FORM 2
THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
A Process for the Preparation of Crystalline Form of Dofetilide
2. APPLICANT (S)
(a) NAME: Enaltec Labs Pvt. Ltd
(b) NATIONALITY: An Indian Company incorporated under the Indian
Companies ACT 1956
(c) ADDRESS:
Enaltec Labs Pvt. Ltd., 17th Floor, Kesar Solitaire, Plot No. 5, Sector 19, Sanpada, Navi Mumbai- 400705, Maharashtra, India.

FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of crystalline form of Dofetilide having structural formula (I).

BACKGROUND OF THE INVENTION:
Dofetilide is a class III antiarrhythmic agent and is chemically defined as N-[4-[2-[methyl [2-[4-[(methylsulfonyl) amino] phenoxy] ethyl] amino] ethyl] phenyl]-methane sulfonamide. Dofetilide is used for the maintenance of sinus rhythm in individuals prone to the occurrence of atrial fibrillation and flutter arrhythmias, and for chemical cardioversion to sinus rhythm from atrial fibrillation and flutter. Dofetilide can be depicted by structural formula (I).

Dofetilide and other related compounds were first disclosed in US4,959,366.
US6,124,363 reported various polymorphic forms of Dofetilide designated as PI62, P162a, and PI43. Furthermore, US'363 also mentions that the methods for the preparation of Dofetilide disclosed in US'366 are difficult to reproduce and have either produced a mixture of dofetilide polymorphs P162/P162a, P162b/P136 or

P162b/P136/P143 or, essentially, dofetilide polymorph P136 or P162b, all of which . tend to crystallise in an agglomerated form that would have to be deagglomerated (e.g. by milling or micronisation) to achieve the required small particle size. Hence, none of these products would be directly suitable for use in a formulation.
The identification and characterization of these polymorphous forms and, simultaneously, the definition of the experimental conditions for obtaining them is very important for a compound endowed with pharmacological activity which, like Dofetilide, is marketed as medicinal preparation. In fact it is known that the polymorphism of a compound that can be used as active ingredient contained in a medicinal preparation can influence the pharmaco-toxicologic properties of the drug. Different polymorphous forms of an active ingredient administered as drug under oral or topical form can modify many properties thereof like bioavailability, solubility, stability, colour, compressibility, flowability and workability with consequent modification of the profiles of toxicological safety, clinical effectiveness and productive efficiency.
In view of above, the inventors of present invention have developed a process for preparation of crystalline form Dofetilide which is convenient to scale up and process provides high yields and quality,

OBJECT OF THE INVENTION:
i) The main object of present invention to provide a process for the preparation
of crystalline form of Dofetilide of structural formula (I)
ii) Another object of present invention is provide a process for preparation of crystalline form Dofetilide which is convenient to scale up and provides high yields and quality.
iii) Yet another object of present invention is to provide a process for the preparation of crystalline form which is highly reproducible and to result in dofetilide which is easy to filter and has good bulk handling.
SUMMARY OF THE INVENTION:
An aspect of the present application, the present invention is to provides a process for the preparation of crystalline form of Dofetilide of structural formula (I),

comprising;
a) combining the Dofetilide with an organic solvent
b) heating to reflux temperature followed by cooling gradually; and
c) isolating a crystalline form from reaction mixture.
In another aspect of the present application, the present invention provides Dofetilide crystalline characterized by X-ray powder diffraction pattern comprising

characteristic 2θ° peaks at 4.192, 8.383, 12.585, 17.465, 18.295, 19.460, 19.770, 21.039, 21.531, 22.508, 22.756, 23.035, 24.260, 25.308, 26.057, 26.365, 28.162, 29.014, 29.413, 30.935, 32.243, 33.441, 35.090, 35.888, 36.218, 36.890, 38.729, 39.533, 40.181, 40.727, 41.681, 42.565 and 44.215 ±0.1 2θ°.
BRIEF DESCRIPTION OF DRAWING:
Figure 1 shows X-Ray Diffraction Pattern of dofetilide crystalline form.
DETAILED DESCRIPTION OF DRAWING:
Dofetilide of structural formula I can be prepared by method disclosed in US patent number 4,959,366.
The dofetilide crystalline form obtained may be characterized by X-Ray Diffraction Pattern as depicted in Figure 1.
The dofetilide crystalline form obtained may be characterized by X-ray powder diffraction pattern comprising characteristic 29° peaks at 4.192, 8.383, 12.585, 17.465, 18.295, 19.460, 19.770, 21.039, 21.531, 22.508, 22.756, 23.035, 24.260, 25.308, 26.057, 26.365, 28.162, 29.014, 29.413, 30.935, 32.243, 33.441, 35.090, 35.888, 36.218, 36.890, 38.729, 39.533, 40.181, 40.727, 41.681, 42.565 and 44.215 ±0.1 20°.
Any form of Crude or Pure Dofetilide obtained by known processes can be used for preparing said crystalline form.
The organic solvent used for preparing crystalline form of Dofetilide can be selected from the group consisting of acetonitrile, ethyl acetate, tetrahydrofuran and acetone.

