WO2005068471A1 - New crystalline forms of clopidogrel hydrobromide and methods of their preparation - Google Patents
New crystalline forms of clopidogrel hydrobromide and methods of their preparation Download PDFInfo
- Publication number
- WO2005068471A1 WO2005068471A1 PCT/CZ2004/000089 CZ2004000089W WO2005068471A1 WO 2005068471 A1 WO2005068471 A1 WO 2005068471A1 CZ 2004000089 W CZ2004000089 W CZ 2004000089W WO 2005068471 A1 WO2005068471 A1 WO 2005068471A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- clopidogrel
- hydrobromide
- solution
- crystalline form
- clopidogrel hydrobromide
- Prior art date
Links
- QKLHYWAZTQRTBR-RSAXXLAASA-N methyl (2s)-2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetate;hydrobromide Chemical compound Br.C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl QKLHYWAZTQRTBR-RSAXXLAASA-N 0.000 title claims abstract description 38
- 229950010562 clopidogrel hydrobromide Drugs 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 84
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims abstract description 62
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 claims abstract description 31
- 229960003009 clopidogrel Drugs 0.000 claims abstract description 31
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 claims abstract description 31
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims abstract description 27
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 22
- 238000002329 infrared spectrum Methods 0.000 claims abstract description 11
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 239000013078 crystal Substances 0.000 claims description 19
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 230000001376 precipitating effect Effects 0.000 abstract description 6
- 238000003756 stirring Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 230000008018 melting Effects 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 238000007605 air drying Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
- GKTWGGQPFAXNFI-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetic acid methyl ester Chemical compound C1CC=2SC=CC=2CN1C(C(=O)OC)C1=CC=CC=C1Cl GKTWGGQPFAXNFI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000001407 anti-thrombic effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229950010477 clopidogrel hydrogen sulphate Drugs 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- FDEODCTUSIWGLK-UHFFFAOYSA-N hydrogen sulfate;hydron;methyl 2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetate Chemical compound OS(O)(=O)=O.C1CC=2SC=CC=2CN1C(C(=O)OC)C1=CC=CC=C1Cl FDEODCTUSIWGLK-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the invention concerns new crystalline forms of the hydrobromide of the (alpha S) alpha-(2- chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester (thereinafter clopidogrel hydrobromide), which are characterized by X-ray (RTG) diffraction and infrared spectra, and methods of their preparation.
- RTG X-ray
- the respective salt of clopidogrel with camphorsulfonic acid is converted, by a solution of sodium hydrogen carbonate in methylene chloride medium, into an optically active base, which is obtained by evaporation of the solvent.
- the evaporation residue of the active base is converted into the respective salt.
- the hydrobromide is obtained by dissolving the base in diethyl or diisopropyl ether and precipitating drop by drop with 48% hydrobromic acid. Drying the formed precipitate affords crystals with the melting point of 111 °C.
- toxicity of the hydrobromide is also evaluated, which is even somewhat lower than that of the currently used hydrogensulfate.
- LD50 of clopidogrel hydrogen sulfate is 2591 mg and LD 50 of clopidogrel hydrobromide is 4268 g).
- the new crystalline Form I of clopidogrel hydrobromide is characterized by interplanar distances ascertained by X-ray diffraction, d: 4.01 A; 4.39 A and 3.17 A, or by infrared spectrogram with bands at 1743; 1421; 1237, 760 and 728 cm “1 .
- the new crystalline Form II of clopidogrel hydrobromide is characterized by interplanar distances ascertained by X-ray diffraction, d: 4.52 A; 3.83 A; 3.48 A, or by infrared spectrogram with bands at 1754; 1436; 1317 and 1223 cm “1 .
- the new crystalline form III of clopidogrel hydrobromide is characterized by the following peaks ascertained by X-ray diffraction at 20 positions: 7.796 °; 15.380 °; 18.389 °; 19.369 ° and 23.895 °.
- the crystalline Form I can be obtained from a solution of the base in toluene by precipitating with 48% hydrobromic acid. This procedure yields first an oily emulsion of the hydrobromide in toluene, which is, however, with further stirring converted into a crystalline matter. Stirring can be performed at room temperature but it is also possible to decrease the temperature gradually.
- a preferable method of preparation of crystalline form I involves adding a 48% solution of hydrobromic acid in water to a solution of 5 to 15%o of the clopidogrel base in toluene, whereas the molar ratio of the clopidogrel base and hydrogen bromide is 1 : 0.9 to 1.5.
- Form II can be obtained by reaction of a solution of the clopidogrel base in an organic solvent, e.g. ethyl acetate or toluene, with a solution of hydrobromic acid in toluene. Crystalline Form II gradually matures at decreased temperature, i.e. precipitation is performed preferably at temperatures 0 to 30 °C and crystals grow preferably at temperatures lower than 10 °C.
