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 title claims abstract description 119
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 title claims abstract description 98
- 229960001271 desloratadine Drugs 0.000 title claims abstract description 93
- 229910002092 carbon dioxide Inorganic materials 0.000 title claims abstract description 58
- 239000001569 carbon dioxide Substances 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 claims abstract description 46
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000004480 active ingredient Substances 0.000 claims abstract description 14
- 150000001450 anions Chemical class 0.000 claims abstract description 3
- 230000003266 anti-allergic effect Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 90
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 72
- 238000000034 method Methods 0.000 claims description 40
- 239000000203 mixture Substances 0.000 claims description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 21
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 18
- 229960003088 loratadine Drugs 0.000 claims description 14
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 11
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 10
- 229940093475 2-ethoxyethanol Drugs 0.000 claims description 10
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 9
- 238000009835 boiling Methods 0.000 claims description 8
- 238000010586 diagram Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 6
- 235000011089 carbon dioxide Nutrition 0.000 claims description 6
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 238000002329 infrared spectrum Methods 0.000 claims description 5
- 239000011976 maleic acid Substances 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 4
- 238000002441 X-ray diffraction Methods 0.000 claims description 4
- 239000012752 auxiliary agent Substances 0.000 claims description 4
- 239000001530 fumaric acid Substances 0.000 claims description 4
- 239000001117 sulphuric acid Substances 0.000 claims description 4
- 235000011149 sulphuric acid Nutrition 0.000 claims description 4
- 206010020751 Hypersensitivity Diseases 0.000 claims description 3
- 208000026935 allergic disease Diseases 0.000 claims description 3
- 230000007815 allergy Effects 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 235000019441 ethanol Nutrition 0.000 description 23
- 239000013078 crystal Substances 0.000 description 21
- 239000000725 suspension Substances 0.000 description 16
- 239000003826 tablet Substances 0.000 description 16
- 239000002585 base Substances 0.000 description 13
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 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 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 230000008030 elimination Effects 0.000 description 4
- 238000003379 elimination reaction Methods 0.000 description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000008297 liquid dosage form Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- -1 amine compounds Chemical class 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000006748 scratching Methods 0.000 description 2
- 230000002393 scratching effect Effects 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- PBIUDEUWYGBHDW-UHFFFAOYSA-N 2-chloro-1-pyridin-3-ylethanone;hydrochloride Chemical compound Cl.ClCC(=O)C1=CC=CN=C1 PBIUDEUWYGBHDW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 235000019568 aromas Nutrition 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 229940093476 ethylene glycol Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000002207 metabolite 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
- 239000012452 mother liquor Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011863 silicon-based powder Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Definitions
- the present invention relates to a new pseudopolymorph of desloratadine. More specifically, the present invention relates to a new pseudopolymorphic form of desloratadine formed with carbon dioxide of the Formula
- IV. is a known antihistamine drag, which is an active metabolite of the compound 8-chloro-6,ll-dihydro-ll-(l-ethoxy-carbonyl-4- piperilydene)-5H-benzo[5,6]cyclohepta[l .2-b]pyridine (INN name: loratadine) of the formula
- the ethoxycarbonyl group of the loratidine of the formula V is eliminated by boiling in a mixture of ethanol, water and sodium hydroxide for 24 hours.
- the product is obtained as an acetic acid salt after extraction with chloroform.
- Desloratadine acetate is converted into the free base by reacting with a base, whereupon the crude product is recrystallized from a mixture of benzene and hexane.
- ⁇ -chloro-6,11-dihydro-l 1-(1- methyl-4-piperilydene)-5H-benzo[5,6]cyclohepta[l,2- bjpyridine is demethylated by reacting with bromo cyane, whereupon the produced 1-cyano compound is hydrolysed by refiuxing for 20 hours in a mixture of concentrated hydrochloric acid and acetic acid. After removing the solvents desloratadine base is prepared from the residue by reacting with base. The crude product is purified by recrystallisation from hexane until its melting point rises to 149-151 0 C.
- Hungarian published patent application No. POO/04701 relates to salts of desloratadine with one ore two mole of acids and the preparation thereof.
- desloratadine of the formula IV is prepared by elimination of the ethoxycarbonyl group in the position 1 of the loratadine of the formula V by boiling in concentrated mineral acids, preferably in 60-80% of sulphuric acid at 12O 0 C for 6-8 hours.
- Desloratadine salts in a ratio of 1 :2 of desloratadine to acid prepared according to the Hungarian patent application No. P 00/04701 are unstable. According to our experience the stochiometry of these salts is changed during their storage because of the partly eliminated acidic compounds.
- the preparation of desloratadine salts in a molar ratio of 1 : 1 is more preferable than that of salts in a molar ratio of 1 :2.
- the essential condition for the preparation of these salts is the use of sufficently pure desloratadine base of the formula IV, which can be obtained only by appropriate purification methods after the desethoxycarbonylation reaction.
- the object of present invention is the preparation of a new desloratadine pseudopolymorph suitable for use in the preparation of high purity desloratidine base or high purity desloratine salts.
- the present invention relates to a pseudopolymorph of desloratadine formed with carbon dioxide of the formula I, characterized by its X-ray diffractogram according to diagram
- a process for the preparation of the above mentioned pseudopolymoph of desloratadine formed with carbon dioxide of the formula I which comprises a.) reacting a solution of desloratadine of the formula IV in an organic solvent with carbon dioxide or, b) decarboxyethylating loratidine of the formula V in a solution of 2-methoxyethanol or 2-ethoxyethanol with an alkali metal hydroxide, whereupon reacting the obtained desloratadine of the formula IV with carbon dioxide in an organic solvent.
- the present invention is based on the recognition, that during the reaction of desloratadine of the formula IV with carbon dioxide in an organic solvent an adduct of 2 moles of desloratadine and 1 mole of carbon dioxide of the formula I is precipitated.
- This is a new pseudopolymorphic form of desloratadine.
- the new pseudopolymorphic form formed with carbon dioxide is very pure according to HPLC examinations. Carbon dioxide forms adduct only with desloratadine, meanwhile the amine type contaminations remain in the
- mother liquor and can be easily separated from the desired adduct by filtration or centrifugation.
- the X-ray diffractogram shown in the diagram 1 of the psedopolymorph formed with carbon dioxide is absolutely different from the X-ray difractograms of the Pl and P2 polymorphs (diagram 2. and 3.) of desloratadine.
- the X-ray powder diffractograms were made using a BRUKER D8 ADVANCED X-ray powderdiffractometer under the following circumstances:
- Sample flat surface, unpulverised , stored and measured at room temperature.
- the infrared spectra of the known Pl and P2 polymorphs are made in solid phase and shown in the diagrams 5 and 6.
- the infrared spectrum of the pseudopolymorphs of desloratadine formed with carbon dioxide according to the diagaram 4 has significant differences as compared with infrared spectra of polymorphs Pl and P2.
