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WO2011158252A1 - Méthode de préparation de la forme polymorphe ii du chlorhydrate de valacyclovir - Google Patents

Méthode de préparation de la forme polymorphe ii du chlorhydrate de valacyclovir Download PDF

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Publication number
WO2011158252A1
WO2011158252A1 PCT/IN2011/000392 IN2011000392W WO2011158252A1 WO 2011158252 A1 WO2011158252 A1 WO 2011158252A1 IN 2011000392 W IN2011000392 W IN 2011000392W WO 2011158252 A1 WO2011158252 A1 WO 2011158252A1
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WO
WIPO (PCT)
Prior art keywords
valaciclovir hydrochloride
polymorphic form
solvent
preparation
valaciclovir
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Ceased
Application number
PCT/IN2011/000392
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English (en)
Inventor
Ramakoteswara Rao Jetti
Asha Rani Gorantla
Neelima Bhagavatula
Debashish Datta
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.)
Mylan Laboratories Ltd
Original Assignee
Matrix Laboratories Ltd
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Filing date
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Publication of WO2011158252A1 publication Critical patent/WO2011158252A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine

Definitions

  • the present invention relates to a process for the preparation of pure anhydrous crystalline Valaciclovir hydrochloride polymorphic form II.
  • Valaciclovir is an L-valyl ester prodrug of acyclovir.
  • Acyclovir is an acyclic analog of a natural nucleoside which has been found to have high anti-viral activity.
  • Acyclovir is widely used in the treatment and prophylaxis of viral infections in humans, particularly infections caused by the herpes group of viruses. See Goodman and Gilman's, The Pharmacological Basis of Therapeutics 1193-1198 (9th ed. 1996).
  • Valaciclovir hydrochloride L-valine, 2-[(2-amino-1 ,6-dihydro-6-oxo-9H- purin-9-yl)methoxy]ethyl ester, monohydrochloride. It has the following structural formula:
  • Valaciclovir hydrochloride is a white to off-white powder with the molecular formula C13H20N6O4*HCI and maximum solubility in water at 174 mg/mL.
  • the Pka's of Valaciclovir hydrochloride are 1.90, 7.47, and 9.43.
  • Valaciclovir it is advantageous to administer Valaciclovir rather than acyclovir because acyclovir is poorly absorbed from the gastrointestinal tract after oral administration in both animals and humans. In contrast, Valaciclovir is rapidly absorbed from the gastrointestinal tract after oral administration. Moreover, Valaciclovir is converted rapidly and virtually completely to acyclovir after oral administration in healthy adults. The conversion of Valaciclovir is thought to result from first-pass intestinal and hepatic metabolism through enzymatic hydrolysis.
  • Acyclovir kills viruses by inhibiting viral DNA synthesis. Because acyclovir is a guanosine analog which lacks the 3'-hydroxyl on the side chain, it causes DNA chain termination during viral DNA replication. In virus infected cells, acyclovir is converted to the monophosphate derivative (acyclovir-MP) by a viral enzyme, thymidinine kinase.
  • acyclovir-MP monophosphate derivative
  • Acyclovir-MP is then phosphorylated to the diphosphate and triphosphate analogs by cellular enzyme. Incorporation of activated acyclovir into the primer strand during viral DNA replication, leads to chain termination, since without the 3'hydroxyl the DNA chain can not be extended. Since infected cells lack the viral enzyme thymidine kinase, acyclovir is selectively activated only in cells infected with viruses that code for the appropriate kinases.
  • U. S. Pat. No. 4, 199, 574 discloses the treatment of viral infections with acyclovir.
  • the basic NCE patent for Valaciclovir is EP 0 308 065B (the '065 patent") discloses amino acid esters of the purine nucleoside acyclovir, pharmaceutically acceptable salts thereof and their use in the treatment of herpes virus infections. Also disclosed are pharmaceutical formulations and processes for the preparation of such compounds. Valaciclovir and its salts, including the hydrochloride salt, are among the disclosed compounds.
  • Example IA relates to the preparation of Valaciclovir as free base and
  • Example IB relates to the preparation of Valaciclovir hydrochloride monohydrate.
