FORM 2
THE PATENTS A CT, I970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention -Novel polymorphic form of Teriflunomide
2. Applicant(s)
(a) NAME: ALEMBIC LIMITED
(b) NATIONALITY: An Indian Company.
(c) ADDRESS: Alembic Campus, Alembic Road,
Vadodara-390, 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which is
to be performed.

Field of the invention:
The present invention relates to novel polymorphic form of Teriflunomide and preparation thereof. Specifically present invention relates to polymorphic form of Teriflunomide especially Form I.
Background of the invention:
The chemical name of Teriflunomide is 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide and formula is C12H9F3N2O2 and molecular weight is 270.207.
Teriflunomide is used as Immunosupressant. It acts as tyrosine kinase inhibitor. It is used in treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis.
Teriflunomide was first disclosed and claimed in US patent no. 5,679,709 but this patent does not mention any polymorphic form or process of preparation for polymorphic form.
US 5,494,911, US 5,990,141 disclose various processes for preparing Teriflunomide. These patents do not disclose process for preparation Teriflunomide polymorphic form or mention any its polymorphic form.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum, therm0gravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC") which have been used to distinguish polymorphic forms.
The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the

bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubility. Pharmaceutical compounds having different crystalline forms or polymorphs have different dissolution property. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
Pharmaceutical formulation is affected by the rate of delivery or the bioavailability of the pharmaceutically active substance is the crystalline forms or polymorphs. This relationship between crystalline forms or polymorphs and bioavailability is well known in the pharmaceutical industry and across a range of pharmaceutical products.
It is therefore, a need to develop novel polymorphs of Teriflunomide so that it can be useful for formulation.
Present inventors have directed their research work towards developing a process for the preparation of Teriflunomide novel polymorphic forms thereof.
Present inventors have also directed their research work towards developing a process for the preparation of pure Teriflunomide.

Object of the invention:
It is therefore an object of the present invention to provide new crystalline Form I of Teriflunomide.
Another object of the present invention is to provide a process for preparation of new crystalline Form I of Teriflunomide.
Another object of the present invention is to provide a process for preparation of pure Teriflunomide.
Summary of the invention:
According to one aspect of the present invention, there is provided a new crystalline polymorphic Form I of Teriflunomide characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at 20 at about 7.9, 10.1, 15.7, 15.9, 19.5, 20.0, 20.3, 24.7, 26.9, 27.9, 31.7 ±0.2 degrees 20.
The XRD of crystalline polymorphic Form I of Teriflunomide is depicted in Fig. 1.
According to second aspect of the present invention, there is provided a process for preparation of a crystalline polymorphic Form I of Teriflunomide comprising steps of:
(i) providing a solution or suspension of Teriflunomide in acetonitrile;
(ii) crystallizing the product from the said solution;
(iii)isolating crystalline Form I of Teriflunomide.
According to third aspect of the present invention, there is provided a process for preparation of pure Teriflunomide comprising steps of:
(i) treating Teriflunomide in acetonitrile;
(ii) isolating Teriflunomide form the solution or suspension;
(iii)triturating the Teriflunomide solid with acetonitrile.

Brief description of the drawings:
Fig. 1 shows the X-ray powder diffraction pattern of new polymorph Form I of Teriflunomide.
Detailed description of the invention:
The present invention provides a polymorphic crystalline Form I of Teriflunomide characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at 20atabout7.9, 10.3, 15.7, 15.9, 19.5, 20.0, 20.3, 24.7, 26.9, 27.9, 31.7±0.2 degrees20.
The XRD of polymorphic crystalline Form I of Teriflunomide is depicted in Fig. 1.
The present invention provides a process for preparation of a crystalline Form I of Teriflunomide comprising steps of:
(i) providing a solution or suspension of Teriflunomide in acetonitrile;
(ii) crystallizing the product from the said solution;
(iii)isolating crystalline Form I of Teriflunomide.
Here the term "crystallizing" means crystallizing compounds using methods known in the art. For example either reducing the volume of the solvent with respect to solute or decreasing the temperature of the solution or using both so as to crystallize the compound.
Teriflunomide is dissolved or suspended in acetonitrile at about reflux temperature. The acetonitrile is taken 2 to 50 times the quantity of Teriflunomide. The solution is filtered through know filtration methods. The filtrate was kept at room temperature for crystallization. The precipitate were filtered and dried to give crystalline Form I of Teriflunomide.
Analysis of this solid gives XRD which is as shown in Fig. 1, XRD is recorded by X-pert-PRORDAD-1044.

The present invention provides a process for preparation of pure Teriilunomide comprising steps of:
(i) treating Teriflunomide in acetonitrile;
(ii) isolating Teriilunomide form the solution or suspension;
(iii)triturating the Teriflunomide solid with acetonitrile.
The term ''treating" as used hereinabove refers to suspending, dissolving or mixing and contacting or reacting of Teriflunomide with solvent or reagents followed by isolating Teriflunomide by removal of reagents and solvents.
The term "triturating" as used hereinabove refers to suspending Teriflunomide in solvent and stirring for period of time sufficient for surface contact of solid with solvent and then filtering the compound from the mixture.
The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.
Ex am pic-1
Preparation of polymorphic form I of Teriflunomide
Teriflunomide (5.0g) was dissolved in acetonitrile (125ml). The mixture was stirred at reflux temperature. The solution is filtered through celite bed. The filtrate was kept overnight at room temperature for crystallization. XRD of the compound is as shown in Fig. 1

We claim
1. A crystalline form of Teriflunomide.
2. A polymorphic crystalline Form I of Teriflunomide characterized by an X-ray powder diffraction pattern having peaks expressed as 29 at about 7.9, 10.1, 15.7, 15.9, 19.5, 20.0, 20.3, 24.7, 26.9, 27.9, 31.7 ±0.2 degrees 20.
3. A polymorphic crystalline Form I of Teriflunomide of claim 2, further characterized by an X-ray powder diffraction pattern as in Fig. 1.
4. A process of preparation of a crystalline Form I of Teriflunomide as comprising steps of:
(i) providing a solution or suspension of Teriflunomide in acetonitrile; (ii) crystallizing the product from the said solution; (iii)isolating crystalline Form I of Teriflunomide.
5. A process for preparation of pure Teriflunomide comprising steps of:
(i) treating Teriflunomide in acetonitrile;
(ii) isolating Teriflunomide form the solution or suspension; (iii)triturating the Teriflunomide solid with acetonitrile .