- the pseudopolymorph does not deliver carbon dioxide upto a temperature of 12O 0 C and according to X-ray crystallographical experiments its crystal structure remains unchanged. Decomposition begins near its melting point, at 14O 0 C, where the compound of the formula I delivers calculated amount of carbon dioxide.
- the reaction is carried out in a solution formed with an ester, ether, or in a mixture of an ester and a lower aliphatic alcohol or in a mixture of an ether and a lower aliphatic alcohol.
- the reaction is carried out in ethyl acetate, tetrahydrofurane, diethyl ether, preferably a mixture of ethyl acetate and methanol, a mixture of ethyl acetate and ethanol, a mixture of tetrahydrofurane and methanol, a mixture of diethyether and ethanol, or a mixture of diethyether and methanol. More preferably it is carried out in a media containing ethyl acetate.
- the process can be carried out by introducing gaseous carbon dioxide or by addition of dry ice to a solution of desloratadine formed with an organic solvent.
- the reaction of desloratadine of the formula IV and carbon dioxide is accomplished between room temperature and 40 0 C, preferably at room temperature.
- the pseudopolymorph of the formula I can be isolated by filtration or centrifugation.
- the product is very pure, additional purification is unnecessary.
- loratadine of the formula V is decarboxyethylated with alkali metal hydroxide in a solution of 2-methoxyethanol or 2-ethoxyethanol, the desloratadine of the formula IV obtained is dissolved in an organic solvent and reacted with carbon dioxide.
- alkali metal hydroxide sodium hydroxide or potassium hydroxide can be used.
- the reaction can be carried out under heating, preferably at the boiling point of the solvent. On completion of the reaction 2-methoxyethanol or 2- ethoxyethanol is evaporated, the residue is dissolved in an organic solvent.
- the solvents enumerated according to the process a), preferably ethyl acetate can be used as organic solvents.
- the solution is reacted similarly to the process a) with carbon dioxide.
- process b) after elimination of the ester group the 2-methoxyethanol or 2- ethoxyethanol solvent is evaporated, the residue is dissolved in ethyl acetate, carbon dioxide is introduced or dry ice is added to the obtained solution and the pseudopolymorph of the formula I is separated by filtration or centrifugation.
- alkali metal hydroxide sodium hydroxide or potassium hydroxide can be used.
- the reaction can be carried out under heating, preferably at the boiling point of the solvent.
- the reaction time is short and it takes 1-3 hours.
- 2-methoxyethanol or 2- ethoxyethanol is removed, the residue obtained is dissolved in an organic solvent, preferably in ethyl acetate. After evaporation of the organic solvent desloratadine base is obtained.
- Vl wherein X stands for an anion and n is 1 or 2, which comprises reacting the solution of a pseudopolymorph salt of desloratadine formed with carbon dioxide of the formula I in an organic solvent with a solution of the corresponding acid formed with an organic solvent.
- hydrochloric acid hydrobromic acid
- sulfuric acid methanesulfonic acid
- benezenesulfonic acid maleic acid or fumaric acid
- maleic acid or fumaric acid can be used as acid.
- the acid is used in an approximately equimolecular amount, based on the pseudopolymorph of the formula I.
- the acid is used in at least a molar ratio of 2:1, preferably between 2 : 1 -3 : 1 , based on pseudopolymorph of the formula I.
- Esters e.g. ethyl acetate or alcohols e.g. methanol or ethanol can be used as solvent.
- reaction of the compound of the formula I with the acid is carried out between room temperature and 40 0 C, preferably at room temperature.
- a significant advantage of the present invention is that desloratadine of the formula IV or desloratadine salts of the formula VI can be prepared in high purity. This is due to the general fact that the pseudopolymorph of desloratadine formed with carbon dioxide of the formula I can be prepared in a high purity which is suitable for pharmaceutical use without further purification.
- the preparation of the adduct of the formula I is a more effective purification than a recrystallisation step. This is so because during the elimination of carbethoxy group in course of the preparation of desloratadine from loratadine small amounts of basic by-products are produced which do not form adducts with carbon dioxide and, therefore remain in the mother-lye after filtration of the adduct of the formula I.
- compositions comprising as active ingredient a pseudopolymorph of desloratadine of the Formula I in admixture with inert pharmaceutically acceptable carriers and/or auxiliary agents.
- compositions according to the present invention can be prepared in conventional forms in therapy.
- compositions according to the present invention can be preferably administered orally or parenterally.
- the oral compositions can be e.g. tablets, capsules, coated tablets, solutions, syrups, suspensions or emulsions.
- the parenteral compositions can be preferably intravenous or intramuscular administered injections.
- the pharmaceutical compositions can contain usual pharmaceutically acceptable carriers and/or auxiliary agents.
- pharmaceutically acceptable carrier for example magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextose, starch, gelatine, tragakant, methyl cellulose, sodium carboxymethylcellulose, wax with low melting point, cocoa butter etc. can be used.
- capsules carrier is often serves as capsule material, whereby additional carrier is not necessary.
- Further oral dosage forms are sachets and homge.
- the tablets, powders, capsules, pellets, sachets and homges are specially useful as solid dosage forms.
- Waxes with low melting point can be used as carriers for suppositories.
- the wax is melted, the active ingredient is admixed with the melt and homogenized.
- the melted, homogenized mixture is then poured into mould and allowed to cool and solidify.
- Tablets can be prepared by admixing the active ingredient with suitable carriers in an appropriate ratio and pressing the mixture into tablets of a desired form and size.
- Powders are prepared by admixing the finely powdered active ingredient with finely powdered carriers.
- Liquid dosage forms can be solutions, suspensions and emulsions, from which the active ingredient can be release in a sustained relaese if desired.
- Solutions formed with water or a mixture of water and propyleneglycol are preferable.
- Liquid dosage forms suitable for parenteral administration are prepared preferably in a mixture of water and ethyleneglycol.
- Aqueous liquid dosage forms suitable for oral administration can be prepared by dissolving the active ingredient in water, whereupon suitable colourants aroma, stabilisers and thickeners are added, depending on the requirements of use.
- Aqueous suspensions suitable for oral administration can be prepared by suspending the active ingredient in water in the presence of a compound having high viscosity e.g. natural or synthetic gums, resins, methyl cellulose, carboxymethylcellulose sodium or other known suspending agents.
- a compound having high viscosity e.g. natural or synthetic gums, resins, methyl cellulose, carboxymethylcellulose sodium or other known suspending agents.
- liquid dosage form An other group of solid dosage forms is transformed into a liquid dosage form immediately before use and which is administered as an oral liquid composition.
- the liquid forms can be solutions, emulsions or suspensions, comprising in addition to the active ingredient colourants, aromas, stabilisers,
- buffers natural or synthetic sweeteners, dispersing agents, thickeners etc.