  • the only enabling disclosure of a salt of Valaciclovir in EP 0 308 065B is of Valaciclovir hydrochloride monohydrate.
  • EP 0 804 436 discloses an anhydrous crystalline form of Valaciclovir hydrochloride.
  • EP 1436295 discloses various polymorphic crystalline forms of Valaciclovir hydrochloride which are designated Forms I and II and IV-VII.
  • EP 1453834 discloses an anhydrous polymorphic crystalline form of Valaciclovir hydrochloride.
  • EP 1575953 discloses an anhydrous polymorphic crystalline form of Valaciclovir hydrochloride.
  • WO 04106338 A discloses various polymorphic crystalline forms of Valaciclovir hydrochloride which are designated Forms VIII-XIV.
  • WO 05000850A discloses various polymorphic crystalline forms of Valaciclovir hydrochloride which are designated Forms V and VUI-X.II.
  • WO 05085247A discloses various polymorphic crystalline forms of Valaciclovir hydrochloride which are designated Forms I, II, IV, VI and VII.
  • the prior art processes result in the formation of Valaciclovir hydrochloride polymorphic form II as a mixture.
  • the present invention covers a process for the preparation of Valaciclovir hydrochloride which results in pure crystalline Valaciclovir hydrochloride polymorphic form II with improved quality.
  • the main object of the present invention relates to a process for the preparation of Valaciclovir hydrochloride polymorphic form II.
  • Another object of the present invention relates to a process for the preparation of pure anhydrous crystalline Valaciclovir hydrochloride polymorphic form II with improved quality.
  • the present invention provides a process for the preparation of pure anhydrous crystalline Valaciclovir hydrochloride polymorphic form II comprising the steps of
  • the present invention provides a process for the preparation of pure anhydrous crystalline Valaciclovir hydrochloride polymorphic form II comprising the steps of
  • Figure 1 represents powder X - ray diffraction diagram of Valaciclovir hydrochloride polymorphic Form II
  • the present invention provides a process for the preparation of Valaciclovir hydrochloride polymorphic form II.
  • the present invention provides a process for the preparation of pure anhydrous crystalline Valaciclovir hydrochloride polymorphic form II.
  • the present invention provides pure anhydrous crystalline Valaciclovir hydrochloride polymorphic form II characterized by PXRD as shown in Figure 1.
  • the present invention provides a process for the preparation of pure anhydrous crystalline Valaciclovir hydrochloride polymorphic form II comprising the steps of a) dissolving Valaciclovir hydrochloride in a solvent,
  • Valaciclovir hydrochloride is dissolved in a solvent selected from polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide or mixtures thereof. Separately an alcoholic solvent such as n-butanol is taken and cooled to about -15°C to 20°C. The solution containing valaciclovir hydrochloride is added to the alcoholic contents under cooling. The solid thus obtained is filtered washed and dried to obtain pure anhydrous valaciclovir hydrochloride form II.
  • a solvent selected from polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide or mixtures thereof.
  • an alcoholic solvent such as n-butanol
  • the present invention provides a process for the preparation of pure anhydrous crystalline Valaciclovir hydrochloride polymorphic form II comprising the steps of
  • Valaciclovir hydrochloride is dissolved in a solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, cyclohexanol; aprotic solvents like dimethyl sulfoxide, dimethyl formamide or mixtures thereof.
  • the resultant solution is optionally seeded with seed crystals of Valaciclovir hydrochloride form II and added with an antisolvent selected from alcohols such as n-butanol.
  • the solid obtained is isolated as pure anhydrous crystalline Valaciclovir hydrochloride polymorphic form II.
  • the present invention provides a process for the preparation of pure anhydrous crystalline Valaciclovir hydrochloride polymorphic form II comprising the steps of
  • step b adding the contents of step a to the pre seeded alcoholic solvent of step b
  • Valaciclovir hydrochloride is dissolved in water or water miscible aprotic solvents like dimethyl sulfoxide or dimethyl formamide.
