WO2011051976A2 - Procédé amélioré de préparation de la forme i du bisulfate de clopidogrel - Google Patents

Procédé amélioré de préparation de la forme i du bisulfate de clopidogrel Download PDF

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Publication number
WO2011051976A2
WO2011051976A2 PCT/IN2010/000710 IN2010000710W WO2011051976A2 WO 2011051976 A2 WO2011051976 A2 WO 2011051976A2 IN 2010000710 W IN2010000710 W IN 2010000710W WO 2011051976 A2 WO2011051976 A2 WO 2011051976A2
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WO
WIPO (PCT)
Prior art keywords
clopidogrel
clopidogrel bisulfate
solvent
ether
free base
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Application number
PCT/IN2010/000710
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English (en)
Other versions
WO2011051976A3 (fr
Inventor
Ramakoteswara Rao Jetti
Aggi Rami Reddy Bommareddy
Anjaneya Raju Indukuri
Debashish Datta
Original Assignee
Matrix Laboratories Ltd
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Publication date
Application filed by Matrix Laboratories Ltd filed Critical Matrix Laboratories Ltd
Publication of WO2011051976A2 publication Critical patent/WO2011051976A2/fr
Publication of WO2011051976A3 publication Critical patent/WO2011051976A3/fr

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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 present invention relates to an improved process for the preparation of Clopidogrel bisulfate Form I from clopidogrel free base. Whereas free base is isolated from Clopidogrel acid addition salts.
  • Clopidogrel having the chemical name (+)-(S)-a-(2-Chlorophenyl)-6, 7-dihydrothieno [3, 2-c] pyridin-5(4H)-acetic acid methyl ester is an antithrombotic drug. It acts as an inhibitor of ADP- induced platelet aggregation acting by direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of the subsequent ADP-mediated activation of glycoprotein GPIIb/llla complex. By inhibiting platelet aggregation, Clopidogrel reduces the chance of arterial blockage, thus preventing strokes and heart-attacks.
  • ADP adenosine diphosphate
  • Clopidogrel is marketed as bisulfate salt having the following chemical structure of formula 1 :
  • US 4847265 patent first discloses clopidogrel or it's salts, wherein clopidogrel is prepared from racemic clopidogrel using camphoursulfonic acid and further converted to acid addition salts.
  • US 6429210 patent discloses Clopidogrel bisulfate polymorphic forms I and II. This patent also discloses Clopidogrel bisulfate form I is prepared according to the process of US '265 using acetone and sulfuric acid.
  • US 6767913 patent discloses new polymorphic forms III, IV, V and amorphous Clopidogrel bisulfate and processes for their preparation.
  • US 2006/0047121 application discloses the precipitation of Clopidogrel bisulfate Form I by dissolving Clopidogrel bisulfate Form II in a C ⁇ Cs carboxylic acid and by precipitating in the presence of an aliphatic or cyclic ether.
  • WO2004020443 application describes process for preparation of Clopidogrel bisulfate Form I, which comprises separating out crystalline Form I from the solution of Clopidogrel in the form of free base or salt in a solvent selected from the series of the primary, secondary or tertiary alcohols or their esters with carboxylic acids or optionally of mixtures thereof.
  • WO 2004/048385 application discloses processes for the preparation of Clopidogrel bisulfate Form I by dissolving Clopidogrel free base in ethanol followed by addition sulfuric acid and precipitated by adding an anti solvent like methyl tert-butyl ether.
  • the present invention overcomes the problems associated with prior art processes.
  • the present invention further directed to an improved, industrially viable, cost-effective process for the manufacturing of Clopidogrel bisulfate of polymorphic Form I.
  • the present invention relates to an improved process for preparation of Clopidogrel bisulfate Form I.