- the pharmaceutical compositions according to the present invention can be prepared as unit dosage forms.
- the unit dosage forms contain the desirable amount of the active ingredient. These can be marketed as packages, comprising separated amounts of the dosage forms (e.g. packed tablets, capsules, powder in ampoules or bottles).
- the unit dosage form may be capsule, tablet, sachet, losenge and also package containing the appropriate number of unit dosages.
- compositions according to the present invention can be prepared by admixing the pseudopolymorph of desloratadine of the formula I with inert pharmaceutically acceptable earners and/or auxliary agents.
- compositions according to the present invention can be prepared by using conventional processes of the pharmaceutical industry.
- a process for the treatment of allergy which comprises administering the pseudopolymorph of the desloratadine of the formula I to a patient in need of said treatment.
- the white crystalline suspension is cooled to 5 0 C whereupon the mixture is stirred for an additional hour, filtered, the crystals are washed with ethyl acetate and dried at 60 0 C.
- a mixture of 100 ml of 2-methoxyethanol (methylcellosolve) 10 ml of an aqueous 40% sodium hydroxide solution, 2.5 g of sodium hydroxide and 12.5 g (32.65 moles) of loratadine are weighed in a vessel equipped with vigorous stirrer. The mixture is boiled for three hours. The end of the reaction is monitored with TLC.
- the base content of the pale yellow solution is determined, whereupon a solution of an equimolecular amount of hydrogen bromide in ethyl acetate is added.
- the white crystalline product is filtered at 0 0 C, washed with ethanol.
- the suspension is stirred for 3 hours, cooled to 0 0 C, filtered under cooling and washed with ethanol.
- hydrochloric acid is replaced by a solution of 4.05 g (50 mmoles) of hydrogen bromide in ethanol.
- the suspension is stirred for 3 hours, cooled to 0 0 C 5 filtered under cooling and washed with ethanol.
- salt formation is carried out by using a solution of 1.96 g (20mmoles) of sulphuric acid in ethanol at 20-25 0 C. The suspension is stirred for 3 hours, cooled to 0 0 C. filtered under cooling and washed with ethanol.
- salt formation is carried out by using a solution of 2.02 g (21 mmoles) of methanesulphonic acid in ethanol at 20-25 0 C. The suspension is stirred for 3 hours, cooled to 0 0 C 5 filtered under cooling and washed with ethanol.
- salt formation is carried out by using a solution of 3.34 g (21 mmoles) of benzenesulphonic acid in ethanol at 20-25 0 C. The suspension is stirred for two hours, cooled to 0 0 C, filtered under cooling and washed with ethanol.
- the product is crystallised under cooling and scratching.
- the suspension is stirred for two hours at 0 0 C, filtered and washed with ethanol.
- the mixture is homogenized and pressed to tablets.
- the mixture is homogenized and pressed to tablet.
- the mixture is homogenized and pressed to tablet.
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Abstract
The pseudopolymorph of desloratadine formed with carbon dioxide of the formula (I) has valuable anti-allergic effect and can be used as pharmaceutical active ingredient. The present invention also relates to the preparation of desloratadine of high purity. The present invention also relates to the use of the pseudopolymorph of desloratadine of the formula (I) for the preparation of salts of desloratadine of the formula (VI) (wherein X stands for an anion and n is 1 or 2).
Description
New pseudopolymorph of desloratadine formed with carbon dioxide
FIELD OF THE INVENTION
The present invention relates to a new pseudopolymorph of desloratadine. More specifically, the present invention relates to a new pseudopolymorphic form of desloratadine formed with carbon dioxide of the Formula
TECHNICAL BACKGROUND OF THE INVENTION
8-chloro-6,l 1-dihydro-l l-(4-piperilydene)-5H- benzo[5,6]cyclohepta[1.2-b]pyridine (INN name: desloratadine) of the formula
IV. is a known antihistamine drag, which is an active metabolite of the compound 8-chloro-6,ll-dihydro-ll-(l-ethoxy-carbonyl-4- piperilydene)-5H-benzo[5,6]cyclohepta[l .2-b]pyridine (INN name: loratadine) of the formula
V.
In case of oral use of desloratadine the anti-allergic effect is 3 or 4 times higher than the effect of loratadine and the duration of the effect is almost 24 hours which is advantageous in case of once a daily use [Arzneim. Forch. Drag. Res. 40(1), Nr. 4: 345 (2000)].
Two processes are known for preparation of desloratadine of formula IV according to Hungarian patent description No. 194864.
According to one of these processes the ethoxycarbonyl group of the loratidine of the formula V is eliminated by boiling in a mixture of ethanol, water and sodium hydroxide for 24 hours. The product is obtained as an acetic acid salt after extraction with chloroform. Desloratadine acetate is converted into the free base by reacting with a base, whereupon the crude product is recrystallized from a mixture of benzene and hexane.
According to the other process δ-chloro-6,11-dihydro-l 1-(1- methyl-4-piperilydene)-5H-benzo[5,6]cyclohepta[l,2- bjpyridine is demethylated by reacting with bromo cyane, whereupon the produced 1-cyano compound is hydrolysed by refiuxing for 20 hours in a mixture of concentrated hydrochloric acid and acetic acid. After removing the solvents desloratadine base is prepared from the residue by reacting with base. The crude product is purified by recrystallisation from hexane until its melting point rises to 149-1510C.
Salts of desloratadine formed with hidrochloric acid, methanesulfonic acid, sulphuric acid, acetic acid, maleic acid,
fumaric acid and phosphoric acide are mentioned in the Hungarian patent specification No. 198964.
Hungarian published patent application No. POO/04701 relates to salts of desloratadine with one ore two mole of acids and the preparation thereof. According to the published patent application desloratadine of the formula IV is prepared by elimination of the ethoxycarbonyl group in the position 1 of the loratadine of the formula V by boiling in concentrated mineral acids, preferably in 60-80% of sulphuric acid at 12O0C for 6-8 hours. Salts of desloratadine with two moles of the acid according to the general formula
can be isolated directly from the reaction mixture. Salts of desloratadine formed with one mole acid according to the general formula
are prepared by reacting desloratadine base of the formula IV with the corresponding acid in a media containing dichloromethane.
Two polymorphs of desloratadine hemifumarate are described in international PCT patent application No. 2004/012738. The difference between the melting points of these polymorphs are some degrees of Celsius.
The processes for the preparation of desloratadine of the formula IV described above have several disadvantages.
According to the process described in the Hungarian patent No. 194 864 hydrolysis of the ethoxycarbonyl group of loratadine is carried out by boiling in an aqueous base for a very long time. Remarkable degradation and formation of colourful side products takes place during the 24 hours reaction time. The colour of the crude product is unacceptable for pharmaceutical use. The crude product has to be
recrystallised few times to obtain an acceptable product. The recrystallisation is carried out from a mixture of benzene and hexane according to Hungarian patent No. 194 864. The use of carcinogenic benzene and the big loss of recrystallisation are very disadvantegoues on industrial scale.
