WO2004020443A1 - Method for manufacturing crystalline form i of clopidogrel hydrogen sulphate - Google Patents
Method for manufacturing crystalline form i of clopidogrel hydrogen sulphate Download PDFInfo
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- WO2004020443A1 WO2004020443A1 PCT/CZ2003/000049 CZ0300049W WO2004020443A1 WO 2004020443 A1 WO2004020443 A1 WO 2004020443A1 CZ 0300049 W CZ0300049 W CZ 0300049W WO 2004020443 A1 WO2004020443 A1 WO 2004020443A1
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- WIPO (PCT)
- Prior art keywords
- hydrogen sulphate
- clopidogrel
- solution
- formula
- clopidogrel hydrogen
- Prior art date
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- FDEODCTUSIWGLK-RSAXXLAASA-N clopidogrel sulfate Chemical compound [H+].OS([O-])(=O)=O.C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl FDEODCTUSIWGLK-RSAXXLAASA-N 0.000 title claims abstract description 31
- 229950010477 clopidogrel hydrogen sulphate Drugs 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 17
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 claims abstract description 14
- 229960003009 clopidogrel Drugs 0.000 claims abstract description 14
- 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 14
- 150000001298 alcohols Chemical class 0.000 claims abstract description 8
- 150000002148 esters Chemical class 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 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 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract 5
- 150000001735 carboxylic acids Chemical class 0.000 claims abstract 2
- 239000012458 free base Substances 0.000 claims abstract 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- 239000001117 sulphuric acid Substances 0.000 claims description 9
- 235000011149 sulphuric acid Nutrition 0.000 claims description 9
- 239000013078 crystal Substances 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 238000003756 stirring Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000011521 glass Substances 0.000 description 5
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 238000007707 calorimetry Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001131 transforming effect Effects 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Liquid Crystal Substances (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
A method for manufacturing hydrogen sulphate (alpha S) of the alpha-(2-chlorophenyl)-6,7dihydro-thieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester (clopidogrel hydrogen sulphate) of formula I, in crystalline Form I, wherein the compound of formula is separated out of a solution of clopidogrel in the form of the free base or salt in a solvent selected from the series of primary, secondary or tertiary C1-C5 alcohols, their esters with Cl-C4 carboxylic acids, or optionally of mixtures thereof.
Description
METHOD FOR MANUFACTURING CRYSTALLINE FORM I OF CLOPIDOGREL HYDROGEN SULPHATE
Technical Field
The invention relates to a new method for manufacturing hydrogen sulphate (alpha S) of the alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester (clopidogrel hydrogen sulphate) in its crystalline Form I.
Background Art
Hydrogen sulphate (alpha S) of the alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine- 5(4H)-acetic acid methyl ester (clopidogrel hydrogen sulphate) of formula I
is an anti-thrombotic agent that has been described in patent CZ 274 420 (EP 281 459), dealing with the technology for manufacturing dextrorotatory S enantiomer. The manufacturing method disclosed in the cited patent dwells in reacting the racemic mixture with optically active camphor sulphonic acid and subsequent separating the diastereoisomer.
The respective salt of clopidogrel with camphor sulphonic acid is transformed with sodium hydrogen carbonate solution in methylene chloride environment into the optically active base, which is obtained by evaporation of the solvent.
The evaporation residue - the optically active base of clopidogrel - is dissolved in acetone, where it is transformed into hydrogen sulphate by adding drops of an equivalent amount of
sulphuric acid, under cooling with crushed ice. The melting temperature of the resulting precipitate is stated as 184 °C.
The specification of CZ 274 420 (EP 281 459) does not deal with the crystalline form of clopidogrel hydrogen sulphate prepared in this way. A newer patent application, CZ 2000- 4637 (WO 99/65915) gives a description of crystalline Forms I and II of clopidogrel hydrogen sulphate. According to this more recent patent application, the precipitation method described in CZ 274 420 (EP 281 459) had led to crystalline Form I. The above application defines an allegedly new crystalline form, Form II. The process for obtaining Form II according to example 1A of this application dwells in introduction of the salt of clopidogrel with camphor sulphonic acid into methylene chloride and its transformation into the base with a solution of potassium carbonate. Methylene chloride is evaporated and the evaporation residue is dissolved in acetone. By adding sulphuric acid, the hydrogen sulphate precipitates out of acetone.
