WO2005085199A1 - Novel polymorphs of etoricoxib - Google Patents

Novel polymorphs of 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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Prior art keywords
etoricoxib
novel
novel polymorph
ray diffraction
diffraction pattern
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PCT/IN2005/000009
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French (fr)
Inventor
Braj Bhushan Lohray
Vidya Bhushan Lohray
Mayank Ghanshyambhai Dave
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Cadila Healthcare Limited
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Publication of WO2005085199A1 publication Critical patent/WO2005085199A1/en

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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

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 novel forms of Etoricoxib or mixture thereof. Yet another objective is to provide novel crystalline forms or mixture of Etoricoxib which are stable. Yet anothr objective is to provide a process for the preparation of pharmaceutical composition comprising the said novel forms of Etoricoxib. An an embodiment of the present invention pharmaceutical 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.

Description

NOVEL POLYMORPHS OF ETORICOXIB Field of invention:
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.
Background of the invention :
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.
Figure imgf000003_0001
Etoricoxib
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
COX-2 mediated disorders. The therapeutic application of Etoricoxib as a COX-2 inhibitor is disclosed in WO 96/10012 and WO 96/16934. This compound is disclosed in US 5861419 which is hereby incorporated by reference in its entirety.
A process for preparation of this compound is disclosed in US6040319 which is hereby incorporated by reference in its entirety. WO 01/992230 discloses Form V of this compound. It further discloses five polymorphic forms, one amorphous form and two hydrated forms, which also hereby incorporated by reference in its entirety. Thus it describes eight new forms of Etoricoxib.
Our endeavor of developing new forms of Etoricoxib has led to the development of eight new forms of Etoricoxib.
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.
Summary of the Invention:
Accordingly, the present invention provides new crystalline forms of Etoricoxib of formula I or mixture thereof.
Figure imgf000004_0001
Etoricoxib
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.
As an embodiment of the present invention pharmaceutical 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.
Brief Description of Drawings
Fig 1 : X-ray powder diffraction (XRD) pattern of novel form IX of Etoricoxib Fig 2 X-ray powder diffraction (XRD) pattern of novel form X of Etoricoxib
Fig 3 X-ray powder diffraction (XRD) pattern of novel form XI of Etoricoxib
Fig 4 X-ray powder diffraction (XRD) pattern of novel form XII of Etoricoxib
Fig 5 X-ray powder diffraction (XRD) pattern of novel form XIII of Etoricoxib Fig 6 X-ray powder diffraction (XRD) pattern of novel form XIV of Etoricoxib
Fig 7 X-ray powder diffraction (XRD) pattern of novel form XV of Etoricoxib
Fig 8 X-ray powder diffraction (XRD) pattern of novel form XVI of Etoricoxib
Description of Invention: 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
Preparation of Form IX 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
Preparation of Form X
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
Preparation of Form XI 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
Preparation of Form XII
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:
-> a. Preparing a solution of Etoricoxib in isopropyl alcohol at room temperature b. Filtering the reaction mixture. c. Isolating the product by cooling to 0 °c. d. Filtering and drying the isolated product to obtain Form XIII of Etoricoxib.0 Form XIII is characterized by its unique XRD pattern as given in Fig 5.
Preparation of Form XIV 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 Preparation of Form XV 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.
Preparation of Form XVI 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.
10 c. Separating, filtering and drying the solids to obtain the Form XVI of Etoricoxib.
Form XVI is characterised by its unique XRD pattern as given in Fig 8.
The various pharmaceutical compositions and formulations of the novel forms of 15 Etoricoxib of the present invention can be prepared by known processes.
The dosage of 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.
25 The process described in the present invention is illustrated in the following examples which should not be construed to limit the scope of the invention in any way.
EXAMPLE 1 PREPARATION OF FORM -IX OF ETORICOXIB
J 0 Pure 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 product was isolated by drop wise addition of heptan (in two equal lots having interval of 5 minutes). The product was filtered and dried in an oven to constant weight to obtain form IX of Etoricoxib (88% yield , 99.08 % purity).
EXAMPLE 2 PREPARATION OF FORM -X OF ETORICOXIB
Pure 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).
EXAMPLE 3 PREPARATION OF FORM -XI OF ETORICOXIB
Pure 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).
EXAMPLE 4 PREPARATION OF FORM -XI OF ETORICOXIB
Pure 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).
EXAMPLE 6 PREPARATION OF FORM -XIII OF ETORICOXIB
Pure Etoricoxib (1 gm) was dissolved in isopropyl alcohol at atmospheric temperature. After that the reaction mixture was filtered and the solution was cooled at 0°C to isolate the solids which were filtered and dried in an oven to constant weight to get form XIII of Etoricoxib (61% yield , > 98% purity). EXAMPLE 7 PREPARATION OF FORM -XIV OF ETORICOXIB
Pure 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
Pure Etoricoxib (1 gm) was dissolved in aqueous HC1 solution (pH=2) at atmospheric temperature. The solution was washed with toluene and aqueous layer was separated and treated with charcoal and then filtered. Basifying the filtrate by using 25% ammonia solution isolated the product. The product was filtered and dried in an oven to constant weight to get form XV of Etoricoxib (69% yield , > 98% purity). EXAMPLE 9 PREPARATION OF FORM -XVI OF ETORICOXIB
Pure 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).

