WO2005085199A1 - Nouvelles formes polymorphes d'etoricoxib - Google Patents

Nouvelles formes polymorphes d'etoricoxib Download PDF

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Publication number
WO2005085199A1
WO2005085199A1 PCT/IN2005/000009 IN2005000009W WO2005085199A1 WO 2005085199 A1 WO2005085199 A1 WO 2005085199A1 IN 2005000009 W IN2005000009 W IN 2005000009W WO 2005085199 A1 WO2005085199 A1 WO 2005085199A1
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WO
WIPO (PCT)
Prior art keywords
etoricoxib
novel
novel polymorph
ray diffraction
diffraction pattern
Prior art date
Application number
PCT/IN2005/000009
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English (en)
Inventor
Braj Bhushan Lohray
Vidya Bhushan Lohray
Mayank Ghanshyambhai Dave
Original Assignee
Cadila Healthcare Limited
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
Application filed by Cadila Healthcare Limited filed Critical Cadila Healthcare Limited
Publication of WO2005085199A1 publication Critical patent/WO2005085199A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention describes novel forms of Etoricoxib, process for their preparation and pharmaceutical compositions containing them. More particularly, the present invention reveals new polymorphs of Etoricoxib, process for preparing them and various pharmaceutical compositions containing them. The present invention also describes the method of treatment of COX-2 mediated diseases comprising administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of the said novel polymorph and pharmaceutical composition containing them. The present invention relates to the use of novel polymorphs of Etoricoxib disclosed herein and pharmaceutical compositions containing them for the treatment of COX-2 mediated disorders.
  • Etoricoxib is a selective COX-2 inhibitor which has been shown to be as effective as non-selective non-steroidal anti-inflammatory drugs in the management of chronic pain in rheumatoid arthritis, osteoarthritis and other COX-2 mediated disorders.
  • Etoricoxib is 5-chloro-6'-methyl-3-[4-methylsulfonyl)phenyl]-2,3'-bipyridine having structural formula I.
  • Etoricoxib is a potent and selective cyclooxygenase-2 (COX-2) inhibitor.
  • Etoricoxib belongs to a class of drugs known as COX-2 inhibitors that are used in the treatment of
  • the present invention discloses eight different crystalline forms of Etoricoxib i.e Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV and Form XVI.
  • the present invention provides new crystalline forms of Etoricoxib of formula I or mixture thereof.
  • Another objective of the present invention is to provide a process for the preparation of the novel forms of Etoricoxib or mixture thereof.
  • Yet another objective is to provide novel crystalline forms or there mixture of
  • Etoricoxib which are stable. Yet another objective is to provide a process for the preparation of pharmaceutical composition comprising the said novel forms of Etoricoxib.
  • compositions containing one or more of the new forms described in the present invention is provided.
  • a further objective of the present invention is to provide uses of the novel forms of Etoricoxib for the treatment of COX-2 mediated disorders in a mammal including human.
  • Fig 1 X-ray powder diffraction (XRD) pattern of novel form IX of Etoricoxib
  • XRD X-ray powder diffraction
  • the present invention provides novel crystalline forms of Etoricoxib which have different XRD patterns than so far known forms
  • the novel forms of Etoricoxib are characterized by unique XRD pattern as shown in fig 1 to 8 which are different from various forms reported in application nos WO 01/92230, WO 96/10012 and WO 96/16934
  • the present invention also discloses processes for the preparation of the said novel forms of Etoricoxib and pharmaceutical compositions containing them and their use in medicine particularly in the treatment of COX-2 mediated disorders
  • the novel form IX of Etoricoxib may be prepared by a process comprising of the following steps a Preparing a solution of Etoricoxib in toluene at a suitable temperature selected in the range of 60 °C to 75 °C b Cooling the solution c Adding of an antisolvent selected from the group consisting of heptane, dusopropyl ether and the like or mixtures thereof (in two equal lots ) d Filtering and drying the separated solids to obtain Form IX of Etoricoxib
  • Form IX is characterized by its unique XRD pattern as given in Fig 1
  • the novel form X of Etoricoxib may be prepared by a process comprising of the following steps a Preparing a solution of Etoricoxib in toluene at a suitable temperature selected in the range of 60 °C to 75 °C b Cooling the solution c Isolating the product by adding suitable antisolvent heptane (in one lot) d Filtering and drying the separated solids to obtain Form X of Etoricoxib
  • Form X is characterized by its unique XRD pattern as given in Fig 2
  • the novel form XI of Etoricoxib may be prepared by a process comprising of the following steps a Preparing a solution of Etoricoxib in ethyl acetate or isopropyl acetate at room temperature b Filtering the reaction mixture c Concentrating the filtrate under reduced pressure to give solid residue, d Isolating the product by adding suitable antisolvent selected from the group consisting of hexane, dusopropyl ether and the like or mixtures thereof e Filtering and drying the separated solids to obtain Form XI of Etoricoxib