  • an alcoholic solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, cyclohexanol and seed crystals of Valaciclovir hydrochloride form II are taken in a round bottom flask under nitrogen atmosphere.
  • the solution containing valaciclovir hydrochloride is slowly added to pre seeded second solvent. Removing the solvent obtains pure Valaciclovir hydrochloride polymorphic form II.
  • the present invention provides a process for the preparation of pure anhydrous crystalline Valaciclovir hydrochloride polymorphic form II comprising the steps of
  • step c) adding the contents of step b to step a
  • Valaciclovir hydrochloride is dissolved in water or water miscible aprotic solvents like dimethyl sulfoxide or dimethyl formamide.
  • an alcoholic solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, cyclohexanol and seed crystals of Valaciclovir hydrochloride form II are taken in a round bottom flask under nitrogen atmosphere.
  • Pre seeded second solvent mixture is slowly added to the solution containing Valaciclovir hydrochloride. Removing the solvent obtains pure Valaciclovir hydrochloride polymorphic form II.
  • the present invention provides a process for the preparation of pure anhydrous crystalline Valaciclovir hydrochloride polymorphic form II comprising the steps of
  • Valacivlovir hydrochloride is suspended in an organic solvent selected from alcohols preferably n-butanoland, added a co-solvent and isolated pure anhydrous crystalline Valaciclovir hydrochloride polymorphic form II.
  • the present invention provides a purification process for the preparation of anhydrous crystalline Valaciclovir hydrochloride polymorphic form II comprising the steps of a) suspending anhydrous crystalline Valaciclovir hydrochloride polymorphic form II in an alcoholic solvent,
  • step a and b optionally repeating step a and b, and
  • Valaciclovir hydrochloride polymorphic form II is Suspending in alcoholic solvents such as methanol, ethanol, isopropanol, n-propanol and n-butanol, stir the reaction mass, distil-off solvent under vacuum, optionally repeating the same and isolating anhydrous crystalline Valaciclovir hydrochloride polymorphic form II.
  • the obtained solid material was drying under vacuum at 70-80°C, milling the material and further drying the material at 100- 110°C, the solid thus obtained identified as pure anhydrous Valacyclovir hydrochloride anhydrous form II.
  • Valaciclovir hydrochloride 20 g was dissolved in N, N-dimethyl formamide (100 ml) at 25-30°C. The resulting solution was filtered through hiflow to remove any undissolved particulate and washed with N, N-dimethyl formamide (10 ml). n-Butanol (150 ml) was taken in RB flask and cooled to 0-5°C under nitrogen atmosphere. The above Valaciclovir solution was added slowly to n-butanol for 0.5h at 0-5°C and maintained under agitation for 5-6h at 0-5°C under nitrogen atmosphere. The solid obtained was filtered, washed with n-butanol (20 ml) and dried under vacuum at 50°C for 12h. The product obtained was identified as crystalline Valaciclovir hydrochloride Form II.
  • Valaciclovir hydrochloride 100 g was dissolved in N, N-dimethyl formamide (500 ml) at 25-30°C and stirred for 15 minutes. The resulting solution was filtered through hiflow to remove any undissolved particulate and washed with N, N-dimethyl formamide (50 ml).
  • n-Butanol (1500 ml) was taken in RB flask and cooled to 20-25°C under nitrogen atmosphere. The above Valaciclovir solution was slowly added to n-butanol at 20-25°C and stirred for 4-5h at 20-25°C under nitrogen atmosphere. The solid obtained was filtered and dried under vacuum at 50°C for 15h. The product obtained was identified as crystalline Valaciclovir hydrochloride Form II.
  • Valaciclovir hydrochloride 100 g was dissolved in N, N-dimethyl formamide (500 ml) at 25-30°C and stirred for 15 minutes. The resulting solution was filtered through hiflow to remove any undissolved particulate and washed with N, N-dimethyl formamide (50 ml).
  • n-Butanol (1500 ml) was taken in RB flask and cooled to 10-15°C under nitrogen atmosphere. The above Valaciclovir solution was added slowly to n-butanol at 10-15°C and stirred for 3h at 10-15°C under nitrogen atmosphere. Slowly the temperature is raised to 20-25°C and stirred for 2h at 20-25°C under nitrogen atmosphere. The solid obtained was filtered and dried under vacuum at 50°C for 15h. The product obtained was identified as crystalline Valaciclovir hydrochloride Form II.