The methods leading - according to the application CZ 2000-4637 (WO 99/65915) - to Form II, are thus very similar to those leading to Form I according to the same application. Since, moreover, the application defines Form II as thermodynamically more stable, it is obvious that the known methods allegedly resulting in Form I will be poorly reproducible. It can be assumed that even a small change in conditions will result in Form II instead of expected Form I. The Form I under generation can, under these circumstances, transform spontaneously into Form II and it can be expected that it will be at least contaminated with Form II.
The above stated expectations have been proven experimentally.
The present invention provides a reliable method for obtaining Form I of clopidogrel hydrogen sulphate without detectable impurity of Form II.
Disclosure of the Invention
This invention relates to a method for manufacturing crystalline Form I of clopidogrel hydrogen sulphate, consisting in crystallisation or precipitation of this Form from a solvent
selected from the series of C1-C5 alcohols or their esters with C1-C4 acids, optionally of mixtures of alcohols and esters.
The manufacturing method described in the prior art thus allows a non-specific preparation of Form I. It has now been found out that if clopidogrel hydrogen sulphate is allowed to crystallise by the procedure according to this invention, Form I having a high and defined content can be obtained in a reproducible way. The substance of this invention is a process for manufacturing crystalline Form I of clopidogrel hydrogen sulphate, which method resides in:
1. transforming the salt of clopidogrel with camphor sulphonic acid, in an organic solvent medium, using a solution of a weak inorganic base, into an optically active base;
2. isolating, from the organic phase, the corresponding clopidogrel base by evaporating the solvent, and subsequent dissolving said base in a solvent selected from the series of C1-C5 alcohols or their esters with C1-C4 acids, optionally of mixtures of alcohols and esters, and cooling the mixture;
3. adding sulphuric acid and inoculating the mixture with Form I of clopidogrel hydrogen sulphate;
4. stirring the crystallised mixture at a temperature between -5 and 15 °C, filtering and drying the crystals, thus obtaining Form I of clopidogrel hydrogen sulphate.
According to another characteristic, crystalline Form I of clopidogrel hydrogen sulphate can be produced in an alternative procedure, residing in:
1. dissolving clopidogrel hydrogen sulphate in a solvent selected from the series of Cl- C5 alcohols or their esters with C1-C4 acids, optionally of mixtures of alcohols and esters, at the boiling temperature of the respective solvents;
2. filtering the mixture through a filter with an opening size of 0.1 to 1 μm;
3. cooling the solution down, filtering and drying under reduced pressure, thus obtaining Form I of clopidogrel hydrogen sulphate.
The quality of clopidogrel hydrogen sulphate of Form I without detectable contamination by Form LI, obtained in accordance with this invention, is documented by the following measurements by means of common technologies.
A characteristic powder diffractogram of the powder of thus obtained Form I of clopidogrel hydrogen sulphate is shown in Figure 1 ; the table gives the inter-grid distances and relative
intensities (the percentages of the most intensive line). The X-ray diffraction profile of the powder was assessed in the apparatus PHILIPS PW1730/PW1050, Cu radiation (K alpha) Ni filter, with automated data collection, voltage: 40 kV, current: 25 mA, with the advance rate of the goniometer of 1/2° per minute and the time constant of 1.
The quality of thus manufactured Form I of clopidogrel hydrogen sulphate has been confirmed by Fourier Transform infrared spectroscopy (FTIR), shown in Figure 2. The spectra were taken in the spectrometer Nicolet USA, type: Impact 410. Conditions of measurement: KBr tablet technology, 16 scan, resolution: 4 /cm (reciprocal cm), background KBr tablet.
An analysis of differential enthalpy (DSC) has been performed in the apparatus Perkin Elmer DSC 7, calibrated to In. For calorimetric assessment, 1.725 mg were used, in an Al cup, with the temperature ranging from 40 to 200 °C, the speed of heating: 10 °C /min. The melting point and a characteristic DSC curve is shown in Figure 3.
Using combination of the above methods, the detection limit of the alternative crystalline form remains reliably under 2 %. This method thus ensures that the content of the polymorph is 98 % at minimum.
