Claims:1. A crystalline form W1 of Dofetilide, characterized by having one or more of the following properties;
i. a powder X-ray diffraction pattern substantially in accordance with Figure 1 or 4;
ii. a powder X-ray diffraction pattern having peaks at 4.18, 17.42, 18.27, 20.06, 20.86, 21.49, 22.47 or 25.24 ± 0.2°;
iii. a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 2 or 5;
iv. a thermogavimetric Analysis (TGA) substantially in accordance with Figure 3.

2. The crystalline Dofetilide of claim 1 having purity more than 99 % when measured by HPLC.

3. The crystalline Dofetilide of claim 1, having moisture content of 1 to 2 % w/w.

4. A process of preparation of crystalline form W1 of Dofetilide, the process comprising the steps of;
a) dissolving Dofetilide in suitable solvent,
b) heating the mixture of step (a) at suitable temperature, and
c) isolating crystalline form W1 of Dofetilide.

5. The process of claim 4, wherein the suitable solvent is selected from one or more of alcoholic solvents, ester solvent, water or mixtures thereof.

6. The process of claim 5, wherein the alcoholic solvent is selected from one or more of methanol, ethanol, isopropyl alcohol, n-propanol, butanol, isobutanol or propylene glycol.

7. The process of claim 5, wherein the ester solvent is selected from one or more of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, propyl acetate, butyl acetate, isobutyl acetate, butyl acetate, isoamyl acetate, amyl acetate or hexyl acetate.

8. The process of claim 4, wherein the suitable solvent is mixture of isopropyl acetate and water, or mixture of isopropyl alcohol and water in ratio of 10:1 v/v

9. The crystalline form of claim 1 wherein the form is stable after storage for a period of 3 months at 25°C and do not show detectable quantity crystalline forms of P162, P162a, P143.

10. The form of claim 9 substantially free from crystalline forms P162, P162a, P143 or an amorphous form.

11. A pharmaceutical composition comprising crystalline form W1 of Dofetilide of claim 1 in combination with one or more pharmaceutically acceptable excipients.
, Description:Field of the Invention

The invention relates to crystalline form of Dofetilide and process of preparation thereof.

Background of the invention

Dofetilide is chemically known N-[4-[2-[methyl [2-[4-[(methylsulfonyl) amino] phenoxy] ethyl] amino] ethyl] phenyl]-methanesulfonamide and is structurally represented by formula (I)

Formula I
Dofetilide is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties. Its empirical formula is C19H27N3O5S2 and it has a molecular weight of 441.6. Dofetilide approved in USA for indication under the trade name Tikosyn by Pfizer. Tikosyn is indicated for the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter.

US Patent No 4,959,366 describes Dofetilide or a pharmaceutically acceptable salt thereof and its process of preparation.

US Patent No. 6,124,363 describes the Dofetilide polymorphs P162, P162a and P143 and process of preparation thereof.

It was surprisingly discovered that novel polymorph of the Dofetilide hereinafter described as Form W1 can be prepared by improved process of synthesis.

Summary of the Invention

One embodiment discloses a crystalline form W1 of Dofetilide, characterized by having one or more of the following properties;
i. a powder X-ray diffraction pattern substantially in accordance with Figure 1 or 4;
ii. a powder X-ray diffraction pattern having peaks at 4.18, 17.42, 18.27, 20.06, 20.86, 21.49, 22.47 or 25.24 ± 0.2°;
iii. a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 2 or 5;
iv. a thermogravimetric Analysis (TGA) substantially in accordance with Figure 3.

Another embodiment discloses a process of preparation of crystalline form W1 of Dofetilide, the process comprising the steps of;
a) dissolving Dofetilide in suitable solvent,
b) heating the mixture of step (a) at suitable temperature, and
c) isolating crystalline form W1 of Dofetilide.