The organic solvent used for preparing crystalline form of Dofetilide can be in amount of 4 volumes / weight to 15 volumes / weight of Dofetilide.
The solution of Dofetilide in organic solvent can be stirred at a reflux temperature for a period of 2 hours to 5 hours and then resulting reaction mixture can be cooled to a temperature in the range of 25°C to 30°C in 3 hour to 5 hours to get crystalline form of Dofetilide.
The solution of Dofetilide in organic solvent can be stirred at a temperature in the range of 25°C to 30°C for a period of 0.5 hours to 2 hours and then resulting reaction mixture can be cooled to a temperature in the range of 5°C to 20°C
The solution of Dofetilide in organic solvent can be stirred at a temperature in the range of 5°C to 20°C for a period of 2 hours to 5 hours.
The crystalline form of Dofetilide can be isolated by the steps of filtration, centrifugation, washing, drying and combination thereof.
The crystalline form of Dofetilide can be dried under reduced pressure at a temperature in the range of 50°C to 65°C for a period of 6 hours to 18 hours.
EXAMPLES:
In the following examples, the preferred aspects of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.

EXAMPLE 1: PREPARATION OF CRYSTALLINE FORM OF DOFETILIDE
Dofetilide (50 gm) was suspended in acetonitrile (250 ml). The suspension was heated to 82°C and then it was stirred for 2 hours at 80°C to 85°C. The resulting suspension was cooled to 25°C to 30°C in 4 hours and then it was stirred for 1 hour at 25°C to 30°C. The suspension was further cooled to 10°C to 15°C and then it was again stirred for 2 hours at 10°C to 15°C. The resulting solids were filtered, washed with pre-cooled acetonitrile and dried under reduced pressure at 60°C to 65°C for 10 hours.
Yield: 44 gm Purity: 99.5% (By HPLC)
EXAMPLE 2: PREPARATION OF CRYSTALLINE FORM OF DOFETILIDE
Dofetilide (50 gm) was suspended in ethyl acetate (500 ml). The suspension was heated to 77°C and then it was stirred for 2 hours at 75°C to 80°C. The resulting suspension was cooled to 2S°C to 30°C in 4 hours and then it was. stirred for 1 hour at 25°C to 30°C. The suspension was further cooled to 10°C to 15°C and then it was again stirred for 2 hours at 10°C to 15°C. The resulting solids were filtered, washed with pre-cooled ethyl acetate and dried under reduced pressure at 60°C to 65°C for 10 hours.
Yield: 45 gm Purity: 99.5% (By HPLC)
EXAMPLE 3: PREPARATION OF CRYSTALLINE FORM OF DOFETILIDE
Dofetilide (50 gm) was suspended in tetrahydrofuran (500 ml). The suspension was heated to 66°C and then it was stirred for 2 hours at 64°C to 68°C. The resulting suspension was cooled to 2S°C to 30°C in 4 hours and then it was stirred for 1 hour at 25°C to 30°C. The suspension was further cooled to 10°C to 15°C and then it was

again stirred for 2 hours at 10°C to 15°C. The resulting solids were filtered, washed
with pre-cooled tetrahydrofuran and dried under reduced pressure at 60°C to 65°C for
10 hours.
Yield: 45 gm
Purity: 99.5% (By HPLC)
EXAMPLE 4: PREPARATION OF CRYSTALLINE FORM OF DOFETILIDE
Dofetilide (50 gm) was suspended in acetone (250 ml). The suspension was heated to 56°C and then it was stirred for 2 hours at 52°C to 57°C. The resulting suspension was cooled to 25°C to 30°C in 3 hours and then it was stirred for 1 hour at 25°C to 30°C. The suspension was further cooled to 10°C to 15°C and then it was again stirred for 2 hours at 10°C to 15°C. The resulting solids were filtered, washed with pre-cooled acetone and dried under reduced pressure at 60°C to 65°C for 10 hours. Yield: 44 gm Purity: 99.5% (By HPLC)

We claim:
1. The process for the preparation of crystalline form of Dofetilide of structural formula (I),

comprising;
a) combining the Dofetilide with an organic solvent
b) heating to reflux temperature followed by cooling gradually; and
c) isolating a crystalline form from reaction mixture.

2. The process as claimed in claim 1 wherein organic solvent is selected from the group consisting of acetonitrile, ethyl acetate, tetrahydrofuran and acetone.
3. The process as claimed in claim 1 wherein organic solvent is in amount of 4 volumes / weight to 15 volumes / weight of Dofetilide.
4. The process as claimed in claim 1 wherein the solution of Dofetilide in organic solvent is stirred at a reflux temperature for a period of 2 hours to 5 hours.
5. The process as claimed in claim 4 wherein the solution of Dofetilide is stirred in acetonitrile at a temperature in the range of 80°C to 85°C or in ethyl acetate at a temperature in the range of 75°C to 80°C or in tetrahydrofuran at a temperature in the range of 64°C to 68°C or in acetone at a temperature in the range of 52°C to 57°C for a period of 2 hours to 5 hours.

6. The process as claimed in claim 1 wherein reaction mixture is cooled to a temperature in the range of 25°C to 30°C in 3 hour to 5 hours after stirring at reflux temperature.
7. The process as claimed in claim 1 wherein the solution of Dofetilide in organic solvent is stirred at a temperature in the range of 25°C to 30°C for a period of 0.5 hours to 2 hours and then resulting reaction mixture is cooled to a temperature in the range of 5°C to 20°C.
8. The process as claimed in claim 1 wherein the solution of Dofetilide in organic solvent is stirred at a temperature in the range of 5°C to 20°C for a period of 2 hours to 5 hours.
9. The process as claimed in claim 1 wherein the crystalline form of Dofetilide is isolated by the steps of filtration, centrifugation, washing, drying and combination thereof.
10. The process as claimed in claim 1 wherein the crystalline form of Dofetilide is
dried under reduced pressure at a temperature in the range of 50°C to 65 °C for a
period of 6 hours to 18 hours.