Brief Description of Drawings
Figure 1 represents an X-ray diffractogram of Form I of clopidogrel hydrogen sulphate according to Example 4, Figure 2 shows its spectrogram obtained by Fourier Transform IR spectrometry (FTIR) and, Figure 3 is a record of differential calorimetry. Figure 4 represents an X-ray diffractogram of the product according to Example 5, and Figure 5 relates to the product of Example 6.
Examples
Example 1
2.26 gram of clopidogrel base are placed into a flat-bottom flask, equipped with a thermometer and a magnetic stirrer, and dissolved in 32 ml of dried i-propanol. Under stirring, the solution is cooled down to 0 to -5 °C. Then, 0.33 ml of 98% sulphuric acid are added (p-1.8361 g.cm"3) and inoculated with crystals of Form I. The mixture is stirred at the above stated temperature for 2.5 hours, whereby in about 1 hour the look of the separated
crystalline phase changes as it gradually passes into the solution. The temperature of the mixture is increased to 10 °C and it is inoculated with Form I crystals again after about 0.5 hour. The mixture is stirred until the crystalline phase separates at a temperature between 10 and 15 °C for 1.5 to 2 hours, and then at -5 °C for 8 hours. The product is filtered off on fritted glass S-2 and dried with a stream of air. 1.7 g of clopidogrel hydrogen sulphate Form I with minimal polymorph purity of 98 % and having the melting point of 185 to 187 °C are obtained.
0.5 g of clopidogrel hydrogen sulphate Form II, having the melting point of 177 to 179 °C, are separated out of the mother liquors upon standing at 25 °C.
Example 2
25 grams of clopidogrel hydrogen sulphate are placed into a flask, equipped with a magnetic stirrer and a reflux condenser, and dissolved in 1150 ml butyl acetate under reflux in an inert gas atmosphere. The slightly turbid solution is filtered and cooled down to 0 to -2 °C under stirring. It is put aside into a refrigerator and, after 6 hours, the precipitated product is immediately sucked off on a frit S-2. After drying under reduced pressure, Form I of clopidogrel hydrogen sulphate having the melting point of 184 to 186 °C is obtained.
Example 3
20 grams of clopidogrel base are placed into a flat-bottom flask, equipped with a thermometer and a magnetic stirrer, and dissolved in 140 ml dried i-propanol and 140 ml butyl acetate.
Under stirring, the solution is cooled down to 0 to -2 °C. Subsequently, 2.9 ml of 98% sulphuric acid are added (p-1.8361 g.cm"3). The mixture is stirred at the above stated temperature for 1 hour, at 5 °C for 2 hours and at -5 °C for 8 hours. The product is filtered off on fritted glass S-2 and dried at a reduced pressure. 14.5 g of clopidogrel hydrogen sulphate
Form I, showing the melting point of 184 to 186 °C, are obtained.
From the mother liquors, clopidogrel hydrogen sulphate Form II, having the melting point of
177 to 179 °C, is separated upon standing at 25 °C.
Example 4
1.84 gram of clopidogrel base are placed into a flat-bottom flask, equipped with a thermometer and a magnetic stirrer and dissolved in 26 ml dried i-propanol under boiling. Under stirring, the solution is cooled down to 0 °C. Then, 0.33 ml of 98% sulphuric acid are
added (p-1.8361 g.cm"3) and inoculated with crystals of Form I. The mixture is stirred at the above stated temperature for 2.5 hours, whereby in about 1 hour the look of the separated crystalline phase changes as it gradually passes into the solution. The temperature of the mixture is increased to 10 °C and it is inoculated with Form I crystals again after about 0.5 hour. The mixture is stirred until the crystalline phase separates at the temperature of 10 °C for 1.5 to 2 hours, and then at -1 °C for 8 hours. The product is filtered off on fritted glass S-2 and dried with a stream of air. 1.8 g of clopidogrel hydrogen sulphate Form I having the melting point of 184 to 186 °C are obtained.
Example 5
56.9 g clopidogrel base are dissolved in 570 ml of n-butyl acetate and placed in a three-neck round flask, equipped with a thermometer, a KPG stirrer and a dropping funnel. Under mixing, the butyl acetate solution is cooled down to 0 to +5 °C in a water-and-ice bath. The solution is inoculated with crystals of clopidogrel Form I. Under intensive stirring, 9.71 ml of concentrated sulphuric acid (97%) (1.5 equiv.) are added dropwise into the cooled-down solution such that the temperature of the reaction mixture does not exceed +5 °C. After acidifying, the reaction mixture is heated to +10 °C and stirred at this temperature for 3 hours, after which period the temperature of crystallisation is increased to +20 to +24 °C, at which temperature stirring is continued for another 18 hours.
