EP1713812A1 - Nouvelles formes cristallines d'hydrobromure de clopidogrel et leurs procedes de preparation - Google Patents

Nouvelles formes cristallines d'hydrobromure de clopidogrel et leurs procedes de preparation

Info

Publication number
EP1713812A1
EP1713812A1 EP04802610A EP04802610A EP1713812A1 EP 1713812 A1 EP1713812 A1 EP 1713812A1 EP 04802610 A EP04802610 A EP 04802610A EP 04802610 A EP04802610 A EP 04802610A EP 1713812 A1 EP1713812 A1 EP 1713812A1
Authority
EP
European Patent Office
Prior art keywords
clopidogrel
hydrobromide
solution
crystalline form
clopidogrel hydrobromide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04802610A
Other languages
German (de)
English (en)
Inventor
Josef Hajicek
Pavel Pihera
Hana Stepankova
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zentiva KS
Original Assignee
Zentiva KS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CZ200461A external-priority patent/CZ295244B6/cs
Priority claimed from CZ20041192A external-priority patent/CZ20041192A3/cs
Application filed by Zentiva KS filed Critical Zentiva KS
Publication of EP1713812A1 publication Critical patent/EP1713812A1/fr
Withdrawn legal-status Critical Current

Links

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)

Abstract

L'invention concerne de l'hydrobromure de clopidogrel sous la forme cristalline I, caractérisé par un diagramme de diffraction des rayons X présentant des distances d interplanaires caractéristiques de 4,01 ; 4,39 et 3,17 Å et également caractérisé par des bandes dans les spectres infrarouges à 1743 ; 1421 ; 1237, 760 et 728 cm-1. L'hydrobromure de clopidogrel sous la forme cristalline II est caractérisé par un diagramme de diffraction des rayons X présentant des distances d interplanaires caractéristiques de 4,52 ; 3,83 ; 3,48 Å, ainsi que des bandes dans les spectres infrarouges à 1754 ; 1436 ; 1317 et 1223 cm-1. La forme cristalline III est caractérisée par les pics suivants déterminés par diffraction des rayons X au niveau de positions 2 υ : 7,796 °; 15,380 °; 18,389 °; 19,369 ° et 23,895. Le procédé de préparation d'hydrobromure de clopidogrel sous la forme cristalline I consiste à précipiter la base de clopidogrel dissoute dans du toluène avec une solution concentrée d'acide bromhydrique. Le procédé de préparation d'hydrobromure de clopidogrel sous la forme cristalline II consiste à dissoudre la base de clopidogrel dans un solvant organique et à le précipiter avec une solution d'acide bromhydrique dans du toluène ou avec du bromure d'hydrogène gazeux. La forme III peut être utilisée pour la préparation d'une forme II pharmaceutiquement utilisable.
EP04802610A 2004-01-13 2004-12-21 Nouvelles formes cristallines d'hydrobromure de clopidogrel et leurs procedes de preparation Withdrawn EP1713812A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
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
PCT/CZ2004/000089 WO2005068471A1 (fr) 2004-01-13 2004-12-21 Nouvelles formes cristallines d'hydrobromure de clopidogrel et leurs procedes de preparation

Publications (1)

Publication Number Publication Date
EP1713812A1 true EP1713812A1 (fr) 2006-10-25

Family

ID=34796465

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04802610A Withdrawn EP1713812A1 (fr) 2004-01-13 2004-12-21 Nouvelles formes cristallines d'hydrobromure de clopidogrel et leurs procedes de preparation

Country Status (3)

Country Link
EP (1) EP1713812A1 (fr)
EA (1) EA008972B1 (fr)
WO (1) WO2005068471A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0321256D0 (en) 2003-09-11 2003-10-08 Generics Uk Ltd Novel crystalline compounds
ZA200608569B (en) * 2004-04-20 2007-12-27 Sanofi Aventis Polymorphic forms of methyl (+)-(S)-alpha- (2-chlorophenyl)-6, 7-dinydrothieno[3,2-C] pyridine-5(4H) acetate hydrobromide, clopidrogel hydrobromide
ZA200608035B (en) 2004-04-20 2008-07-30 Sanofi Aventis Clopidogrel salt and polymorphic forms thereof
EP1970054A3 (fr) 2007-03-14 2009-06-03 Ranbaxy Laboratories Limited Comprimés de clopidogrel
EP2107061A1 (fr) 2008-04-02 2009-10-07 Krka Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation de clopidogrel enrichi optiquement
BR112015018144B1 (pt) * 2013-02-06 2021-03-09 Jingjun Huang composição de emulsão água/óleo farmacêutica estável com gotículas de óleo manométricas, método para fazer a mesma e alta dose única de clopidogrel usada para tratar um paciente

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUP0200438A3 (en) * 2002-02-06 2003-10-28 Egis Gyogyszergyar Nyilvanosan Novel clopidogrel hydrochloride polymorphs, process for the preparation thereof, their use and pharmaceutical compositions containing them
EP1606231A1 (fr) * 2003-02-03 2005-12-21 Nadkarni, Sunil Sadanand Procede de preparation de clopidogrel, ses sels et compositions pharmaceutiques
GB0321256D0 (en) * 2003-09-11 2003-10-08 Generics Uk Ltd Novel crystalline compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005068471A1 *

Also Published As

Publication number Publication date
EA008972B1 (ru) 2007-10-26
WO2005068471A1 (fr) 2005-07-28
EA200601311A1 (ru) 2006-12-29

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