  • Form XI is characterized by its unique XRD pattern as given in Fig 3
  • the novel form XII of Etoricoxib may be prepared by a process comprising of the following steps a Preparing a solution of Etoricoxib in ethyl acetate at room temperature, b Filtering the reaction mixture c Concentrating the filtrate under reduced pressure to give solid residue d Isolating the product by adding suitable antisolvent hexane e Filtering and drying the separated solids to obtain the Form XII of Etoricoxib
  • Form XII is characterized by its unique XRD pattern as given in Fig 4
  • Preparation of Form XIII The novel form XIII of Etoricoxib may be prepared by a process comprising of the following steps:
  • the novel form XIV of Etoricoxib may be prepared by a process comprising of the5 following steps: a. Preparing a solution of Etoricoxib in ethyl acetate at room temperature, and washed with water. b. Separating the organic layer and treating with silica-gel and charcoal0 c. Drying and concentrating under reduced pressure to get solid residue. d. Isolating the product by adding suitable antisolvent such as dusopropyl ether e. Filtering and drying the isolated product to obtain Form XIV of Etoricoxib.
  • Form XIV is characterized by its unique XRD pattern as given in Fig 6.5
  • the novel form XV of Etoricoxib may be prepared by a process comprising of the following steps: a. Preparing a solution of Etoricoxib in aqueous HC1 at atmospheric temperature. b. Treating the solution with toluene. c. Separating the aqueous layer, treating it with charcoal and filtering it. d. Isolating the material by basifying the filtrate using ammonia solution. e. Filtering and drying the residue to obtain the Form XV of Etoricoxib.
  • Form XV is characterized by its unique XRD pattern as given in Fig 7.
  • the novel form XVI of Etoricoxib may be prepared by a process comprising of the 5 following steps: a. Preparing a solution of Etoricoxib in isopropyl acetate at a temperature selected from the range 70-75 °C. b. Cooling the solution to 0 °C.
  • Form XVI is characterised by its unique XRD pattern as given in Fig 8.
  • compositions and formulations of the novel forms of 15 Etoricoxib of the present invention can be prepared by known processes.
  • novel forms of Etoricoxib of the present invention is selected according to the usage and may vary as per the requirement of the patient.
  • the novel forms of Etoricoxib of the present invention can be used for the treatment of 20 COX-2 mediated disorders such as osteoarthritis, rheumatoid arthritis, pain and inflammatory disorders in a mammal including human.
  • the novel forms of Etoricoxib are characterized by unique XRD pattern which are different from the various forms previously reported.
  • Etoricoxib (1 gm) was dissolved in toluene at a suitable temperature between the range from 60°C to 75°C (in different batches) and the solution was cooled. Then material was isolated with antisolvent such as heptane (one lot) to get the reaction mixture. The crystals were filtered and dried in an oven to constant weight to obtain form X of Etoricoxib (41% yield , 99.92 % purity).
  • Etoricoxib (I gm) was dissolved in ethyl acetate or isopropyl acetate at atmospheric temperature. After that the reaction mixture was filtered through hyflow bed and the filtrate was concentrated under reduced pressure to obtain solid residue which was isolated by a solution of hexane: dusopropyl ether (1 : 1). The isolated residues were filtered and dried in an oven to constant weight to obtain form XI of Etoricoxib (82% yield , > 98% purity).
  • Etoricoxib (1 gm) was dissolved in ethyl acetate or isopropyl acetate at atmospheric temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain solid residue which was isolated by a solution of hexane. The isolated residues were filtered and dried in an oven to constant weight to obtain form XI of Etoricoxib (82% yield , > 98% purity).
  • EXAMPLE 5 PREPARATION OF FORM -XII OF ETORICOXIB Pure Etoricoxib (1 gm) was dissolved in ethyl acetate at atmospheric temperature. After that the reaction mixture was filtered & concentrated under reduced pressure to give solid residue which was isolated by adding antisolvent hexane. The isolated residues were filtered and dried in an oven to constant weight to obtain form XII of Etoricoxib (85% yield , > 98% purity).
  • Etoricoxib (1 gm) was dissolved in ethyl acetate at atmospheric temperature. The solution was washed with water and the organic layer was separated and treated with silica gel and charcoal, then dried and concentrated under reduced pressure to get solid residue. Antisolvent dusopropyl ether was used to isolate the product. The product was filtered and dried in an oven to constant weight to get form XIV of Etoricoxib (83% yield , > 98% purity).
  • EXAMPLE 8 PREPARATION OF FORM -XV OF ETORICOXIB
  • EXAMPLE 9 PREPARATION OF FORM -XVI OF ETORICOXIB
  • Etoricoxib (1 gm) was dissolved in isopropyl acetate at suitable temperature between 70°C-75°C. Then the reaction mixture was cooled at 0°C to isolate the product. The product was filtered and dried in an oven to constant weight to get form XVI of Etoricoxib (60% yield , > 98% purity).