After said period the obtained crystalline fraction is filtered through fritted glass (S2) and dried at a temperature up to 25 °C.
In this way, 63.0 g (84.8 % of theory) of clopidogrel hydrogen sulphate Form I are obtained.
The X-ray diffractogram corresponds to Form I (Figure 4).
Example 6
12.63 g clopidogrel base are dissolved in 126 ml of n-butyl acetate and placed in a three-neck round flask, equipped with a thermometer, a KPG stirrer and a dropping funnel. Under stirring, the butyl acetate solution is cooled down to 0 to +5 °C in a water-and-ice bath. The solution is inoculated with crystals of clopidogrel Form I. Under intensive stirring, 2.4 ml of concentrated sulphuric acid (98%) (1.1 equiv.) are added dropwise into the cooled-down solution such that the temperature of the reaction mixture does not exceed +5 °C. After acidifying, the reaction mixture is heated to +10 °C and stirred at this temperature for 3 hours,
after which period the temperature of crystallisation is increased to +20 to +23 °C, at which temperature stirring is continued for another 19 hours.
After said period the obtained crystalline fraction is filtered through fritted glass (S2) and dried at a temperature up to 25 °C.
In this way, 15.16 g (78.0 % of theory) of clopidogrel hydrogen sulphate Form I are obtained.
The X-ray diffractogram corresponds to Form I (Figure 5).
Claims
1. A method for manufacturing hydrogen sulphate (alpha S) of the alpha-(2- chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester (clopidogrel hydrogen sulphate) of formula I
:D
in crystalline Form I, characterized in that the compound of formula I is separated out of a solution of clopidogrel in the form of the free base or salt in a solvent selected from the series of primary, secondary or tertiary C1-C5 alcohols or their esters with C1-C4 carboxylic acids, or optionally of mixtures thereof.
2. The method according to claim 1, characterized in that the compound of formula I is crystallised out of a solution of clopidogrel hydrogen sulphate by cooling down.
3. The method according to claim 1, characterized in that the compound of formula I is precipitated out of a solution of the base or of its salt by adding of 0.6 to 1.1 equivalent of sulphuric acid.
4. The method according to claim 3, characterized in that the compound of formula I is precipitated out of a solution in a Cl to C5 alcohol.
5. The method according to claim 4, characterized in that the precipitation is performed out of a solution in 2-propanol.
6. The method according to claim 5, characterized in that the precipitation is performed at a temperature between -5 and 15 °C and the solution is inoculated with crystals of Form !
7. Clopidrogrel hydrogen sulphate of formula I, manufactured by the method according to the claim 6, having the contents of 98 % of crystalline Form I at minimum.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003269673A AU2003269673A1 (en) | 2002-08-27 | 2003-08-26 | Method for manufacturing crystalline form i of clopidogrel hydrogen sulphate |
| EP03750270A EP1554284B1 (en) | 2002-08-27 | 2003-08-26 | Method for manufacturing crystalline form i of clopidogrel hydrogen sulphate |
| US10/525,341 US7714133B2 (en) | 2002-08-27 | 2003-08-26 | Method for manufacturing crystalline form I of clopidogrel hydrogen sulphate |
| JP2004569700A JP2006502238A (en) | 2002-08-27 | 2003-08-26 | Process for producing crystalline form I of clopidogrel hydrogensulfate |
| EA200500310A EA007977B1 (en) | 2002-08-27 | 2003-08-26 | Method for manufacturing crystalline form i of clopidogrel hydrogen sulphate |