According to the other process described in the Hungarian patent description No. 194 864 the elimination of the methyl group of the compound of 8-chloro-6,l l-dihydro-l l-(l- methyl-4-piperilydene)-5H-benzo[5,6]cyclohepta[l,2- b]pyridine is carried out by reacting with bromo cyane, the 1- cyano compound obtained is hydrolysed and decarboxylated in one step by refluxing for 20 hours in a mixture of concentrated hidrochloric acid and acetic acid. Bromo cyane is an extremely toxic compound which is undesirable on industrial scale and its use requires special safety measures.
Desloratadine salts in a ratio of 1 :2 of desloratadine to acid prepared according to the Hungarian patent application No. P 00/04701 are unstable. According to our experience the stochiometry of these salts is changed during their storage because of the partly eliminated acidic compounds.
The disadvantage of the preparation of these compounds is that the amine compounds are produced under the extreme reaction
conditions used to form salts with an excess of the corresponding acid and the obtained salts crystallise together with the desired product.
The preparation of desloratadine salts in a molar ratio of 1 : 1 is more preferable than that of salts in a molar ratio of 1 :2. The essential condition for the preparation of these salts is the use of sufficently pure desloratadine base of the formula IV, which can be obtained only by appropriate purification methods after the desethoxycarbonylation reaction.
The object of present invention is the preparation of a new desloratadine pseudopolymorph suitable for use in the preparation of high purity desloratidine base or high purity desloratine salts.
The shown object described above is solved with the present invention.
SUMMARY OF THE INVENTION
The present invention relates to a pseudopolymorph of desloratadine formed with carbon dioxide of the formula I, characterized by its X-ray diffractogram according to diagram
1, IR spectrum according to diagram 4 and X-ray diffraction data as follows:
X-ray diffraction peaks and their relative intensities (>5%) of the X-ray diffractogram of the Desloratadine 1/2 CO2
According to a further aspect of the present invention there is provided a process for the preparation of the above mentioned pseudopolymoph of desloratadine formed with carbon dioxide of the formula I which comprises a.) reacting a solution of desloratadine of the formula IV in an organic solvent with carbon dioxide or, b) decarboxyethylating loratidine of the formula V in a solution of 2-methoxyethanol or 2-ethoxyethanol with an alkali metal hydroxide, whereupon reacting the obtained desloratadine of the formula IV with carbon dioxide in an organic solvent.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is based on the recognition, that during the reaction of desloratadine of the formula IV with carbon dioxide in an organic solvent an adduct of 2 moles of desloratadine and 1 mole of carbon dioxide of the formula I is precipitated. This is a new pseudopolymorphic form of desloratadine. The new pseudopolymorphic form formed with carbon dioxide is very pure according to HPLC examinations. Carbon dioxide forms adduct only with desloratadine, meanwhile the amine type contaminations remain in the
mother liquor and can be easily separated from the desired adduct by filtration or centrifugation.
The formation of the compound of the formula I is so much the more surprising, as only few adducts are known from prior art and even in such cases the amines used have a much smaller molecular weight.
The X-ray diffractograms of polymorphs Pl and P2 are shown in the diagrams 2. and 3.
The X-ray diffractogram shown in the diagram 1 of the psedopolymorph formed with carbon dioxide is absolutely different from the X-ray difractograms of the Pl and P2 polymorphs (diagram 2. and 3.) of desloratadine.
The X-ray powder diffractograms were made using a BRUKER D8 ADVANCED X-ray powderdiffractometer under the following circumstances:
Equipment : BRUKER D8 ADVANCED
Radiation: CuKa1 (λ=l.54060 ), CuKa2 (λ= 1.54439 )
Voltage: 40 kV Zero-signal current: 30 mA Accessories: Gδdel mirror
Soller slot
Used standard reference: SRM 640c Silicon Powder LOT.NO. H-375. Continuous measurement Θ/Θ scan: 5-35.00° 2Θ Step scale: 0.04°
Sample: flat surface, unpulverised , stored and measured at room temperature.
The infrared spectra of the known Pl and P2 polymorphs are made in solid phase and shown in the diagrams 5 and 6. The infrared spectrum of the pseudopolymorphs of desloratadine formed with carbon dioxide according to the diagaram 4 has significant differences as compared with infrared spectra of polymorphs Pl and P2. According to thermo-gravirnetric measurements (DTG, DSC) the pseudopolymorph does not deliver carbon dioxide upto a temperature of 12O0C and according to X-ray crystallographical experiments its crystal structure remains unchanged. Decomposition begins near its melting point, at 14O0C, where the compound of the formula I delivers calculated amount of carbon dioxide.
According to process a) for the preparation of the pseudopolymorph of desloratadine formed with carbon dioxide the desloratadine of the formula IY is reacted with carbon dioxide in an organic solvent.
The reaction is carried out in a solution formed with an ester, ether, or in a mixture of an ester and a lower aliphatic alcohol or in a mixture of an ether and a lower aliphatic alcohol. The reaction is carried out in ethyl acetate, tetrahydrofurane, diethyl ether, preferably a mixture of ethyl acetate and methanol, a mixture of ethyl acetate and ethanol, a mixture of tetrahydrofurane and methanol, a mixture of diethyether and ethanol, or a mixture of diethyether and methanol. More preferably it is carried out in a media containing ethyl acetate. The process can be carried out by introducing gaseous carbon dioxide or by addition of dry ice to a solution of desloratadine formed with an organic solvent.
The reaction of desloratadine of the formula IV and carbon dioxide is accomplished between room temperature and 400C, preferably at room temperature.
The pseudopolymorph of the formula I can be isolated by filtration or centrifugation. The product is very pure, additional purification is unnecessary.
According to the process b) for the preparation of the pseudopolymorph of the formula I loratadine of the formula V is decarboxyethylated with alkali metal hydroxide in a solution of 2-methoxyethanol or 2-ethoxyethanol, the
desloratadine of the formula IV obtained is dissolved in an organic solvent and reacted with carbon dioxide. As alkali metal hydroxide sodium hydroxide or potassium hydroxide can be used. The reaction can be carried out under heating, preferably at the boiling point of the solvent. On completion of the reaction 2-methoxyethanol or 2- ethoxyethanol is evaporated, the residue is dissolved in an organic solvent.
The solvents enumerated according to the process a), preferably ethyl acetate can be used as organic solvents. The solution is reacted similarly to the process a) with carbon dioxide.
According to a preferable embodiment of process b) after elimination of the ester group the 2-methoxyethanol or 2- ethoxyethanol solvent is evaporated, the residue is dissolved in ethyl acetate, carbon dioxide is introduced or dry ice is added to the obtained solution and the pseudopolymorph of the formula I is separated by filtration or centrifugation.