- the method preferably involves using a solution of the clopidogrel base having a concentration 5 to 40 weight % and precipitating it with a solution of hydrogen bromide in toluene of concentrations 5 to 15 weight %, whereas the molar ratio of the clopidogrel base and hydrogen bromide is 1 : 0.9 to 1.1.
- Form II can be obtained by introducing gaseous hydrogen bromide into a solution of clopidogrel base in an organic solvent, preferably in an aromatic C 6 -C 1 hydrocarbon, for example toluene.
- hydrogen bromide is introduced at a lowered temperature, e.g., -15 °C to 30 °C, more preferably at a temperature lower than 10 °C; at this temperature, in a stirred solution, the crystalline Form II further matures.
- Usual time of stirring is 2 to 8 hours.
- a preferable concentration of the solution of the clopidogrel base is 15 to 40 weight % and the molar ratio of the clopidogrel base and hydrogen bromide is 1 : 0.9 to 1.1.
- Form III can be prepared by a similar method, wherein, however, hydrogen bromide is introduced into a solution of clopidogrel having a concentration lower than 15 %, preferably 1 to 10 %. Hydrogen bromide is again introduced at a lowered temperature, for example -15 °C to 30 °C. Form III matures at a lower temperature by stirring for 2 to 8 hours.
- Form III can be used as an intermediate which is further processed into the pharmaceutically applicable Form II. This can be made by crystallization or precipitating an alcoholic solution of clopidogrel hydrobromide. Alcohols for said solution are selected from the series of -Cs; 2-propanol being preferred. Another less polar solvent can be added to the solution, preferably an ether, ester or ketone. Methyl tert-butyl ether has turned out to be especially preferred. In this manner, Form II can be obtained in an especially high purity.
- Figure 1 shows infrared spectra of clopidogrel hydrobromide Form I.
- Figure 2 shows infrared spectra of clopidogrel hydrobromide Form II.
- Figure 3 shows an X-ray diffraction pattern of clopidogrel hydrobromide Form I.
- Figure 4 shows an X-ray diffraction pattern of clopidogrel hydrobromide Form II.
- Figure 5 shows an X-ray diffraction pattern of clopidogrel hydrobromide Form III.
- the crystals provided the following X-ray diffraction pattern:
- the resulting crystalline product was characterized by an X-ray diffraction pattern as new Form III. HPLC purity more than 99.5 %.
- Clopidogrel hydrobromide of Example 6 (368.5 g) was dissolved while stirring in 2000 ml of 2-propanol at a temperature up to 60 °C. To this solution methyl tert-butyl ether (MTBE) was added (2135 ml) at 45 to 55 °C. The solution was slowly cooled down to room temperature (ca. 2 hrs); crystallization started. After 2 hours, the solution was cooled down to 0 to -5 °C with stirring overnight (18 hrs). The precipitated crystals were sucked off and washed with 500 ml of MTBE.
- MTBE methyl tert-butyl ether
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EA200601311A EA008972B1 (ru) | 2004-01-13 | 2004-12-21 | Новые кристаллические формы гидробромида клопидогреля и способы их получения |
| EP04802610A EP1713812A1 (de) | 2004-01-13 | 2004-12-21 | Neue kristalline formen von clopidogrel-hydrobromid und verfahren zu deren herstellung |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZPV2004-61 | 2004-01-13 | ||
| CZ200461A CZ295244B6 (cs) | 2004-01-13 | 2004-01-13 | Klopidogrel hydrobromid v krystalické formě I a způsob jeho přípravy |
| CZ20041192A CZ20041192A3 (cs) | 2004-12-07 | 2004-12-07 | Zpusob výroby krystalického klopidogrelu hydrobromidu |
| CZPV2004-1192 | 2004-12-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2005068471A1 true WO2005068471A1 (en) | 2005-07-28 |
Family
ID=34796465
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CZ2004/000089 WO2005068471A1 (en) | 2004-01-13 | 2004-12-21 | New crystalline forms of clopidogrel hydrobromide and methods of their preparation |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP1713812A1 (de) |