| CA002495823A CA2495823A1 (en) | 2002-08-27 | 2003-08-26 | Method for manufacturing crystalline form i of clopidogrel hydrogen sulphate |
| DE60324301T DE60324301D1 (en) | 2002-08-27 | 2003-08-26 | PROCESS FOR PREPARING CRYSTAL FORM I OF CLOPIDOGREL HYDROGEN SULPHATE |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZ20022906A CZ297472B6 (en) | 2002-08-27 | 2002-08-27 | Process for preparing crystalline form I of clopidogrel hydrogen sulfate |
| CZPV2002-2906 | 2002-08-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2004020443A1 true WO2004020443A1 (en) | 2004-03-11 |
Family
ID=31954588
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CZ2003/000049 WO2004020443A1 (en) | 2002-08-27 | 2003-08-26 | Method for manufacturing crystalline form i of clopidogrel hydrogen sulphate |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US7714133B2 (en) |
| EP (1) | EP1554284B1 (en) |
| JP (1) | JP2006502238A (en) |
| KR (1) | KR20050058492A (en) |
| AT (1) | ATE411998T1 (en) |
| AU (1) | AU2003269673A1 (en) |
| CA (1) | CA2495823A1 (en) |
| CZ (1) | CZ297472B6 (en) |
| DE (1) | DE60324301D1 (en) |
| EA (1) | EA007977B1 (en) |
| PL (1) | PL373578A1 (en) |
| WO (1) | WO2004020443A1 (en) |
Cited By (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005016931A3 (en) * | 2003-08-13 | 2005-04-28 | Krka Torvarna Zdravil D D Novo | Crystallisation of solid forms of clopidogrel addition salts |
| WO2005097804A1 (en) * | 2004-04-09 | 2005-10-20 | Hanmi Pharm. Co., Ltd. | Crystalline clopidogrel naphthalenesulfonate or hydrate thereof, method for preparing same and pharmaceutical composition containing same |
| EP1651646A1 (en) * | 2003-08-04 | 2006-05-03 | Wockhardt Limited | A novel process for the manufacture of (+)-(s)-clopidogrel bisulfate form-i |
| EP1693375A1 (en) * | 2005-02-21 | 2006-08-23 | KRKA, tovarna zdravil, d.d., Novo mesto | Process for preparing clopidrogel hydrogen sulfate of form I |
| EP1740593A1 (en) | 2004-04-19 | 2007-01-10 | KRKA, tovarna zdravil, d.d., Novo mesto | Processes for the preparation of clopidogrel hydrogen sulfate polymorphic form i |
| WO2007017886A1 (en) * | 2005-08-11 | 2007-02-15 | Arch Pharmalabs Limited | Novel process for preparation of clopidogrel bisulphate polymorphic form i |
| KR100736024B1 (en) | 2005-09-21 | 2007-07-06 | 주식회사종근당 | Novel resinate complex of S-clopidogrel and production method thereof |
| JP2007533746A (en) * | 2004-04-20 | 2007-11-22 | サノフイ−アベンテイス | Clopidogrel salt and its polymorphic forms |
| JP2007533744A (en) * | 2004-04-20 | 2007-11-22 | サノフイ−アベンテイス | (+)-(S) -α- (2-Chlorophenyl) -6,7-dihydrothieno [3,2-C] pyridine-5 (4H) acetic acid methyl hydrobromide, clopidrogel hydrobromic acid Polymorphic form of salt |
| WO2008093357A3 (en) * | 2007-01-29 | 2008-12-04 | Ipca Lab Ltd | Process for preparation of crystalline clopidogrel hydrogen sulphate form i |
| EP2107061A1 (en) | 2008-04-02 | 2009-10-07 | Krka Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of optically enriched clopidogrel |
| WO2009156279A2 (en) * | 2008-06-24 | 2009-12-30 | Zach System S.P.A. | Process for the preparation of clopidogrel hydrogen sulfate crystalline form i |
| US7772398B2 (en) | 2005-03-11 | 2010-08-10 | Dr. Reddy's Laboratories, Inc. | Process for making crystalline form I of clopidogrel hydrogen sulphate |
| WO2011051976A2 (en) | 2009-10-30 | 2011-05-05 | Matrix Laboratories Ltd | An improved process for the preparation of clopidogrel bisulfate form i |