  • the present invention provides process for the preparation of clopidogrel bisulfate form I comprising the steps of: a) dissolving Clopidogrel bisulfate in organic solvent and water, b) adding a base to get clopidogrel freebase, c) dissolving Clopidogrel free base in an organic solvent, d) optionally adding a catalyst, e) adding an ether solvent containing sulfuric acid, and f) isolating Clopidogrel bisulfate Form I.
  • Another aspect of the present invention provides a process for preparation of Clopidogrel free base comprising the steps of: a) dissolving Clopidogrel bisulfate in organic solvent and water, b) adding a base, and c) isolating Clopidogrel free base.
  • Yet another aspect of the present invention provides a process for preparation of Clopidogrel bisulfate Form I comprising the steps of: a) dissolving Clopidogrel bisulfate form II in an organic solvent at an elevated temperature, b) cooling the solution, c) adding an ether solvent, and d) isolating Clopidogrel bisulfate Form I.
  • Yet another aspect of the present invention provides stable Clopidogrel bisulfate Form I during storage.
  • Yet another aspect of the present invention provides a process for packaging and storing Clopidogrel bisulfate Form I with increased stability and shelf life, which includes placing Clopidogrel bisulfate Form I in a sealed container along with a moisture adsorbent.
  • Clopidogrel bisulfate polymorphic form I which comprise the steps of: a) Placing Clopidogrel bisulfate form I in innermost LDPE or HMLDPE bag under nitrogen atmosphere, twisted and tied or vacuumized nitrogen sealing,
  • Fig 1 shows an X-ray Diffraction diagram of Clopidogrel Bisulfate Form I.
  • Fig 2 shows the DSC Thermogram of Clopidogrel Bisulfate Form I.
  • the present invention is related to an improved process for the preparation of Clopidogrel bisulfate Form I by dissolving clopidogrel bisulfate form II in aqueous organic solvent, neutralizing the salt with a base to get clopidogrel freebase, followed by treatment with sulfuric acid in the presence of ether solvent.
  • the present invention provides a process for preparation of Clopidogrel bisulfate Form I comprising the steps of:
  • Clopidogrel bisulfate is dissolved in a mixture of an organic solvent and water at ambient temperature, neutralized with a base. Organic layer is separated; solvent is removed to get clopidogrel freebase as oil. Clopidogrel base is dissolved in solvent at ambient temperature; the resulting solution is cooled to -20 to 5°C, preferably -15 to -5°C. To this solution is added to pre-cooled solution of sulfuric acid containing ether solvent for about 45-90 min. the suspension is further stirred for about 15-24hours. The obtained solid is isolated as clopidogrel bisulfate form I
  • the organic solvent used for the dissolution of clopidogrel bisulfate is selected from chlorinated hydrocarbon solvent such as dichloromethane, aliphatic ester solvent such as ethyl acetate or mixture thereof.
  • base used for neutralization is selected from aqueous alkali metal carbonates such as sodium bicarbonate or aqueous alkali metal hydroxides such as sodium hydroxide.
  • solvent is removed to get clopidogrel freebase by distillation, or evaporation.
  • solvent used for the dissolution of clopidogrel free base is selected from ether solvents such as isopropyl ether, carboxylic acids such as acetic acid, ketone solvent such as acetone or mixture thereof.
  • the ratio of carboxylic acid to the C 3 to C 6 aliphatic ketone varies from 1 :5 to 5: 1 , preferably from 1 :3 to 3:1.
  • the sulfuric acid is dissolved in an ether solvent, which is preferably pre-cooled to a temperature of -25°C to 0°C, more preferably to a temperature of -15°C to -10°C.
  • Clopidogrel solution is then added to a pre-cooled solution of sulfuric acid, the product #
  • the present invention provides a process for preparation of Clopidogrel free base comprising the steps of:
  • Clopidogrel bisulfate is dissolved in a mixture of an organic solvent and water at ambient temperature, neutralized with aqueous inorganic base. Organic layer is separated, optionally added catalyst and solvent is removed to get clopidogrel freebase as oil.
  • the organic solvent used for the dissolution of clopidogrel bisulfate is selected from chlorinated hydrocarbon solvent such as dichloromethane, aliphatic ester solvent such as ethyl acetate or mixture thereof.