  • Valaciclovir hydrochloride 50 g was dissolved in N, N-dimethyl formamide (250 ml) at 25-30°C and stirred for 15 minutes. The resulting solution was filtered through hiflow to remove any undissolved particulate and washed with N, N-dimethyl formamide (25 ml).
  • n-Butanol 750 ml was taken in RB flask and cooled to -10 to -15°C under nitrogen atmosphere. The above Valaciclovir solution was added slowly to n-butanol at -10 to -15°C and stirred for 15h at -10 to - 15°C under nitrogen atmosphere. The solid obtained was filtered and dried under vacuum at 50°C for 15h. The product obtained was identified as crystalline Valaciclovir hydrochloride Form II.
  • Valaciclovir hydrochloride 50 g was dissolved in N, N-dimethyl formamide (250 ml) at 25-30°C and stirred for 15 minutes. The resulting solution was filtered through hiflow to remove any undissolved particulate and washed with N, N-dimethyl formamide (25 ml), and to this filtrate added Form II seeds (250mg) and stirred for 4-5hrs at 25-30 °C. After 1hr the material was precipitated out. Then added n-Butanol (250ml) and stirred for 1hr at 25-30 °C and the solid obtained was isolated and identified as crystalline Valaciclovir hydrochloride Form II.
  • Valaciclovir hydrochloride 50 g was dissolved in N, N-dimethyl formamide with 10% water (250 ml) at 25-30°C and stirred for 15 minutes. The resulting solution was filtered through hiflow to remove any undissolved particulate and washed with N, N-dimethyl formamide (25 ml). n-Butanol (750 ml) and Form II (250mg) seeds were taken in RB flask at 25-30°C under nitrogen atmosphere. The above Valaciclovir solution was added slowly to n-butanol at 25-30°C and stirred for 1 h at 25-30°C under nitrogen atmosphere. Then cooled to 0-5°C and stirred for 1 hr.
  • Valaciclovir hydrochloride 50 g was dissolved in N, N-dimethyl formamide with 20% water (250 ml) at 25-30°C and stirred for 15 minutes. The resulting solution was filtered through hiflow to remove any undissolved particulate and washed with N, N-dimethyl formamide (25 ml). n-Butanol (750 ml) and Form II (250mg) seeds were taken in RB flask at 25-30°C under nitrogen atmosphere. The above Valaciclovir solution was added slowly to n-butanol at 25-30°C and stirred for 1 h at 25-30°C under nitrogen atmosphere.
  • Valaciclovir Hydrochloride Form II Suspended Valaciclovir Hydrochloride hydrate (50g) in n-Butanol with 1% DMF (750ml) and refluxed for 3 hours then cool to RT, filtered the material and washed with n-Butanol (50ml). Then dried at 70°C under vacuum for 15 hrs obtained material was identified as Valaciclovir Hydrochloride Form II.
  • Valaciclovir Hydrochloride Form II Suspended Valaciclovir Hydrochloride hydrate (50g) in n-Butanol with 2% DMF (750ml) and refluxed for 3 hours then cool to 50-55°C, filtered the material and washed with n-Butanol (50ml). Then dried at 110°C under vacuum for 15 hrs obtained material was identified as Valaciclovir Hydrochloride Form II.
  • Example 10 Process for the preparation of Valaciclovir hydrochloride Form II
  • Valaciclovir Hydrochloride Form II Suspended Valaciclovir Hydrochloride hydrate (50g) in n-Butanol with 3% DMF (750ml) and refluxed for 3 hours then cool to 50-55°C, filtered the material and washed with n-Butanol (50ml). Then dried at 110°C under vacuum for 15 hrs obtained material was identified as Valaciclovir Hydrochloride Form II.
  • Example 11 Preparation of Valacyclovir hydrochloride Form II
  • valacyclovir hydrochloride 50 g was dissolved in N, N-dimethyl formamide with 10% water (250 ml) and stirred for 15 minutes at 25-30°C. The resulting solution was filtered through hiflow to remove any undissolved particulate and washed with N, N-dimethyl formamide (25 ml).
  • n-Butanol 750 ml was taken in RB flask at 25-30°C under nitrogen atmosphere and Form II (250mg) seeds were added.
  • the valacyclovir-N, N-dimethyl formamide solution was added slowly to the above n-butanol and stirred for 1 h at 25-30°C. Further, cooled and stirred for 1 hr to 0-5°C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une méthode de préparation de la forme polymorphe II cristalline, anhydre, pure, du chlorhydrate de valacyclovir.
PCT/IN2011/000392 2010-06-15 2011-06-10 Méthode de préparation de la forme polymorphe ii du chlorhydrate de valacyclovir Ceased WO2011158252A1 (fr)

