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
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- 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
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- Prior art keywords
- clopidogrel
- hydrobromide
- solution
- crystalline form
- clopidogrel hydrobromide
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- 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
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- 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)
Abstract
The invention concerns clopidogrel hydrobromide in the crystalline Form I characterized by an X-ray diffraction pattern with characteristic interplanar distances d of 4.01; 4.39 and 3.17 ú and which is further characterized by bands in the infrared spectra at 1743; 1421; 1237, 760 and 728 cm-1. Clopidogrel hydrobromide in the crystalline Form II is characterized by an Xray diffraction pattern with characteristic interplanar distances d of 4.52; 3.83; 3.48 ú, as well as bands in the infrared spectra at 1754; 1436; 1317 and 1223 cm-1. Crystalline form III 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 method of preparation of clopidogrel hydrobromide in the crystalline Form I consist in precipitating the clopidogrel base dissolved in toluene with a concentrated solution of hydrobromic acid. The method of preparation of clopidogrel hydrobromide in the crystalline Form II consist in dissolving the clopidogrel base in an organic solvent and precipitating it with a solution of hydrobromic acid in toluene or with gaseous hydrogen bromide. Form III can be used for the preparation of pharmaceutically applicable Form II.
Description
New crystalline forms of clopidogrel hydrobromide and methods of their preparation
Technical Field
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.
Background Art
The (alpha S) alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester, clopidogrel of formula I
is an anti-thrombic agent that was described in CZ patent 274 420 (EP 281 459), wherein blood coagulation decreasing activities of various salts of this substance were also demonstrated. Currently sold clopidogrel-based pharmaceutical formulations contain this active agent in the form of its hydrogensulfate salt (HSO4 " anion). The method of preparation of the S-enantiomer published in the above-cited patent involves reaction of the racemic mixture with optically active camphorsulfonic acid and subsequent separation of the diastereoisomer.
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. Specifically, 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.
In the cited patent, 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 LD50 of clopidogrel hydrobromide is 4268 g).
Disclosure of Invention
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.
Alternatively, Form II can be obtained by introducing gaseous hydrogen bromide into a solution of clopidogrel base in an organic solvent, preferably in an aromatic C6-C1 hydrocarbon, for example toluene. Preferably, 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.
Melting points of all the forms are difficult to reproduce and identification fails. They range between about 113 and 145 °C.
Brief Description of Drawings
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.
Examples
The invention is elucidated by the following examples, which have purely illustrative character and do not limit the extent of the invention in any respect.
Scheme
Example 1
3.38 g (0.0105 mol) of the clopidogrel base of formula (I) are dissolved in 10 ml of toluene at room temperature. A solution of HBr in toluene (11.5 ml of the solution containing 0.86 g of HBr) is added at once under stirring. The resulting precipitate is stirred at room temperature for 1 hour. After this time, the reaction mixture is left sitting at temperature +6 °C for 4 hours. The precipitate is sucked off and washed with toluene. After air drying, 2.9 g of yellowish crystals of hydrobromide of formula (II) (69%) are obtained, having the melting point 132 to 138 °C. The crystals were characterized by an X-ray diffraction pattern and infrared spectra as the crystalline Form II (Figure 2).
The results of the X-ray diffraction were converted into interplanetary distances D:
Example 2
6.1 g (0.0189 mol) of the clopidogrel base of formula (I) are dissolved in 60 ml ethyl acetate at room temperature. The solution is cooled down in a water-ice bath to temperature +5 °C and 20.8 ml of solution of HBr in toluene is added drop by drop within 0.5 hours at this temperature. The mixture of crystals in toluene is stirred for another 2 hours at temperature 0 to +5 °C. The resulting crystalline fraction is sucked off and washed with ethyl acetate. After air drying, 3.7 g of cream-coloured crystals of the hydrobromide of formula (II) (54.2%) were obtained, having the melting point 135 to 139 °C. The crystals were characterized by an X-ray diffraction pattern (Figure 4) and infrared spectra as the crystalline Form II.
Example 3
6.88 g (0.02137 mol) of the clopidogrel base of formula (I) are dissolved in 100 ml toluene at room temperature. At this temperature, 2.25 ml of 48% HBr is added to the solution drop by drop. An oily matter precipitated out of the solution, which crystallized after 4 hours of stirring at room temperature. The resulting crystals were sucked off and washed with toluene. After air drying, 6.66 g of yellowish crystals of the hydrobromide of formula (II) (77.4%) were obtained, having the melting point 120 to 134 °C. The crystals were characterized by an X-ray diffraction pattern (Figure 3) and infrared spectra as the crystalline Form I (Figure 1).
The crystals provided the following X-ray diffraction pattern:
Example 4
21.48 g (0.0667 mol) of the clopidogrel base of formula (I) were dissolved in 312 ml toluene at room temperature. The resulting solution is cooled down in a water-ice bath to temperature +5 °C. At this temperature, 7 ml of 48% HBr in toluene is added drop by drop within 10 minutes. The reaction mixture is then tempered to temperature 18 to 20 °C and stirred at this temperature for 3 hours. The resulting crystals are sucked off, washed with toluene and air dried at room temperature. 19.46 g of yellowish crystals of the hydrobromide of formula (II) (72.4%o) are obtained, having the melting point 113-120 °C. The resulting crystals were characterized with an X-ray diffraction pattern and infrared spectra as the crystalline Form I.