  • base used for neutralization is selected from alkali metal carbonates such as sodium bicarbonate or alkali metal hydroxides such as sodium hydroxide.
  • solvent is removed to get clopidogrel freebase by distillation, or evaporation.
  • an anti-oxidant employed is selectged from butylated hydroxy toluene (BHT), sodium dithionite, sodium metabisulphite or resveratrol.
  • the present invention provides a process for preparation of Clopidogrel bisulfate Form I comprising the steps of:
  • Clopidogrel bisulfate Form II is dissolved in acetic acid at an elevated temperature, preferably at 80°C to 1 10°C, more preferably at 90°C to 100°C. The solution was thereafter cooled to 25-30°C.
  • the ether solvent selected from the group consisting of diisopropyl ether, methyl tert-butyl ether, diethyl ether, preferably diisopropyl ether.
  • the suspension is allowed to stir for a time period of 12 to 24 hours, preferably 15 to 18 hours, to enable the precipitation of free flowing white solid.
  • Clopidogrel bisulfate polymorphic form I which comprise the steps of: a) Placing Clopidogrel bisulfate form I in innermost LDPE or HMLDPE bag under nitrogen atmosphere, twisted and tied or vacuumized nitrogen sealing,
  • the moisture adsorbent is included to absorb any moisture which enters the packaging.
  • Suitable moisture adsorbents which can be used in the present invention are selected from molecular sieve zeolites, high silica zeolites, having a high silica/alumina ratio of 25 or more, such as ZSM-5 (made by Mobil Oil Co., silica/alumina ratio of 400), silicalite, USY (Ultra Stable Y type).
  • ZSM-5 made by Mobil Oil Co., silica/alumina ratio of 400
  • silicalite USY (Ultra Stable Y type).
  • Clopidogrel free base (73 g) was dissolved in acetone (1500 ml) at 25-30°C and cooled to 0-5°C. To this solution, cone, sulfuric acid (22.2 g) was added drop wise for 10 min at 0-5 °C followed by slowly raising the temperature to 25-30°C. The reaction mass was stirred for 15 h at 25-30 °C. The obtained solid was filtered, washed with acetone (100 ml) and dried under vacuum at 50°C for 2 hours.
  • Clopidogrel bisulfate Form II (200 g) was dissolved in ethyl acetate and water [800 ml (1 : 1 )] at 25-30°C. The clear solution was cooled to 0-5°C and pH was adjusted to 7 using saturated sodium bicarbonate solution. The organic layer was extracted with ethyl acetate (2X200 ml). The combined organic layer was dried over Na 2 S0 4 and concentrated under vacuum at 40- 45°C to give Clopidogrel free base as viscous oil.
  • Example 3 Preparation of Clopidogrel Bisulfate Form I from free base
  • Isopropyl ether (750 ml) and cone, sulfuric acid (7.6 g) were charged in a RB flask and cooled to -10°C to -15°C.
  • Clopidogrel free base (25 g) was dissolved in acetic acid (25 ml) at 25-30°C and cooled to 0-5°C. This solution was added to the above pre-cooled Isopropyl ether solution drop wise for 5-10 min.
  • the solid suspension obtained was stirred for 5 hours at -10 to -15°C and further stirring continued at 25-30 °C for 15 hours.
  • the solid obtained was filtered, washed with isopropyl ether (3X25 ml) and dried at 50 °C for 3h.
  • the solid was then grinded thoroughly and slurred in isopropyl ether (250 ml) for 2h at 25-30°C. The solid was filtered, washed with isopropyl ether (25 ml) and dried under vacuum at 50 °C for 15hours.
  • Isopropyl ether (750 ml) and sulfuric acid (7.6 g) were charged in a RB flask and cooled to -10 to -15°C.
  • Clopidogrel free base (25 g) was dissolved in mixture of acetone (7 ml) and acetic acid (18 ml) at 25-30°C and cooled to 0-5°C. This solution was added to the above pre-cooled isopropyl ether solution in 5-10 min.
  • the solid suspension obtained was stirred for 5 h at. -10 to -15°C and further stirring continued at 25-30 °C for 15 hours.
  • the solid obtained was filtered, washed with isopropyl ether (3X25 ml) and dried at 50 °C for 3hours.
  • the solid was then grinded thoroughly and slurred in isopropyl ether (250 ml) for 2 hours at 25-30°C.
  • the solid obtained was filtered, washed with isopropyl ether (25 ml) and dried under vacuum at 50 °C for 15hours.