Abstract

La présente invention a trait à de nouvelles formes cristallines d'Etoricoxib de formule (I) ou un mélange de celui-ci. L'invention a également trait à un procédé pour la préparation de nouvelles formes d'Etoricoxib ou un mélange de celui-ci. L'invention a trait en outre à de nouvelles formes ou de mélange d'Etoricoxib stables. L'invention a trait enfin à un procédé pour la préparation de composition pharmaceutique comportant lesdites nouvelles formes d'Etoricoxib. Dans un mode de réalisation l'invention propose des compositions pharmaceutiques contenant une ou des nouvelles formes de la présente invention. La présente invention a également trait à des utilisations des nouvelles formes d'Etoricoxib pour le traitement de troubles liés à la COX2 chez un mammifère y compris un humain.
PCT/IN2005/000009 2004-01-14 2005-01-07 Nouvelles formes polymorphes d'etoricoxib WO2005085199A1 (fr)

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IN39MU2004 2004-01-14
IN39/MUM/2004 2004-01-14

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010097802A2 (fr) 2009-02-27 2010-09-02 Cadila Healthcare Limited Procédé de préparation d'étoricoxib
WO2011158250A1 (fr) 2010-06-16 2011-12-22 Glenmark Generics Limited Procédé de préparation de pyridines à substitution 2,3-diaryl-5 et leurs intermédiaires
WO2012004677A1 (fr) 2010-07-05 2012-01-12 Actavis Group Ptc Ehf Formes à l'état solide de sels d'étoricoxib
WO2012163839A1 (fr) 2011-05-27 2012-12-06 Farma Grs, D.O.O. Procédé pour la préparation de la forme polymorphe i de l'étoricoxib
WO2013075732A1 (fr) * 2011-11-21 2013-05-30 Synthon Bv Procédé de préparation d'une forme cristalline i de l'étoricoxib
EP2601952A1 (fr) 2011-12-07 2013-06-12 Zentiva, k.s. Nouveaux sels et cocrristaux pharmaceutiqement acceptables du 5- chloro-3-(4-méthanesulfonylphényl)-6'-méthyl-[2,3'] bipyridinyle et leurs utilisations thérapeutiques
WO2013105106A1 (fr) 2011-11-03 2013-07-18 Cadila Healthcare Limited Procédé amélioré pour la préparation d'étoricoxibe et de polymorphes de celui-ci
WO2013144977A2 (fr) 2012-03-30 2013-10-03 Mylan Laboratories Ltd. Procédé amélioré pour la préparation d'étoricoxib
WO2014033526A1 (fr) 2012-08-27 2014-03-06 Cadila Healthcare Limited Compositions pharmaceutiques d'étoricoxib
CN104418799A (zh) * 2013-09-03 2015-03-18 天津药物研究院 一种依托考昔的晶型及其制备方法和应用
CN107056691A (zh) * 2017-06-21 2017-08-18 四川尚锐生物医药有限公司 一种制备依托考昔晶型v的方法
WO2019130049A1 (fr) 2017-12-29 2019-07-04 Grünenthal GmbH Combinaison pharmaceutique comprenant du chlorhydrate de tramadol à libération prolongée et de l'étoricoxib à libération immédiate, et son utilisation pour le traitement de la douleur
CN112826804A (zh) * 2019-11-22 2021-05-25 北京泰德制药股份有限公司 一种依托考昔组合物
WO2022216975A1 (fr) 2021-04-09 2022-10-13 Tremeau Pahrmaceuticals, Inc. Étoricoxib deutéré, ses procédés de fabrication et ses méthodes d'utilisation
US11858909B2 (en) 2021-04-09 2024-01-02 Tremeau Pharmaceuticals, Inc. Deuterated etoricoxib, methods of manufacture, and use thereof