Example 5
203 g of the clopidogrel base (0.6308 mol) were dissolved in 1000 ml of toluene. With stirring, the solution was cooled down to 0 to +5 °C. Introduction of gaseous hydrogen bromide into the cooled solution was started. The pressure bomb was positioned on a balance and after 50 g of hydrogen bromide has gone, the introduction was stopped; its total duration was ca. 15 mins. The temperature while adding hydrogen bromide ranged between +5 and +10 °C. The thick reaction mixture was then stirred at 0 to -5 °C for 4 hrs. The resulting crystalline matter was sucked off through a filter glass and washed with 500 ml of toluene. Air drying afforded 243.7 g of clopidogrel hydrobromide. An X-ray analysis proved the Form II. HPLC purity more than 99.0 %.
Example 6
260.7 g of the clopidogrel base (0.8101 mol) were dissolved in 2600 ml of toluene. With stirring, the solution was cooled down to 0 to +5 °C. Introduction of gaseous hydrogen bromide into the cooled solution was started. The pressure bomb was positioned on a balance and after 65 g of hydrogen bromide has gone, the introduction was stopped; its total duration was ca. 15 mins. The temperature while adding hydrogen bromide ranged between +5 and +10 °C. The thick reaction mixture was then stirred at 0 to -5 °C for 4 hrs. The resulting crystalline matter was sucked off through a filter glass and washed with 500 ml of toluene. Air drying afforded 368.5 g of clopidogrel hydrobromide.
The resulting crystalline product was characterized by an X-ray diffraction pattern as new Form III. HPLC purity more than 99.5 %.
The resulting crystals provided the following X-ray diffraction pattern:
Example 7
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.
91.2 % of theory of clopidogrel hydrobromide were obtained, which has been characterized by an X-ray diffraction pattern as Form II. HPLC purity more than 99.5 %.
Melting points were measured at Ko tier's block. The diffraction pattern was obtained by means of X'PERT PRO MPD PANalytical diffractometer.
Claims
1. Clopidogrel hydrobromide in the crystalline Form I characterized by an X-ray diffraction pattern with characteristic interplanar distances d of4.01; 4.39 and 3.17 A.
2. Clopidogrel hydrobromide in the crystalline Form I according to claim 1 characterized by interplanar distances d of 3.12; 6.99; 5.5; 4.29 and 3.65 A.
3. Clopidogrel hydrobromide in the crystalline Form I according to claims 1 or 2 characterized by bands in the infrared spectra at 1743; 1421; 1237, 760 and 728 cm"1.
4. Clopidogrel hydrobromide in the crystalline Form II characterized by an X-ray diffraction pattern with characteristic interplanar distances d of 4.52; 3.83; 3.48 A.
5. Clopidogrel hydrobromide in the crystalline Form II according to claim 4 characterized by interplanar distances d of 6.38; 2.76 and 3.23 A.
6. Clopidogrel hydrobromide in the crystalline Form II according to claims 4 or 5 characterized by bands in the infrared spectra at 1754; 1436; 1317 and 1223 cm"1.
7. Clopidogrel hydrobromide of Form III, characterized with peaks ascertained by X-ray diffraction in the following 2Θ positions: 7.796 °; 15.380 °; 18.389 °; 19.369 ° and 23.895 °.
8. A method of preparation of clopidogrel hydrobromide of the crystalline Form I according to claims 1-3 characterized in that clopidogrel base dissolved in toluene is precipitated with a concentrated solution of hydrobromic acid.
9. The method according to claim 8 characterized in that after precipitation, the resulting oily matter is mixed with toluene for a time necessary for formation of crystal.
10. The method according to claim 8 characterized in that a 48% solution of hydrobromic acid in water is added to a solution of 5 to 15% of the clopidogrel base in toluene, whereas the molar ratio of the clopidogrel base and hydrogen bromide is 1 : 0.9 to 1.5.
11. A method of preparation of clopidogrel hydrobromide of the crystalline Form II according to claims 4-6 characterized in that the clopidogrel base is dissolved in an organic solvent and precipitated with a solution of hydrobromic acid in toluene.
12. The method according to claim 11 characterized in that precipitation is performed at temperatures 0 to 30 °C and growth crystals occurs at temperatures lower than 10 °C.
13. The method according to claim 11 characterized in that a solution of the clopidogrel base having a concentration of 5 to 40 weight % is used and is precipitated with a solution of hydrogen bromide in toluene having a concentration of 5 to 15 weight %, whereas the molar ratio of the clopidogrel base and hydrogen bromide is 1 : 0.9 to 1.1.