| WO2011055378A1 (en) * | 2009-11-09 | 2011-05-12 | Pharmazell Gmbh | Improved process for preparation of clopiodogrel bisulfate crystalline form-1 |
| WO2011042804A3 (en) * | 2009-10-08 | 2011-07-21 | Jubliant Life Sciences Limited | An improved process for the preparation of clopidogrel hydrogen sulfate form i |
| WO2011125069A1 (en) | 2010-03-22 | 2011-10-13 | Rpg Life Sciences Limited | A process for preparation of crystalline form i of clopidogrel bisulfate |
| CN102558194A (en) * | 2010-12-11 | 2012-07-11 | 山东方明药业股份有限公司 | Preparation method of I-type clopidogrel hydrogen sulfate |
| CN102875568A (en) * | 2012-09-06 | 2013-01-16 | 苏州晶云药物科技有限公司 | Method for preparing (+)-(S)-clopidogrel hydrogen sulfate pure crystal type I |
| KR20160142578A (en) | 2015-06-03 | 2016-12-13 | 경동제약 주식회사 | Method for preparing crystalline form I of Clopidogrel hydrogen sulfate |
| CN107118221A (en) * | 2017-05-24 | 2017-09-01 | 常州制药厂有限公司 | A kind of bisulfate clopidogrel crystal formation I preparation methods |
| CN107163060B (en) * | 2017-05-24 | 2021-03-02 | 常州制药厂有限公司 | Preparation method of clopidogrel hydrogen sulfate crystal form II |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP1680430B1 (en) * | 2003-11-03 | 2010-01-20 | Cadila Healthcare Ltd. | Processes for preparing form i of (s)-(+)- clopidogrel bisulfate |
| US20080188663A1 (en) * | 2007-01-29 | 2008-08-07 | Ashok Kumar | Process for the preparation of crystalline clopidogrel hydrogen sulphate Form I |
| KR20160033792A (en) | 2007-04-27 | 2016-03-28 | 사이덱스 파마슈티칼스, 인크. | Formulations containing clopidogrel and sulfoalkyl ether cyclodextrin and methods of use |
| US8236782B2 (en) | 2009-05-13 | 2012-08-07 | Cydex Pharmaceuticals, Inc. | Pharmaceutical compositions comprising prasugrel and cyclodextrin derivatives and methods of making and using the same |
| KR101130445B1 (en) * | 2009-10-29 | 2012-03-27 | 동아제약주식회사 | Process for preparing crystalline Form I Clopidogrel bisulfate |
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| EP1651646B1 (en) * | 2003-08-04 | 2012-05-09 | Wockhardt Limited | A novel process for the manufacture of (+)-(s)-clopidogrel bisulfate form-i |
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- 2002-08-27 CZ CZ20022906A patent/CZ297472B6/en not_active IP Right Cessation
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2003
- 2003-08-26 WO PCT/CZ2003/000049 patent/WO2004020443A1/en active Application Filing
- 2003-08-26 CA CA002495823A patent/CA2495823A1/en not_active Abandoned
- 2003-08-26 PL PL03373578A patent/PL373578A1/en not_active Application Discontinuation
- 2003-08-26 EA EA200500310A patent/EA007977B1/en not_active IP Right Cessation
- 2003-08-26 AU AU2003269673A patent/AU2003269673A1/en not_active Abandoned
- 2003-08-26 DE DE60324301T patent/DE60324301D1/en not_active Expired - Lifetime
- 2003-08-26 AT AT03750270T patent/ATE411998T1/en not_active IP Right Cessation
- 2003-08-26 EP EP03750270A patent/EP1554284B1/en not_active Revoked
- 2003-08-26 KR KR1020057003106A patent/KR20050058492A/en not_active Application Discontinuation
- 2003-08-26 US US10/525,341 patent/US7714133B2/en not_active Expired - Fee Related
- 2003-08-26 JP JP2004569700A patent/JP2006502238A/en active Pending
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| US6429210B1 (en) * | 1998-06-15 | 2002-08-06 | Sanofi-Synthelabo | Polymorphic clopidogrel hydrogenesulphate form |
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| EP1651646A1 (en) * | 2003-08-04 | 2006-05-03 | Wockhardt Limited | A novel process for the manufacture of (+)-(s)-clopidogrel bisulfate form-i |