| EA (1) | EA008972B1 (de) |
| WO (1) | WO2005068471A1 (de) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005103058A1 (en) * | 2004-04-20 | 2005-11-03 | Sanofi-Aventis | Polymorphic forms of methyl (+) - (s) -alpha- (2-chlorophenyl) -6, 7-dihydrothieno `3,2-c!pyridine-584h) acetate hydrobromide, clopidrogel hydrobromide |
| EP1618113A1 (de) | 2003-09-11 | 2006-01-25 | Generics (UK) Limited | Neue kristalline polymorphe von clopidogrel |
| EP1970054A2 (de) | 2007-03-14 | 2008-09-17 | Ranbaxy Laboratories Limited | Clopidogrel-Tabletten |
| EP2107061A1 (de) | 2008-04-02 | 2009-10-07 | Krka Tovarna Zdravil, D.D., Novo Mesto | Herstellungsverfahren für optisch angereichertes Clopidogrel |
| US7652139B2 (en) | 2004-04-20 | 2010-01-26 | Sanofi-Aventis | Clopidogrel salt and polymorphic forms thereof |
| KR20150112975A (ko) * | 2013-02-06 | 2015-10-07 | 징준 후앙 | 경구 및 비경구적 전달을 위한 클로피도그렐 유리 염기의 안정한 약학 조성물 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003066637A1 (en) * | 2002-02-06 | 2003-08-14 | EGIS Gyógyszergyár Rt. | Polymorphs of clopidogrel hydrochloride and their use as antithrombic compounds |
| WO2004074215A1 (en) * | 2003-02-03 | 2004-09-02 | Sunil Sadanand Nadkarni | Process for preparation of clopidogrel, its salts and pharmaceutical compositions |
| WO2005026174A1 (en) * | 2003-09-11 | 2005-03-24 | Generics [Uk] Limited | Novel crystalline polymorphs of clopidogrel |
-
2004
- 2004-12-21 WO PCT/CZ2004/000089 patent/WO2005068471A1/en not_active Application Discontinuation
- 2004-12-21 EP EP04802610A patent/EP1713812A1/de not_active Withdrawn
- 2004-12-21 EA EA200601311A patent/EA008972B1/ru not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003066637A1 (en) * | 2002-02-06 | 2003-08-14 | EGIS Gyógyszergyár Rt. | Polymorphs of clopidogrel hydrochloride and their use as antithrombic compounds |
| WO2004074215A1 (en) * | 2003-02-03 | 2004-09-02 | Sunil Sadanand Nadkarni | Process for preparation of clopidogrel, its salts and pharmaceutical compositions |
| WO2005026174A1 (en) * | 2003-09-11 | 2005-03-24 | Generics [Uk] Limited | Novel crystalline polymorphs of clopidogrel |
Non-Patent Citations (1)
| Title |
|---|
| CAIRA M R: "CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS", TOPICS IN CURRENT CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198, 1998, pages 163 - 208, XP001156954, ISSN: 0340-1022 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1618113A1 (de) | 2003-09-11 | 2006-01-25 | Generics (UK) Limited | Neue kristalline polymorphe von clopidogrel |
| US7897613B2 (en) | 2003-09-11 | 2011-03-01 | Generics [Uk] Limited | Crystalline polymorphs of clopidogrel |
| WO2005103058A1 (en) * | 2004-04-20 | 2005-11-03 | Sanofi-Aventis | Polymorphic forms of methyl (+) - (s) -alpha- (2-chlorophenyl) -6, 7-dihydrothieno `3,2-c!pyridine-584h) acetate hydrobromide, clopidrogel hydrobromide |
| EA010831B1 (ru) * | 2004-04-20 | 2008-12-30 | Санофи-Авентис | ПОЛИМОРФНАЯ ФОРМА D ГИДРОБРОМИДА МЕТИЛ-(+)-(S)-α-(2-ХЛОРФЕНИЛ)-6,7-ДИГИДРОТИЕНО[3,2-C]ПИРИДИН-5(4H)-АЦЕТАТА |
| US7652139B2 (en) | 2004-04-20 | 2010-01-26 | Sanofi-Aventis | Clopidogrel salt and polymorphic forms thereof |
| EP1970054A2 (de) | 2007-03-14 | 2008-09-17 | Ranbaxy Laboratories Limited | Clopidogrel-Tabletten |
| EP2107061A1 (de) | 2008-04-02 | 2009-10-07 | Krka Tovarna Zdravil, D.D., Novo Mesto | Herstellungsverfahren für optisch angereichertes Clopidogrel |
| KR20150112975A (ko) * | 2013-02-06 | 2015-10-07 | 징준 후앙 | 경구 및 비경구적 전달을 위한 클로피도그렐 유리 염기의 안정한 약학 조성물 |
| KR102238292B1 (ko) | 2013-02-06 | 2021-04-09 | 징준 후앙 | 경구 및 비경구적 전달을 위한 클로피도그렐 유리 염기의 안정한 약학 조성물 |
Also Published As
| Publication number | Publication date |
|---|---|
| EA200601311A1 (ru) | 2006-12-29 |
| EA008972B1 (ru) | 2007-10-26 |
| EP1713812A1 (de) | 2006-10-25 |
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