Claims

We claim:
1 A novel polymorph of Etoricoxib characterized by X-ray diffraction pattern substantially as depicted in fig 1 2 A novel polymorph of Etoricoxib as claimed in claim 1, characterized by X-ray diffraction pattern with peaks at about 5 530, 9 380, 12 910, 16 620, 17 540 18 450, 21 510, 21 880, 22 230, 24 420, 26 340, 29 290, 29 910, 33 970 ± 0 2 degrees two-theta
3 A novel polymorph of Etoricoxib characterized by X-ray diffraction pattern substantially as depicted in fig 2
4 A novel polymorph of Etoricoxib as claimed in claim 3, characterized by X-ray diffraction pattern with peaks at about 5 590, 7 080, 9 450, 9 750, 12 980, 15 520, 16 670, 17 600, 18 160, 18 560, 19 790, 22 280, 22 750, 24 120, 25 000, 26 430, 29 360, 31 3 10 ± 0 2 degrees two-theta 5 A novel polymorph of Etoricoxib characterized by X-ray diffraction pattern substantially as depicted in fig 3
6 A novel polymorph of Etoricoxib as claimed in claim 5, characterized by X-ray diffraction pattern with peaks at about 5 490, 9 350, 10 670, 12 680, 16 590, 16 950, 17 520, 17 810, 18 450, 18 800, 19 680, 21 490, 21 880, 22 200, 23 630, 24 410, 24 910,26 310, 29 270, 29 880, 30 540 ± 0 2 degrees two-theta
7 A novel polymorph of Etoricoxib characterized by X-ray diffraction pattern substantially as depicted in fig 4
8 A novel polymorph of Etoricoxib as claimed in claim 7, characterized by X-ray diffraction pattern with peaks at about 5 510, 9 360, 10 680, 12 890, 16 600, 16 910, 17 510, 18 480, 19 680, 22 210, 22 610, 23 600, 24 400, 24 910, 26 330, 27 890, 29 280, 29 910, 30 590 ± 0 2 degrees two-theta
9 A novel polymorph of Etoricoxib characterized by X-ray diffraction pattern substantially as depicted in fig 5 10 A novel polymorph of Etoricoxib as claimed in claim 9, characterized by X-ray diffraction pattern with peaks at about 6 990, 8 480, 9 660, 1 1 730, 12 350, 15 030, 15 430, 16 510, 17 710, 18 070, 18 800, 19 380, 19 990, 21 110, 21 510, 21 800, 22 700, 23 250, 23 510, 24 040, 26 300, 27 390, 29 260, 29 820, 31 210, 35 750 ± 0 2 degrees two-theta
1. A novel polymorph of Etoricoxib characterized by X-ray diffraction pattern substantially as depicted in fig 6.
12. A novel polymorph of Etoricoxib as claimed in claim 11, characterized by X-ray diffraction pattern with peaks at about 5.490, 9.340, 10.670, 12.880, 16.590, 16.920, 17.500, 18.440, 21.860, 22.180, 23.620, 24.390, 24.930, 26.310, 29.880 ± 0.2 degrees two-theta.
13. A novel polymorph of Etoricoxib characterized by X-ray diffraction pattern substantially as depicted in fig 7.
14. A novel polymorph of Etoricoxib as claimed in claim 13, characterized by X-ray diffraction pattern with peaks at about 8.050, 10.680, 13.790, 15.490, 16.190, 17.220, 19.220, 21.960, 22.720, 23.140, 23.850, 25.350, 28.690, 31.230, 31.710, 32.950 + 0.2 degrees two-theta.
15. A novel polymorph of Etoricoxib characterized by X-ray diffraction .pattern substantially as depicted in fig 8. 16. A novel polymorph of Etoricoxib as claimed in claim 15, characterized by X-ray diffraction pattern with peaks at about 8.590, 13.010, 13.370, 15.140, 16.720, 17.010, 17.810, 18.900, 21.660, 22.330, 22.840, 23.370, 23.630, 24.890, 27.510, 28.580, 32.170 ± 0.2 degrees two-theta.
17. A process for the preparation of the novel polymorph of Etoricoxib as claimed in claims 1 or 2 comprising, a) Contacting/Dissolving Etoricoxib with toluene at 60-75 °C temperature followed by cooling. b) Adding suitable antisolvent selected from the group consisting of heptane, dusopropyl ether or mixtures thereof, in two equal lots. c) Removing the solvent.