  • the solid was then grinded thoroughly and slurred in isopropyl ether (250 ml) for 2 hours at 25-30°C.
  • the solid obtained was filtered, washed with isopropyl ether (25 ml) and dried under vacuum at 50 °C for 15hours.
  • Clopidogrel Bisulfate Form II (25 g) was dissolved in acetic acid (20 ml) at 90-100°C. The clear solution was cooled to 25-30°C and isopropyl ether (750 ml) was added slowly for 3 hours. Initially gummy material formed which was stirred overnight at 25-30°C to give free flowing solid. The obtained solid was filtered, washed with isopropyl ether (2X25 ml) and dried at 50 °C for 3 hours.
  • the solid was then grinded thoroughly and slurred in isopropyl ether (250 ml) for 2 hours at 25-30°C.
  • the solid obtained was filtered, washed with isopropyl ether (25 ml) and dried at 50 °C for 15hours.
  • Clopidogrel bisulfate Form II (100 g) was dissolved in dichloromethane and water [400 ml (1 :1 )] at 20-25°C. The clear solution was cooled to 20-25°C and pH was adjusted to 7
  • Clopidogrel free base as viscous oil (76.6 g). This was dissolved in isopropyl ether (1 149 mL) and filtered through hyflow bed and the bed was further washed with isopropyl ether (383 mL). The filtrate was cooled to -15 to - 10°C and added acetone (72.7 mL) and acetic acid (3.83 mL) at the same temperature.
  • Clopidogrel bisulfate Form II (100 g) was dissolved in dichloromethane and water [400 ml (1 : 1 )] at 20-25°C. The clear solution was cooled to 20-25°C and pH was adjusted to 7
  • Clopidogrel free base as viscous oil (76.6 g). This was dissolved in isopropyl ether (1 149 mL) and filtered through hyflow bed and the bed was further washed with isopropyl ether (383 mL). The filtrate was cooled to - -15 to -10°C and added acetone (76.6 mL) at the same temperature.
  • Clopidogrel bisulfate Form II (100 g) was dissolved in dichloromethane and water [400 ml (1 :1 )] at 20-25°C. The clear solution was cooled to 20-25°C and pH was adjusted to 6.5-7.5 using saturated NaHC03 solution. The organic layer was extracted with dichloromethane (2 ⁇ 100 ml). The combined organic layers was dried over Na 2 S0 4 and added butylated hydroxy toluene (0.52 g), and then concentrated under vacuum at 40-45°C to give Clopidogrel free base as viscous oil (76.6 g).
  • Clopidogrel bisulfate Form II (100 g) was dissolved in dichloromethane and water [400 ml (1 :1 )] at 20-25°C. The clear solution was cooled to 20-25°C and pH was adjusted to 7
  • Clopidogrel free base (10 g) was dissolved in mixture of acetone (9.7 ml) and acetic acid (0.3 ml) at 25-30°C and cooled to 0-5°C and added butylated hydroxy toluene (0.068 g). This solution was added to a pre-cooled (-10 to -15°C) solution of isopropyl ether (300 ml) and sulfuric acid (2.7 g) over 5-10 min. The solid suspension obtained was stirred for 5 hours at -10 to -15°C and then at 25-30 °C for 15 hours. The solid obtained was filtered, washed with isopropyl ether (2x20 ml) and dried under vacuum at 50-60°C for 15hours.
  • Clopidogrel free base 50 g was dissolved in acetone (50 ml) and cooled to 0-5°C and added butylated hydroxy toluene (0.342 g). This solution was added to a pre-cooled (-10 to -15°C) solution of isopropyl ether (1500 mL) and sulfuric acid (14 g) over 5-10 min. The solid suspension obtained was stirred for 5 hours at -10 to -15°C and then at 25-30 °C for 15 hours. The solid formed was filtered, washed with isopropyl ether (2x50 ml) and dried under vacuum at 50-60°C for 15hours.
  • Example14 Process for packing and storage conditions of Clopidogrel bisulfate form I. Packing conditions: The material shall be packed in LDPE/ HMLDPE bag then twisted and tied/ vacuumised nitrogen sealing. It is then inserted in triple laminated aluminum bag and adds two silica and one molecular sieve sachet and vacuumised nitrogen sealing. Both these bags are then put into outer bag of triple laminated aluminum bag and add two silica gel sachets and one molecular sieve sachet and vacuumised nitrogen sealing.
  • Storage conditions Preserve in well-closed, tight containers and store at room temperature 0 to ambient temperature.

