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 <BR> <BR> is 5-chloro-6'-methyl-3- [4-methylsulfonyl) phenyl] -2, 3'-bipyridine having structural formula I.

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.

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, diisopropyl 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, diisopropyl 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.

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 the 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 charcoal c. Drying and concentrating under reduced pressure to get solid residue. d. Isolating the product by adding suitable antisolvent such as diisopropyl ether e. Filtering and drying the isolated product to obtain Form XIV of Etoricoxib.

Form X1V is characterized by its unique XRD pattern as given in Fig 6.

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 HCl 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 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. 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 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 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.

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 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 (1 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: diisopropyl ether (1: 1). The isolated residues were filtered and dried in an oven to constant weight to obtain form XI of Etoricoxib (82% yield, 2 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 FOR1VI-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, 2 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 diisopropyl 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).