According to a further aspect of present invention there is provided a process for the preparation of high purity "desloratadine of the formula IV by decarbbxyethylatϊon of loratadine of the formula V with alkali metal hydroxide
characterized in that the reaction is carried out in 2- methoxyethanol or 2-ethoxyethanol.
As alkali metal hydroxide sodium hydroxide or potassium hydroxide can be used. The reaction can be carried out under heating, preferably at the boiling point of the solvent. The reaction time is short and it takes 1-3 hours. After the completion of the reaction 2-methoxyethanol or 2- ethoxyethanol is removed, the residue obtained is dissolved in an organic solvent, preferably in ethyl acetate. After evaporation of the organic solvent desloratadine base is obtained.
According to a further aspect of present invention there is provided a process for the preparation of desloratadine salts of the formula
Vl.
wherein X stands for an anion and n is 1 or 2, which comprises reacting the solution of a pseudopolymorph salt of desloratadine formed with carbon dioxide of the formula I in an organic solvent with a solution of the corresponding acid formed with an organic solvent.
Thus, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, benezenesulfonic acid, maleic acid or fumaric acid can be used as acid.
According to an embodiment of the process described above for the preparation of compounds of the general formula VI, wherein n — 1 , the acid is used in an approximately equimolecular amount, based on the pseudopolymorph of the formula I.
According to an other embodiment of the process described above for the preparation of compounds of the general formula VI, wherein n = 2, the acid is used in at least a molar ratio of 2:1, preferably between 2 : 1 -3 : 1 , based on pseudopolymorph of the formula I.
Esters, e.g. ethyl acetate or alcohols e.g. methanol or ethanol can be used as solvent.
The reaction of the compound of the formula I with the acid is carried out between room temperature and 40 0C, preferably at room temperature.
According to the process described above salts of the formula VI are obtained in high purity.
A significant advantage of the present invention is that desloratadine of the formula IV or desloratadine salts of the formula VI can be prepared in high purity. This is due to the general fact that the pseudopolymorph of desloratadine formed with carbon dioxide of the formula I can be prepared in a high purity which is suitable for pharmaceutical use without further purification.
The preparation of the adduct of the formula I is a more effective purification than a recrystallisation step. This is so because during the elimination of carbethoxy group in course of the preparation of desloratadine from loratadine small amounts of basic by-products are produced which do not form adducts with carbon dioxide and, therefore remain in the mother-lye after filtration of the adduct of the formula I.
Thus, desloratadine easily can be removed from the amine type impurities.
According to a further aspect of our invention there are provided pharmaceutical compositions comprising as active ingredient a pseudopolymorph of desloratadine of the Formula I in admixture with inert pharmaceutically acceptable carriers and/or auxiliary agents.
The pharmaceutical compositions according to the present invention can be prepared in conventional forms in therapy.
The compositions according to the present invention can be preferably administered orally or parenterally.
The oral compositions can be e.g. tablets, capsules, coated tablets, solutions, syrups, suspensions or emulsions. The parenteral compositions can be preferably intravenous or intramuscular administered injections.
The pharmaceutical compositions can contain usual pharmaceutically acceptable carriers and/or auxiliary agents. As pharmaceutically acceptable carrier for example magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextose, starch, gelatine, tragakant, methyl cellulose, sodium carboxymethylcellulose, wax with low melting point, cocoa butter etc. can be used.
In case of the capsules carrier is often serves as capsule material, whereby additional carrier is not necessary.
Further oral dosage forms are sachets and losenge. The tablets, powders, capsules, pellets, sachets and losenges are specially useful as solid dosage forms.
Waxes with low melting point (for example a mixture of fatty acid glycerides or cocoa butter) can be used as carriers for suppositories. The wax is melted, the active ingredient is admixed with the melt and homogenized. The melted, homogenized mixture is then poured into mould and allowed to cool and solidify.
Tablets can be prepared by admixing the active ingredient with suitable carriers in an appropriate ratio and pressing the mixture into tablets of a desired form and size.
Powders are prepared by admixing the finely powdered active ingredient with finely powdered carriers.
Liquid dosage forms can be solutions, suspensions and emulsions, from which the active ingredient can be release in a sustained relaese if desired.
Solutions formed with water or a mixture of water and propyleneglycol are preferable.
Liquid dosage forms suitable for parenteral administration are prepared preferably in a mixture of water and ethyleneglycol.
Aqueous liquid dosage forms suitable for oral administration can be prepared by dissolving the active ingredient in water, whereupon suitable colourants aroma, stabilisers and thickeners are added, depending on the requirements of use.
Aqueous suspensions suitable for oral administration can be prepared by suspending the active ingredient in water in the presence of a compound having high viscosity e.g. natural or synthetic gums, resins, methyl cellulose, carboxymethylcellulose sodium or other known suspending agents.
An other group of solid dosage forms is transformed into a liquid dosage form immediately before use and which is administered as an oral liquid composition. The liquid forms can be solutions, emulsions or suspensions, comprising in addition to the active ingredient colourants, aromas, stabilisers,
buffers, natural or synthetic sweeteners, dispersing agents, thickeners etc.
The pharmaceutical compositions according to the present invention can be prepared as unit dosage forms. The unit dosage forms contain the desirable amount of the active ingredient. These can be marketed as packages, comprising separated amounts of the dosage forms (e.g. packed tablets, capsules, powder in ampoules or bottles). The unit dosage form may be capsule, tablet, sachet, losenge and also package containing the appropriate number of unit dosages.
The pharmaceutical compositions according to the present invention can be prepared by admixing the pseudopolymorph of desloratadine of the formula I with inert pharmaceutically acceptable earners and/or auxliary agents.
The pharmaceutical compositions according to the present invention can be prepared by using conventional processes of the pharmaceutical industry.
According to the further aspect of the present invention there is provided the pseudopolymorph of desloratadine of the formula I for use as pharmaceutical active ingredient.
According to a still further aspect of present invention there is provided the use of the pseudopolymorph of desloratadine of the formula I in a pharmaceutically effective amount for the treatment of allergy.
According to a still further aspect of present invention there is provided a process for the treatment of allergy which comprises administering the pseudopolymorph of the desloratadine of the formula I to a patient in need of said treatment.
Further details of the present invention are to be found in the following Examples without limiting the scope of protection to said Examples.
Example 1. Desloratadine base
100 ml of 2-methoxyethanol (methylcellosolve), 10 ml of an aqueous 40% sodium hydroxide solution, 2.5 g of sodium hydroxide and 12.5 g (32.65 moles) of loratadine are weighed in a vessel equipped with an intensive stirrer. The mixture is boiled for three hours. The end of the reaction is monitored with TLC. Preparation:
90 ml 2-methoxyethanol are distilled off from the reaction mixture, whereupon 100 ml of icecold water and 100 ml of ethyl acetate are added to the residue. After the separation the organic layer is dried, the solvent is evaporated and the residue is crystallised from a mixture of hexane : ethyl acetate in a ratio of 10:1.