18. A process for the preparation of the novel polymorph of Etoricoxib as claimed in claims 3 or 4 comprising, a) Contacting/Dissolving Etoricoxib with toluene at 60-75 °C temperature followed by cooling. b) Adding suitable antisolvent selected from the group consisting of heptane, dusopropyl ether or mixtures thereof in one lot. c) Removing the solvent.
π
19. A process for the preparation of the novel polymorph of Etoricoxib as claimed in claims 5 or 6 comprising, a) Contacting/Dissolving Etoricoxib with a suitable solvent ethyl acetate and isopropyl acetate at room temperature. b) Filtering the solution. c) Concentrating the filtrate. d) Adding an antisolvent selected from the group consisting of heptane, dusopropyl ether or mixtures thereof. e) Removing the solvent. 20. A process for the preparation of the novel polymorph of Etoricoxib as claimed in claims 7 or 8 comprising, a) Contacting/Dissolving Etoricoxib with ethyl acetate at room temperature. b) Filtering the mixture. c) Concentrating the filtrate. d) Adding hexane to the filtrate, e) Removing the solvent.
21. A process for the preparation of the novel polymorph of Etoricoxib as claimed in claims 9 or 10 comprising, a) Contacting/Dissolving Etoricoxib with isopropyl alcohol at room temperature. b) Filtering the solution. c) Isolating the product by cooling to 0-5 °C.
22. A process for the preparation of the novel polymorph of Etoricoxib as claimed in claims 1 1 or 12 comprising, a) Contacting/Dissolving Etoricoxib with ethyl acetate at room temperature and" washing with water. b) Separating the organic layer and purifying. c) Concentrating the organic layer. d) Adding dusopropyl ether to the organic layer. e) Removing the solvent to obtain the product. 23. A process for the preparation of the novel polymorph of Etoricoxib as claimed in claims 13 or 14 comprising, a) Contacting/Dissolving Etoricoxib with aqueous HC1. b) Treating the solution with toluene. c) Separating the aqueous layer and purifying. d) Basifying the filtrate. e) Filtering and drying to obtain the product.
24. A process for the preparation of the novel polymorph of Etoricoxib as claimed in claims 11 or 12 comprising, a) Contacting/Dissolving Etoricoxib with isopropyl acetate at 70-75°C temperature. b) Cooling the solution to 0-5 °C. c) Filtering and drying to obtain the product.
25. A pharmaceutical composition comprising the novel polymorphs of Etoricoxib of the present invention as claimed in any of the preceding claims, comprising either a single polymorph or their mixtures in combination with the pharmaceutically acceptable excipients.
26. A pharmaceutical dosage form comprising the pharmaceutical compositions containing the novel polymorphs of Etoricoxib of the present invention as claimed in claim 25. 27. Use of the novel forms of Etoricoxib of the present invention or their pharmaceutical compositions as claimed in any preceding claims, for preparing medicaments suitable for the treatment of COX-2 mediated disorders such as o st eo arthritis, rheumatoid arthritis, pain and inflammatory disorders in a mammal including human. 28, Method of treatment comprising administering to a person in need thereof, pharmaceutical compositions or pharmaceutically acceptable dosage forms containing the new forms of Etoricoxib of the present invention, as claimed in any preceding claims, for the treatment of COX-2 mediated disorders.
PCT/IN2005/000009 2004-01-14 2005-01-07 Novel polymorphs of etoricoxib WO2005085199A1 (en)