14. A method of preparation of clopidogrel hydrobromide of crystalline Form II characterized in that clopidogrel base is dissolved in an organic solvent and precipitated with gaseous hydrogen bromide, and, optionally, the resulting clopidogrel hydrobromide is further dissolved and crystallized from a solvent comprising a Cι.-C5 alcohol or a mixture of a Cj.-C5 alcohol with an ether, ester or ketone.
15. The method according to claim 14 characterized in that clopidogrel hydrobromide is precipitated from an organic solvent selected from the group of C6-C12 aromatic hydrocarbons.
16. The method according to claim 14 characterized in that precipitation is carried out at a temperature of -15 °C to 30 °C and growth of crystals occurs at a temperature lower than 10 °C.
17. The method according to claim 14 characterized in that a solution of the clopidogrel base having a concentration of 1 to 40 % is used, the molar ratio of the clopidogrel base and hydrogen bromide being 1 : 0.9 to 1.1.
18. The method according to any of claims 14-17, characterized in that gaseous hydrogen bromide is introduced into a solution of the clopidogrel base having a concentration of 15 to 40 %.
19. The method according to any of claims 14-16 characterized in that gaseous hydrogen bromide is introduced into a solution of the clopidogrel base having a concentration of 1 to 10 %, clopidogrel hydrobromide of Foπn III thus being precipitated, which is further crystallized from a -Cs alcohol or a Cι-C15 alcohol in an admixture with an ether, ester or ketone.
20. The method according to claim 18 characterized in that clopidogrel hydrobromide of Form II is crystallized from a mixture of a - alcohol and an ether.
21. The method according to claim 19 characterized in that clopidogrel hydrobromide of Form II is crystallized from a mixture of 2-propanol and methyl tert-butyl ether.
22. Use of clopidogrel hydrobromide of Form III according to claim 7 for the preparation of clopidogrel hydrobromide of Foπn II, applicable as a pharmaceutical active substance.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EA200601311A EA008972B1 (en) | 2004-01-13 | 2004-12-21 | New crystalline forms of clopidogrel hydrobromine and methods of their preparation |
| EP04802610A EP1713812A1 (en) | 2004-01-13 | 2004-12-21 | New crystalline forms of clopidogrel hydrobromide and methods of their preparation |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZPV2004-61 | 2004-01-13 | ||
| CZ200461A CZ295244B6 (en) | 2004-01-13 | 2004-01-13 | Clopidogrel hydrobromide in crystalline form I and process for its preparation |
| CZ20041192A CZ20041192A3 (en) | 2004-12-07 | 2004-12-07 | Process for preparing crystalline clopidogrel hydrobromide |
| CZPV2004-1192 | 2004-12-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2005068471A1 true WO2005068471A1 (en) | 2005-07-28 |
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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 (en) |
| EA (1) | EA008972B1 (en) |
| WO (1) | WO2005068471A1 (en) |
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 (en) | 2003-09-11 | 2006-01-25 | Generics (UK) Limited | Novel crystalline polymorphs of clopidogrel |
| EP1970054A2 (en) | 2007-03-14 | 2008-09-17 | Ranbaxy Laboratories Limited | Clopidogrel tablets |
| EP2107061A1 (en) | 2008-04-02 | 2009-10-07 | Krka Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of optically enriched clopidogrel |
| US7652139B2 (en) | 2004-04-20 | 2010-01-26 | Sanofi-Aventis | Clopidogrel salt and polymorphic forms thereof |
| KR20150112975A (en) * | 2013-02-06 | 2015-10-07 | 징준 후앙 | Stable pharmaceutical composition of clopidogrel free base for oral and parenteral delivery |
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| 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 EA EA200601311A patent/EA008972B1/en not_active IP Right Cessation
- 2004-12-21 EP EP04802610A patent/EP1713812A1/en not_active Withdrawn
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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| 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 (en) | 2003-09-11 | 2006-01-25 | Generics (UK) Limited | Novel crystalline polymorphs of 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 (en) * | 2004-04-20 | 2008-12-30 | Санофи-Авентис | Polymorphic forms of methyl (+)-(s)-alpha-2-(chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4h) acetate hydrobromide, clopidrogel hydrobromide |
| US7652139B2 (en) | 2004-04-20 | 2010-01-26 | Sanofi-Aventis | Clopidogrel salt and polymorphic forms thereof |
| EP1970054A2 (en) | 2007-03-14 | 2008-09-17 | Ranbaxy Laboratories Limited | Clopidogrel tablets |
| EP2107061A1 (en) | 2008-04-02 | 2009-10-07 | Krka Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of optically enriched clopidogrel |
| KR20150112975A (en) * | 2013-02-06 | 2015-10-07 | 징준 후앙 | Stable pharmaceutical composition of clopidogrel free base for oral and parenteral delivery |
| KR102238292B1 (en) | 2013-02-06 | 2021-04-09 | 징준 후앙 | Stable pharmaceutical composition of clopidogrel free base for oral and parenteral delivery |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1713812A1 (en) | 2006-10-25 |
| EA008972B1 (en) | 2007-10-26 |
| EA200601311A1 (en) | 2006-12-29 |
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