Abstract

L'invention concerne un procédé amélioré de préparation de la forme I du bisulfate de clopidogrel à partir d'une base exempte de clopidogrel, la base exempte de clopidogrel étant isolée à partir d'un sel d'addition d'acide de clopidogrel.
PCT/IN2010/000710 2009-10-30 2010-10-29 Procédé amélioré de préparation de la forme i du bisulfate de clopidogrel WO2011051976A2 (fr)

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IN2637CH2009 2009-10-30
IN2637/CHE/2009 2009-10-30

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WO2011051976A3 WO2011051976A3 (fr) 2011-07-14

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104211714A (zh) * 2014-08-14 2014-12-17 广东东阳光药业有限公司 一种血小板聚集抑制剂的制备方法
CN105473456A (zh) * 2013-06-26 2016-04-06 巴洛克斯私人有限公司 涂覆白藜芦醇层的饮料容器
KR20160142578A (ko) 2015-06-03 2016-12-13 경동제약 주식회사 클로피도그렐 황산염 결정형 i형의 제조방법

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4847265A (en) 1987-02-17 1989-07-11 Sanofi Dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate and the pharmaceutical compositions containing it
US6429210B1 (en) 1998-06-15 2002-08-06 Sanofi-Synthelabo Polymorphic clopidogrel hydrogenesulphate form
WO2004020443A1 (fr) 2002-08-27 2004-03-11 Zentiva, A.S. Procede de fabrication de la forme cristalline i du clopidogrel hydrogene sulfate
WO2004048385A2 (fr) 2002-11-28 2004-06-10 Instytut Farmaceutyczny Procede de preparation de la forme cristalline 1 du clopidogrel hydrogene sulfate
US6767913B2 (en) 2001-12-18 2004-07-27 Teva Pharmaceutical Industries Ltd. Crystal forms iii, iv, v, and novel amorphous form of clopidogrel hydrogensulfate, processes for their preparation, processes for the preparation of form i, compositions containing the new forms and methods of administering the new forms
US20060047121A1 (en) 2004-09-01 2006-03-02 Sawant Kamlesh D Novel process for preparation of clopidogrel bisulfate polymorph - Form I

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7999106B2 (en) * 2004-04-19 2011-08-16 Krka, Tovarna Zdravil, D.D., Novo Mesto Processes for the preparation of clopidogrel hydrogen sulfate polymorphic form I
US20090093635A1 (en) * 2006-03-09 2009-04-09 Sandor Garadnay PROCESS FOR MAKING POLYMORPH FROM I OF (S) - (+) -METHYL-ALPHA- (2-CHLOROPHENYL) -6, 7-DYHIDRO-THIENO- [3, 2-c] PYRIDINE-5 (4H) -ACETATE HYDROGEN SULFATE
SI22383A (sl) * 2006-09-22 2008-04-30 Krka, Tovarna Zdravil, D.D., Novo Mesto Nov postopek sinteze klopidogrela in nove oblike njegovih farmacevtsko sprejemljivih soli
PL382055A1 (pl) * 2007-03-23 2008-09-29 Koźluk Tomasz Nobilus Ent Sposób wytwarzania formy krystalicznej 1 wodorosiarczanu klopidogrelu

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4847265A (en) 1987-02-17 1989-07-11 Sanofi Dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate and the pharmaceutical compositions containing it
US6429210B1 (en) 1998-06-15 2002-08-06 Sanofi-Synthelabo Polymorphic clopidogrel hydrogenesulphate form
US6767913B2 (en) 2001-12-18 2004-07-27 Teva Pharmaceutical Industries Ltd. Crystal forms iii, iv, v, and novel amorphous form of clopidogrel hydrogensulfate, processes for their preparation, processes for the preparation of form i, compositions containing the new forms and methods of administering the new forms
WO2004020443A1 (fr) 2002-08-27 2004-03-11 Zentiva, A.S. Procede de fabrication de la forme cristalline i du clopidogrel hydrogene sulfate
WO2004048385A2 (fr) 2002-11-28 2004-06-10 Instytut Farmaceutyczny Procede de preparation de la forme cristalline 1 du clopidogrel hydrogene sulfate
US20060047121A1 (en) 2004-09-01 2006-03-02 Sawant Kamlesh D Novel process for preparation of clopidogrel bisulfate polymorph - Form I

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105473456A (zh) * 2013-06-26 2016-04-06 巴洛克斯私人有限公司 涂覆白藜芦醇层的饮料容器
US9962734B2 (en) 2013-06-26 2018-05-08 Barokes Pty Ltd Process for making a container with a resveratrol layer
CN104211714A (zh) * 2014-08-14 2014-12-17 广东东阳光药业有限公司 一种血小板聚集抑制剂的制备方法
CN104211714B (zh) * 2014-08-14 2016-09-14 广东东阳光药业有限公司 一种血小板聚集抑制剂的制备方法
KR20160142578A (ko) 2015-06-03 2016-12-13 경동제약 주식회사 클로피도그렐 황산염 결정형 i형의 제조방법

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