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Publication number Priority date Publication date Assignee Title
US5861419A (en) * 1996-07-18 1999-01-19 Merck Frosst Canad, Inc. Substituted pyridines as selective cyclooxygenase-2 inhibitors
WO2001037833A1 (fr) * 1999-11-29 2001-05-31 Merck Frosst Canada & Co. Formes polymorphes, amorphes et hydratees de 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyle
US20020147221A1 (en) * 2000-05-26 2002-10-10 Crocker Loius S. 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3]bipyridinyl in pure crystalline form and process for synthesis

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US5861419A (en) * 1996-07-18 1999-01-19 Merck Frosst Canad, Inc. Substituted pyridines as selective cyclooxygenase-2 inhibitors
WO2001037833A1 (fr) * 1999-11-29 2001-05-31 Merck Frosst Canada & Co. Formes polymorphes, amorphes et hydratees de 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyle
US20020147221A1 (en) * 2000-05-26 2002-10-10 Crocker Loius S. 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3]bipyridinyl in pure crystalline form and process for synthesis

Non-Patent Citations (1)

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Title
DAVIES I W ET AL: "A PRACTICAL SYNTHESIS OF A COX-2-SPECIFIC INHIBITOR", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 65, 2000, pages 8415 - 8420, XP002326845, ISSN: 0022-3263 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010097802A2 (fr) 2009-02-27 2010-09-02 Cadila Healthcare Limited Procédé de préparation d'étoricoxib
EP2479166A1 (fr) 2009-02-27 2012-07-25 Cadila Healthcare Limited Procédé de préparation d'étoricoxib
WO2011158250A1 (fr) 2010-06-16 2011-12-22 Glenmark Generics Limited Procédé de préparation de pyridines à substitution 2,3-diaryl-5 et leurs intermédiaires
EP2582690A4 (fr) * 2010-06-16 2013-09-18 Glenmark Generics Ltd Procédé de préparation de pyridines à substitution 2,3-diaryl-5 et leurs intermédiaires
WO2012004677A1 (fr) 2010-07-05 2012-01-12 Actavis Group Ptc Ehf Formes à l'état solide de sels d'étoricoxib
WO2012163839A1 (fr) 2011-05-27 2012-12-06 Farma Grs, D.O.O. Procédé pour la préparation de la forme polymorphe i de l'étoricoxib
WO2013105106A1 (fr) 2011-11-03 2013-07-18 Cadila Healthcare Limited Procédé amélioré pour la préparation d'étoricoxibe et de polymorphes de celui-ci
WO2013075732A1 (fr) * 2011-11-21 2013-05-30 Synthon Bv Procédé de préparation d'une forme cristalline i de l'étoricoxib
EP2601952A1 (fr) 2011-12-07 2013-06-12 Zentiva, k.s. Nouveaux sels et cocrristaux pharmaceutiqement acceptables du 5- chloro-3-(4-méthanesulfonylphényl)-6'-méthyl-[2,3'] bipyridinyle et leurs utilisations thérapeutiques
WO2013144977A3 (fr) * 2012-03-30 2013-12-12 Mylan Laboratories Ltd. Procédé amélioré pour la préparation d'étoricoxib
WO2013144977A2 (fr) 2012-03-30 2013-10-03 Mylan Laboratories Ltd. Procédé amélioré pour la préparation d'étoricoxib
WO2014033526A1 (fr) 2012-08-27 2014-03-06 Cadila Healthcare Limited Compositions pharmaceutiques d'étoricoxib
CN104418799A (zh) * 2013-09-03 2015-03-18 天津药物研究院 一种依托考昔的晶型及其制备方法和应用
CN107056691A (zh) * 2017-06-21 2017-08-18 四川尚锐生物医药有限公司 一种制备依托考昔晶型v的方法
CN107056691B (zh) * 2017-06-21 2020-03-10 四川尚锐生物医药有限公司 一种制备依托考昔晶型v的方法
WO2019130049A1 (fr) 2017-12-29 2019-07-04 Grünenthal GmbH Combinaison pharmaceutique comprenant du chlorhydrate de tramadol à libération prolongée et de l'étoricoxib à libération immédiate, et son utilisation pour le traitement de la douleur
CN112826804A (zh) * 2019-11-22 2021-05-25 北京泰德制药股份有限公司 一种依托考昔组合物
CN112826804B (zh) * 2019-11-22 2022-07-15 北京泰德制药股份有限公司 一种依托考昔组合物
WO2022216975A1 (fr) 2021-04-09 2022-10-13 Tremeau Pahrmaceuticals, Inc. Étoricoxib deutéré, ses procédés de fabrication et ses méthodes d'utilisation
US11858909B2 (en) 2021-04-09 2024-01-02 Tremeau Pharmaceuticals, Inc. Deuterated etoricoxib, methods of manufacture, and use thereof

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