Yield: 9.28 g (91.5% ) almost white crystals Mp.: 149-151 0C. Elementary analysis: C19Hi9ClN2 (310.8)
Calculated: C:73.42 H:6.16 Cl:11.41 N:9.01
Found: C:73.38 H:6.22 Cl: 11.44 N:9.04
HPLC purity: 99.1 % .
Example 2
Preparation of pseudopolymorph of desloratadine with half mole of carbon dioxide
One proceeds as in example 1 except that the solution of desloratine formed with ethyl acetate obtained by the preparation of the base is saturated with carbon dioxide by introducing carbon dioxide gas into the solution instead of evaporation. The separated crystals are filtered in the cold and washed with ethyl acetate.
Yield: 10.1 g (92.8 %) white crystals.
Mp.: 144-148 0C (slowly decomposes above 100 0C)
Analysis: C19H19ClN2 x 1Z2 CO2 (332.87)
Calculated: C:70.71 H:5.79 Cl:10.62 N:8.41
Found: C:71.10 H:5.56 Cl:10.71 N:8.53
HPLC purity: 99.88 %.
Example 3
Preparation of pseudopolymorph of desloratadine with half moles of carbon dioxide
100 ml of 2-methoxyethanol (methylcellosolve), 12 ml of an aqueous 50% sodium hydroxide solution and 12.5 g of loratadine are weighed in a vessel equipped with vigorous stirrer. The mixture is boiled for two hours. The end of the reaction is monitored with TLC. Preparation:
90 ml 2-methoxyethanol are distilled off from the reaction mixture, whereupon 100 ml of icecold water and 100 ml of ethyl acetate are added to the residue. After the separation of the layers the organic layer is clarified, dried, and 5.O g dry ice are added to the pale yellow solution in small parts during half hours. The crystals precipitate and the cold solution is filtered, the crystals obtained washed with ethyl acetate.
Yield: 9.61 g (88.4 %) almost white crystals. Analysis: C19H19ClN2X 1/2CO2 (332.87)
Mp.: 144-148 0C (slowly dec. above 100 0C) Calculated: C:70.71 H:5.79 Cl: 10.62 N:8.41
Found: C:70.01 H:5.86 Cl:10.51 N:8.38
HPLC purity: 99.7 % .
Example 4
Preparation of pseudopolymorph of desloratadine with half mole of carbon dioxide from the base
500 ml of ethyl acetate are placed in a vessel equipped vigorous stirrer, then a solution of 29.0 g ( 0.93 moles) of desloratadine in 120 ml of ethanol is added dropwise during an hour. During the addition and the crystallisation steps carbon dioxide developped from 20.0 g of dry ice is introduced continuously into the suspension.
Preparation:
During the carbon dioxide introduction the white crystalline suspension is cooled to 5 0C whereupon the mixture is stirred for an additional hour, filtered, the crystals are washed with ethyl acetate and dried at 60 0C.
Yield: 28.42 g (92.5 %) white crystals.
Mp.: 144-148 0C (slowly decomposes above 100 0C) Analysis: for the formula Of C19H19ClN2X 1/2 CO2 (332.87) Calculated: C:70.71 H:5.79 Cl: 10.62 N:8.41
Found: C:71.18 H:5.86 Cl:10.66 N:8.46
HPLC purity: 99.84 % , total contaminations 0.16% (6 impurities).
Example 5
Preparation of desloratadine hydrobromide (1:1)
A mixture of 100 ml of 2-methoxyethanol (methylcellosolve) 10 ml of an aqueous 40% sodium hydroxide solution, 2.5 g of sodium hydroxide and 12.5 g (32.65 moles) of loratadine are weighed in a vessel equipped with vigorous stirrer. The mixture is boiled for three hours. The end of the reaction is monitored with TLC.
Preparation:
90 ml 2-methoxyethanol is distilled off from the reaction mixture under reduced pressure, whereupon 100 ml of the icecold water and 100 ml of ethyl acetate are added to the residue. After the separation of layers the product is extracted from the organic layer with a mixture of 5 ml of concentrated hydrochloric acid and 100 ml of icecold water. The aqueous
layer is clarified with activated carbon then filtered. Desloratadine base is set free with 5 ml of a 40% sodium hydroxide solution, extracted with 120 ml of ethyl acetate and dried. The base content of the pale yellow solution is determined, whereupon a solution of an equimolecular amount of hydrogen bromide in ethyl acetate is added. The white crystalline product is filtered at 0 0C, washed with ethanol.
Yield: 7.33 g (93.6 %) white crystals. Mp.: 268-272 0C (transformed at 198-200 0C ) Analysis for the formula C19H19ClN2 * HBr (391.74) Calculated: C:58.26 H:5.15 Br:20.40 Cl:9.05 N:7.15 Found: 58.08 H:5.17 Br:20.45 Cl:9.05 N:7.14
HPLC purity >99.7 %
Example 6
Preparation of desloratadine hydrobromide (1:1) from the carbon dioxide pseudopolymorph of desloratadine formed with half mole of carbon dioxide
To a suspension of 7.1 g (20 mmoles) of the carbon dioxide adduct of desloratadine prepared according to example 2 in 100 ml ethyl acetate a solution at 1.61 g (20 mmoles) of hydrogen bromide in ethyl acetate is added at 20-25 0C within
10 minutes. The suspension is stirred for 2-3 hours until the gas evolution is finished, then cooled to 0 0C and filtered. The crystals are washed with ethanol.
Yield: 7.52 g (93.6 %) white crystals.
Mp.: 268-272 0C (transforms at 198-200 0C)
Analysis: for the formula of C19H19ClN2 * HBr (391.74) Calculated: C:58.26 H:5.15 Br:20.40 Cl:9.05 N:7.15 Found: C:58.18 H:5.19 Br:20.55 Cl:9.15 N:7.19 HPLC purity >99.7 %
Example 7
Preparation of desloratadine hydrochloride (1:1) from the carbon dioxide pseudopolymorph of desloratadine formed with half mole of carbon dioxide
To a suspension of 7.1 g (20 mmoles) of the carbon dioxide adduct of desloratadine prepared according to example 2 in 100 ml ethyl acetate a solution of 0.73 g (20 mmoles) of hydrogen chloride in ethyl acetate at 20-25 0C within 10 minutes. The suspension is stirred for 3 hours until the gas evolution is finished, then cooled to 0 0C, filtered, and the crystals are washed with ethanol. Yield: 6.61 g (95.2 %) white crystals.