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WO2010097802A2 (en) 2009-02-27 2010-09-02 Cadila Healthcare Limited A process for the preparation of etoricoxib
WO2011158250A1 (en) 2010-06-16 2011-12-22 Glenmark Generics Limited Process for preparation of 2, 3-diaryl-5-substituted pyridines and their intermediates
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WO2012163839A1 (en) 2011-05-27 2012-12-06 Farma Grs, D.O.O. A process for the preparation of polymorphic form i of etoricoxib
WO2013075732A1 (en) * 2011-11-21 2013-05-30 Synthon Bv Process for making crystalline form i of etoricoxib
EP2601952A1 (en) 2011-12-07 2013-06-12 Zentiva, k.s. Novel pharmaceutically acceptable salts and cocrystals of 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl and their therapeutic uses
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WO2013144977A2 (en) 2012-03-30 2013-10-03 Mylan Laboratories Ltd. An improved process for the preparation of etoricoxib
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CN104418799A (en) * 2013-09-03 2015-03-18 天津药物研究院 Etoricoxib crystal as well as preparation method and application thereof
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WO2022216975A1 (en) 2021-04-09 2022-10-13 Tremeau Pahrmaceuticals, Inc. Deuterated etoricoxib, methods of manufacture and use thereof
US11858909B2 (en) 2021-04-09 2024-01-02 Tremeau Pharmaceuticals, Inc. Deuterated etoricoxib, methods of manufacture, and use thereof

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WO2010097802A2 (en) 2009-02-27 2010-09-02 Cadila Healthcare Limited A process for the preparation of etoricoxib
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WO2011158250A1 (en) 2010-06-16 2011-12-22 Glenmark Generics Limited Process for preparation of 2, 3-diaryl-5-substituted pyridines and their intermediates
EP2582690A4 (en) * 2010-06-16 2013-09-18 Glenmark Generics Ltd Process for preparation of 2, 3-diaryl-5-substituted pyridines and their intermediates
WO2012004677A1 (en) 2010-07-05 2012-01-12 Actavis Group Ptc Ehf Solid state forms of etoricoxib salts
WO2012163839A1 (en) 2011-05-27 2012-12-06 Farma Grs, D.O.O. A process for the preparation of polymorphic form i of etoricoxib
WO2013105106A1 (en) 2011-11-03 2013-07-18 Cadila Healthcare Limited An improved process for the preparation of etoricoxib and polymorphs thereof
WO2013075732A1 (en) * 2011-11-21 2013-05-30 Synthon Bv Process for making crystalline form i of etoricoxib
EP2601952A1 (en) 2011-12-07 2013-06-12 Zentiva, k.s. Novel pharmaceutically acceptable salts and cocrystals of 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl and their therapeutic uses
WO2013144977A3 (en) * 2012-03-30 2013-12-12 Mylan Laboratories Ltd. An improved process for the preparation of etoricoxib
WO2013144977A2 (en) 2012-03-30 2013-10-03 Mylan Laboratories Ltd. An improved process for the preparation of etoricoxib
WO2014033526A1 (en) 2012-08-27 2014-03-06 Cadila Healthcare Limited Pharmaceutical compositions of etoricoxib
CN104418799A (en) * 2013-09-03 2015-03-18 天津药物研究院 Etoricoxib crystal as well as preparation method and application thereof
CN107056691A (en) * 2017-06-21 2017-08-18 四川尚锐生物医药有限公司 A kind of method for preparing Etoricoxib crystal formation V
CN107056691B (en) * 2017-06-21 2020-03-10 四川尚锐生物医药有限公司 Method for preparing etoricoxib crystal form V
WO2019130049A1 (en) 2017-12-29 2019-07-04 Grünenthal GmbH Pharmaceutical combination comprising extended-release tramadol hydrochloride and immediate-release etoricoxib, and its use for the treatment of pain
CN112826804A (en) * 2019-11-22 2021-05-25 北京泰德制药股份有限公司 Etoricoxib composition
CN112826804B (en) * 2019-11-22 2022-07-15 北京泰德制药股份有限公司 Etoricoxib composition
WO2022216975A1 (en) 2021-04-09 2022-10-13 Tremeau Pahrmaceuticals, Inc. Deuterated etoricoxib, methods of manufacture and use thereof
US11858909B2 (en) 2021-04-09 2024-01-02 Tremeau Pharmaceuticals, Inc. Deuterated etoricoxib, methods of manufacture, and use thereof

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