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IN1058CH2010 2010-06-15
IN1058/CHE/2010 2010-06-15

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WO2011158252A1 true WO2011158252A1 (fr) 2011-12-22

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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4199574A (en) 1974-09-02 1980-04-22 Burroughs Wellcome Co. Methods and compositions for treating viral infections and guanine acyclic nucleosides
EP0308065B1 (fr) 1987-08-15 1995-01-04 The Wellcome Foundation Limited Nucléosides thérapeutiques
EP0804436A1 (fr) 1995-01-20 1997-11-05 The Wellcome Foundation Limited Derive de guanine
EP1436295A2 (fr) 2001-09-07 2004-07-14 Teva Pharmaceutical Industries, Inc. Formes cristallines de chlorhydrate de valacyclovir
EP1453834A1 (fr) 2001-11-05 2004-09-08 Glaxo Group Limited Forme cristalline anhydre du valaciclovir chlorhydrate
WO2004106338A1 (fr) 2003-05-30 2004-12-09 Eos Eczacibasi Ozgun Kimyasal Urunler Sanayi Ve Ticaret A.S. Nouvelles formes cristallines de chlorhydrate de valacyclovir
WO2005000850A2 (fr) 2003-06-02 2005-01-06 Teva Pharmaceutical Industries, Ltd. Nouvelles formes cristallines de chlorhydrate de valacyclovir
US20050043329A1 (en) * 2002-09-06 2005-02-24 Shlomit Wizel Crystalline forms of valacyclovir hydrochloride
EP1575953A1 (fr) 2002-12-09 2005-09-21 Texcontor Etablissement Forme cristalline anhydre d'hydrochlorure de valacyclovir
US20080281099A1 (en) * 2007-05-07 2008-11-13 Mayur Devjibhai Khunt Process for purifying valacyclovir hydrochloride and intermediates thereof

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4199574A (en) 1974-09-02 1980-04-22 Burroughs Wellcome Co. Methods and compositions for treating viral infections and guanine acyclic nucleosides
EP0308065B1 (fr) 1987-08-15 1995-01-04 The Wellcome Foundation Limited Nucléosides thérapeutiques
EP0804436A1 (fr) 1995-01-20 1997-11-05 The Wellcome Foundation Limited Derive de guanine
EP1436295A2 (fr) 2001-09-07 2004-07-14 Teva Pharmaceutical Industries, Inc. Formes cristallines de chlorhydrate de valacyclovir
EP1453834A1 (fr) 2001-11-05 2004-09-08 Glaxo Group Limited Forme cristalline anhydre du valaciclovir chlorhydrate
US20050043329A1 (en) * 2002-09-06 2005-02-24 Shlomit Wizel Crystalline forms of valacyclovir hydrochloride
EP1575953A1 (fr) 2002-12-09 2005-09-21 Texcontor Etablissement Forme cristalline anhydre d'hydrochlorure de valacyclovir
WO2004106338A1 (fr) 2003-05-30 2004-12-09 Eos Eczacibasi Ozgun Kimyasal Urunler Sanayi Ve Ticaret A.S. Nouvelles formes cristallines de chlorhydrate de valacyclovir
WO2005000850A2 (fr) 2003-06-02 2005-01-06 Teva Pharmaceutical Industries, Ltd. Nouvelles formes cristallines de chlorhydrate de valacyclovir
WO2005085247A1 (fr) 2004-03-01 2005-09-15 Teva Pharmaceutical Industries Ltd. Formes cristallines du chlorhydrate de valacyclovir
US20080281099A1 (en) * 2007-05-07 2008-11-13 Mayur Devjibhai Khunt Process for purifying valacyclovir hydrochloride and intermediates thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GOODMAN AND GILMAN: "The Pharmacological Basis of Therapeutics", 1996, pages: 1193 - 1198

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