| EP1651646A4 (en) * | 2003-08-04 | 2007-03-21 | Wockhardt Ltd | A novel process for the manufacture of (+)-(s)-clopidogrel bisulfate form-i |
| WO2005016931A3 (en) * | 2003-08-13 | 2005-04-28 | Krka Torvarna Zdravil D D Novo | Crystallisation of solid forms of clopidogrel addition salts |
| WO2005097804A1 (en) * | 2004-04-09 | 2005-10-20 | Hanmi Pharm. Co., Ltd. | Crystalline clopidogrel naphthalenesulfonate or hydrate thereof, method for preparing same and pharmaceutical composition containing same |
| JP2007532530A (en) * | 2004-04-09 | 2007-11-15 | ハンミ ファーム． シーオー．， エルティーディー． | Crystalline clopidogrel naphthalene sulfonate or hydrate thereof, process for producing the same and pharmaceutical composition containing the same |
| NO339878B1 (en) * | 2004-04-19 | 2017-02-13 | Krka Tovarna Zdravil Dd | Process for Preparation of Clopidogrel Hydrogen Sulfate Polymorph Form I |
| EP1740593A1 (en) | 2004-04-19 | 2007-01-10 | KRKA, tovarna zdravil, d.d., Novo mesto | Processes for the preparation of clopidogrel hydrogen sulfate polymorphic form i |
| EA010198B1 (en) * | 2004-04-19 | 2008-06-30 | Крка, Товарна Здравил, Д.Д., Ново Место | Processes for the preparation of clopidogrel hydrogen sulfate polymorphic form i |
| JP2007533746A (en) * | 2004-04-20 | 2007-11-22 | サノフイ−アベンテイス | Clopidogrel salt and its polymorphic forms |
| JP2007533744A (en) * | 2004-04-20 | 2007-11-22 | サノフイ−アベンテイス | (+)-(S) -α- (2-Chlorophenyl) -6,7-dihydrothieno [3,2-C] pyridine-5 (4H) acetic acid methyl hydrobromide, clopidrogel hydrobromic acid Polymorphic form of salt |
| WO2006087226A1 (en) * | 2005-02-21 | 2006-08-24 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for preparing clopidogrel hydrogen sulfate of form i |
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| WO2011051976A2 (en) | 2009-10-30 | 2011-05-05 | Matrix Laboratories Ltd | An improved process for the preparation of clopidogrel bisulfate form i |
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| WO2011125069A1 (en) | 2010-03-22 | 2011-10-13 | Rpg Life Sciences Limited | A process for preparation of crystalline form i of clopidogrel bisulfate |
| CN102558194A (en) * | 2010-12-11 | 2012-07-11 | 山东方明药业股份有限公司 | Preparation method of I-type clopidogrel hydrogen sulfate |
| CN102875568A (en) * | 2012-09-06 | 2013-01-16 | 苏州晶云药物科技有限公司 | Method for preparing (+)-(S)-clopidogrel hydrogen sulfate pure crystal type I |
| KR20160142578A (en) | 2015-06-03 | 2016-12-13 | 경동제약 주식회사 | Method for preparing crystalline form I of Clopidogrel hydrogen sulfate |
| CN107118221A (en) * | 2017-05-24 | 2017-09-01 | 常州制药厂有限公司 | A kind of bisulfate clopidogrel crystal formation I preparation methods |
| CN107163060B (en) * | 2017-05-24 | 2021-03-02 | 常州制药厂有限公司 | Preparation method of clopidogrel hydrogen sulfate crystal form II |
| CN107118221B (en) * | 2017-05-24 | 2021-09-07 | 常州制药厂有限公司 | Preparation method of clopidogrel hydrogen sulfate crystal form I |
Also Published As
| Publication number | Publication date |
|---|---|
| ATE411998T1 (en) | 2008-11-15 |
| PL373578A1 (en) | 2005-09-05 |
| AU2003269673A1 (en) | 2004-03-19 |
| US20060041136A1 (en) | 2006-02-23 |
| CZ297472B6 (en) | 2006-12-13 |
| EA007977B1 (en) | 2007-02-27 |
| CA2495823A1 (en) | 2004-03-11 |
| EP1554284A1 (en) | 2005-07-20 |
| US7714133B2 (en) | 2010-05-11 |
| JP2006502238A (en) | 2006-01-19 |
| KR20050058492A (en) | 2005-06-16 |
| EP1554284B1 (en) | 2008-10-22 |
| DE60324301D1 (en) | 2008-12-04 |
| EA200500310A1 (en) | 2005-08-25 |
| CZ20022906A3 (en) | 2004-05-12 |
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