Mp.: 261-263 0C
Analysis: for the formula Of C19Hi9ClN2 * HCl (347.29) Calculated: C:65.71 H:5.80 Cl:20.42 N:8.07
Found: C:65.39 H:5.75 Cl:20.26 N:8.02
HPLC purity >99.8 %
Example 8
Preparation of desloratadine dihydrochloride (1:2) from the carbon dioxide pseudopolymorph of desloratadine formed with half mole of carbon dioxide
One proceeds according to example 6 is repeated except that ethyl acetate is replaced with ethanol and a solution of 1.82 g
(50 mmoles) of hydrochloric acid in ethanol is added at 20-25
0C.
The suspension is stirred for 3 hours, cooled to 0 0C, filtered under cooling and washed with ethanol.
Yield: 7.40 g (96.4 %) white crystals.
Mp.: 218-22O 0C
Example 9
Preparation of desloratadine dihydrobromide (1:2) from the carbon dioxide pseudopolymorph of desloratadine formed with half mole of carbon dioxide
One proceeds according to the example 7 except that hydrochloric acid is replaced by a solution of 4.05 g (50 mmoles) of hydrogen bromide in ethanol. The suspension is stirred for 3 hours, cooled to 0 0C5 filtered under cooling and washed with ethanol.
Yield: 8.61 g (91.2 %) white crystals. Mp.: 247-250 0C
Example 10
Preparation of desloratadine hemisulphate (1:1) from the carbon dioxide pseudopolymorph of desloratadine formed with half mole of carbon dioxide
One proceeds according to example 7 except that salt formation is carried out by using a solution of 1.96 g (20mmoles) of sulphuric acid in ethanol at 20-25 0C. The suspension is stirred for 3 hours, cooled to 0 0C. filtered under cooling and washed with ethanol.
Yield: 7.88 g (96.4 %)white crystals. Mp.: 281-283 0C
Example 11
Preparation of desloratadine methanesulphonate (1:1) from the carbon dioxide pseudopolymorph of desloratadine formed with half mole of carbon dioxide
One proceeds according to example 9 except that salt formation is carried out by using a solution of 2.02 g (21 mmoles) of methanesulphonic acid in ethanol at 20-25 0C. The suspension is stirred for 3 hours, cooled to 0 0C5 filtered under cooling and washed with ethanol.
Yield: 7.02 g (86.5 %) white crystals. Mp.: 255-257 0C
Example 12
Preparation of desloratadine besylate
One proceeds according to example 3 except that salt formation is carried out by using a solution of 3.34 g (21 mmoles) of benzenesulphonic acid in ethanol at 20-25 0C. The suspension is stirred for two hours, cooled to 0 0C, filtered under cooling and washed with ethanol.
Yield: 8.39 g (89.5 %) white crystals. Mp.: 223-225 0C
Example 13
Preparation of desloratadine fumarate (1:1)
To a solution of 3.55 g (10 mmoles) of the compound of the formula I (Example 3) in 25 ml of ethanol 1.16 g (10 mmoles) of fumaric acide are added, whereupon the solution is heated to boiling for 5 minutes meanwhile i.e. until the fumaric acid is dissolved.
The product is crystallised under cooling and scratching. The suspension is stirred for two hours at 0 0C, filtered and washed with ethanol.
Yield: 3.91 g (91.5 %) white crystals.
Mp.: 185-187 0C
Example 14
Preparation of desloratadine maleate (1:1)
To a solution of 3.55 g (10 mmoles) of the compound of the formula I (Example 3) in 25 ml of ethanol 1.16 g (10 mmoles) of maleic acid are added, whereupon the solution is heated to boiling for 5 minutes i.e. until the maleic acid is dissolved. The product is crystallised by cooling and scratching. The suspension is stirred for two hours at 0 0C, filtered and washed with ethanol.
Yield: 3.74 g (87.6 %) white crystals. Mp.: 181-184 0C
Example 15 Pharmaceutical composition
For the preparation of tablets (100 mg) the following ingredients are weighed in (for 1 tablet):
Desloratadine pseudopolymorph of the formula I 5.0 mg
(prepared according to example 4) Lactose 47.0 mg
Corn starch 47.0 mg
Magnesium stearate 1.0 mg
The mixture is homogenized and pressed to tablets.
Example 16 Pharmaceutical composition
For the preparation of tablets (100 mg) the following ingredients are weighed in (for 1 tablet):
Desloratadine pseudopolymorph of the formula I 5.0 mg
(prepared according to example 3)
Lactose 30 mg
Corn starch 64 .O mg
Magnesium stearate 1 •O mg
The mixture is homogenized and pressed to tablet.
Example 17 Pharmaceutical composition
For the preparation of tablets (100 mg) the following ingredients are weighed in (for 1 tablet): Desloratadine pseudopolymorph of the formula I 5.0 mg
(prepared according to example 4) Lactose 70 mg
Corn starch 24.0 mg
Magnesium stearate 1.0 mg
The mixture is homogenized and pressed to tablet.
Claims
1. Pseudopolymorph of desloratadine formed with carbon dioxide of the formula
I. characterized by its X-ray diffractogram according to diagram 1, IR spectrum according to diagram 4 and X-ray diffraction data as follows:
X-ray diffraction peaks and their relative intensities (>5%) of the X-ray diffractogram of the Desloratadine 1/2 CO2
2. Process for the preparation of pseudopolymorph of desloratadine formed with carbon dioxide of the formula I according to claim 1 which comprises
a.) reacting a solution of desloratadine of the formula
IV. in an organic solvent with carbon dioxide, or b.) decarbethoxylating loratadine of the formula
V. in 2-methoxyethanol or 2-ethoxyethanol, with an alkali metal hydroxide, thereafter reacting the desloratadine of the formula IV with carbon dioxide in a solution formed with an organic solvent.
3. Process a) according to claim 2 which comprises carrying out the reaction in an ester, ether, or a mixture of a lower aliphatic alcohol and an ester, or a mixture of an ether and a lower aliphatic alcohol.
4. Process according to claim 3 which comprises carrying out the reaction in ethyl acetate, tetrahydrofurane, diethyl ether, dioxane, or in a mixture of ethyl acetate and methanol, a mixture of ethyl acetate and ethanol, a mixture of tetrahydrofurane and methanol, a mixture of tetrahydrofurane and ethanol, a mixture of diethyl ether and ethanol, or a mixture of diethyl ether and methanol.
5. Process according to claim 4 which comprises carrying out the reaction in ethyl acetate.
6. Process a) according to claim 2 or any of claims 3-5 which comprises introducing carbon dioxide or adding dry ice to a solution of desloratadine of formula the IV formed with an organic solvent .
7. Process b) according to claim 2 which comprises distilling off the 2-methoxyethanol or 2-ethoxyethanol, dissolving the residue in an organic solvent, and thereafter introducing carbon dioxide or adding dry ice to the solution.
8. Process according to claim 7 which comprises using ethyl acetate as organic solvent.
9. Process according any of the claims 2-8 which comprises carrying out the reaction of desloratadine of the formula IV with carbon dioxide at a temperature between room temperature and 40 0C5 preferably at room temperature.
10. Process for the preparation of desloratadine of the formula IV of high purity via decarbethoxylation of loratadine of the formula V which comprises carrying out the reaction in 2-methoxymethanol or 2-ethoxyethanol.
11. Process according to claim 10 which comprises removing the 2-methoxyethanol or 2-ethoxyethanol from the reaction mixture, dissolving the residue in an organic solvent and evaporating the solution.
12. Process according to claim 11 which comprises using ethyl acetate as organic solvent.
13. Process b) according to claim 2 and any of claims 10-12 which comprises carrying out the reaction under heating, preferably at the boiling point of solvent used.
14. Process for preparation of salts of desloratadine of the general formula
VI.
(wherein X stands for an anion and n is 1 or 2) which comprises reacting the solution of the pseudopolymorph of desloratadine formed with carbon dioxide of the formula I in an organic solvent with a solution of the corresponding acid formed with an organic solvent.
15. Process according to claim 14 which comprises using hydrochloric acid, hydrobromic acid, sulphuric acid,
methanesulphonic acid, benzenesulphonic acid, maleic acid or fumaric acid.
16. Process for the preparation of the salts of the general formula VI (wherein n is 1) according to any of the claims of 14 or 15 which comprises using the acid in an approximately equimolecular amount, related to the pseudopolymorph of the formula I.
17. Process for the preparation of the salts of the general formula VI (wherein n is 2) according to any of the claims of 14 or 15 which comprises using the acid in at least a molar ratio of 2:1, preferably in a molar ratio of 2:1-3:1, related to the pseudopolymorph of the formula I.
18. Process according any of the claims 14-17 which comprises carrying out the reaction at a tremperature between room temperature and 40 0C, preferably at room temperature.
19. Pharmaceutical composition comprising as active ingredient the pseudopolymorph of desloratadine of the formula I in admixture with pharmaceutically acceptable carriers and/or auxiliary agents.
20. Process for the preparation of pharmaceutical composition according to claim 19 which comprises admixing the pseudopolymorph of desloratadine of the formula I with pharmaceutically acceptable carriers and/or auxiliary agents.
21. Pseudopolymorph form of desloratadine of the formula I for the use as pharmaceutical active ingredient.
22. Use according to claim 21 as an anti-allergic pharmaceutical active ingredient.
23. Process for treatment of allergy which comprises administering the pseudopolymorph of the desloratadine of the formula I to a patient in need of such treatment.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0401373A HU0401373D0 (en) | 2004-07-07 | 2004-07-07 | Pseudopolimorphic form of desloratadine with carbondioxide |
| HU0500664A HU226951B1 (en) | 2005-07-06 | 2005-07-06 | Pseudopolimorphic form of desloratadine with carbon dioxide, process for its preparation and its use |
| PCT/HU2005/000073 WO2006003479A2 (en) | 2004-07-07 | 2005-07-07 | New pseudopolymorph of desloratadine formed with carbon dioxide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1817307A2 true EP1817307A2 (en) | 2007-08-15 |
Family
ID=89986128
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP05763423A Withdrawn EP1817307A2 (en) | 2004-07-07 | 2005-07-07 | New pseudopolymorph of desloratadine formed with carbon dioxide |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP1817307A2 (en) |
| BG (1) | BG109814A (en) |
| CZ (1) | CZ200798A3 (en) |
| EA (1) | EA011894B1 (en) |
| HR (1) | HRP20070025A2 (en) |
| PL (1) | PL381813A1 (en) |
| RS (1) | RS20070008A (en) |
| SK (1) | SK50112007A3 (en) |
| WO (1) | WO2006003479A2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU230417B1 (en) * | 2006-10-26 | 2016-05-30 | Egis Gyógyszergyár Zrt | Process for producing adduct comprising desloratadine and carbon dioxide |
| CN103755682A (en) * | 2013-12-30 | 2014-04-30 | 山东达因海洋生物制药股份有限公司 | Novel crystal form for desloratadine and preparation method thereof |
| WO2016024249A1 (en) * | 2014-08-14 | 2016-02-18 | Sun Pharmaceutical Industries Limited | Crystalline forms of palbociclib |
| CN104610225B (en) * | 2014-12-29 | 2017-02-01 | 广东九明制药有限公司 | Preparation method of desloratadine |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU570306B2 (en) * | 1984-02-15 | 1988-03-10 | Schering Corporation | 8-chloro-6, 11-dihydro-11-(4-piperidylidene)-5h-benzo (5,6) cyclohepta (1,2-b) pyridine and its salts. |
| US5595997A (en) * | 1994-12-30 | 1997-01-21 | Sepracor Inc. | Methods and compositions for treating allergic rhinitis and other disorders using descarboethoxyloratadine |
| UA62976C2 (en) * | 1997-07-02 | 2004-01-15 | Schering Corp | Polymorphs of 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5h-benzo[5,6]cyclohepta[1,2-b]pyridine |
| HU226998B1 (en) * | 2000-11-23 | 2010-04-28 | Richter Gedeon Nyrt | Desloratadine hemisulphate, process for the preparation thereof and pharmaceutical compositions containing the same |
| BR0313231A (en) * | 2002-08-05 | 2007-07-24 | Sandoz Ag | desloratadine hemifumarate salt and polymorphs |
| DE60217934T2 (en) * | 2002-09-24 | 2007-05-24 | Morepen Laboratories Ltd. | PROCESS FOR THE PRODUCTION OF DESLORATADIN |
-
2005
- 2005-07-07 EP EP05763423A patent/EP1817307A2/en not_active Withdrawn
- 2005-07-07 RS RSP-2007/0008A patent/RS20070008A/en unknown
- 2005-07-07 EA EA200700208A patent/EA011894B1/en not_active IP Right Cessation
- 2005-07-07 CZ CZ20070098A patent/CZ200798A3/en unknown
- 2005-07-07 WO PCT/HU2005/000073 patent/WO2006003479A2/en active Application Filing
- 2005-07-07 SK SK5011-2007A patent/SK50112007A3/en unknown
- 2005-07-07 PL PL381813A patent/PL381813A1/en not_active Application Discontinuation
-
2007
- 2007-01-26 HR HR20070025A patent/HRP20070025A2/en not_active Application Discontinuation
- 2007-02-06 BG BG109814A patent/BG109814A/en unknown
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2006003479A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2006003479A3 (en) | 2006-06-08 |
| BG109814A (en) | 2008-04-30 |
| SK50112007A3 (en) | 2007-07-06 |
| PL381813A1 (en) | 2007-07-23 |
| RS20070008A (en) | 2008-11-28 |
| HRP20070025A2 (en) | 2008-11-30 |
| EA200700208A1 (en) | 2007-08-31 |
| CZ200798A3 (en) | 2007-06-20 |
| WO2006003479A2 (en) | 2006-01-12 |
| EA011894B1 (en) | 2009-06-30 |
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