Brief Description of the Drawings

Figure 1 shows X-ray powder diffraction pattern of crystalline form W1 of Dofetilide prepared according to Example-2

Figure 2 shows differential scanning calorimetry thermogram of crystalline form W1 of Dofetilide prepared according to Example-2

Figure 3 shows thermogavimetric Analysis (TGA) of crystalline form W1 of Dofetilide prepared according to Example-2

Figure 4 shows X-ray powder diffraction pattern of crystalline form W1 of Dofetilide prepared according to Example-3

Figure 5 shows differential scanning calorimetry thermogram of crystalline form W1 of Dofetilide prepared according to Example-3

Description of the Invention

One embodiment discloses crystalline form W1 of Dofetilide, compound of Formula I,

Formula I

Another embodiment discloses crystalline form W1 of Dofetilide characterized by X-ray powder diffraction pattern substantially as shown in Figure 1 and 4; differential scanning calorimetry thermogram as shown in Figure 2 and Figure 5; and thermogavimetric Analysis (TGA) as shown in Figure 3.

Still another embodiment discloses crystalline form W1 of Dofetilide, characterized by X-ray diffraction pattern according to Figure 1 or 4. The X-ray powder diffraction pattern includes one or more peaks selected from 4.18, 17.42, 18.27, 20.06, 20.86, 21.49, 22.47 or 25.24  0.2.

The XRPD characteristic peaks of the crystalline form W1 of Dofetilide are disclosed in Table 1 below:

Crystalline XRD Dofetilide
2 Theta peaks d-spacing [Aº] Relative Intensity [%]
4.18 21.12 38.85
8.34 10.59 2.18
12.50 7.08 2.60
17.42 5.08 25.08
18.27 4.85 42.05
18.86 4.70 9.01
19.38 4.57 19.60
20.06 4.42 100.00
20.86 4.25 17.37
21.49 4.13 14.95
22.47 3.95 15.56
24.21 3.67 4.59
25.24 3.52 12.53
29.34 3.04 3.38
30.82 2.90 2.55
35.04 2.56 1.50
36.00 2.49 2.17
37.05 2.42 3.76

Another embodiment discloses the process for preparation of crystalline form W1 of Dofetilide, the process comprising the steps of:
a) dissolving Dofetilide in suitable solvent,
b) heating the mixture of step (a) at suitable temperature, and
c) isolating crystalline form W1 of Dofetilide.

The steps (a) and (b) of the process may involve dissolving Dofetilide in a mixture of suitable solvents and heating the mixture to obtain clear solution. The solution was treated with charcoal to remove color impurities and refluxed at suitable temperature ranging from 70°C to 100°C for a period of 30 minutes.

The suitable solvent may be one or more of alcoholic solvents, ester solvent, water or mixture thereof. The alcoholic solvents me be selected from methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol or propylene glycol; ester solvent may be selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, propyl acetate, butyl acetate, isobutyl acetate, butyl acetate, isoamyl acetate, amyl acetate or hexyl acetate.

Preferably, the mixture of solvent is isopropyl acetate and water in 10:1 ratio by volume or mixture of isopropyl alcohol and water in 10:1 ratio by volume.

The step (c) of the process involves isolation of Dofetilide through filtration. The reaction mixture of step (b) is filtered through hyflo pad and cooled to ambient temperature and stirred. The reaction mixture is granulated for 6 hours. The precipitate obtained was filtered, washed with suitable solvent and dried under vacuum at temperature of 70°C to get crystalline form W1 of Dofetilide. The obtained crystalline form W1 of Dofetilide has the moisture content of about 1 to 2 % w/w.

Another embodiment discloses crystalline form W1 of Dofetilide having purity more than 99 % when measured by HPLC.

The crystalline form W1 of Dofetilide when stored at 25°C for a period of 3 months did not show contamination of other polymorphic forms.

Another embodiment discloses crystalline form W1 of Dofetilide which is stable and is substantially free from other known crystalline forms of Dofetilide such as P162, P162a, P143 or an amorphous form. The stable crystalline form W1 has no detectable quantity of crystalline forms P162, P162a, P143 or an amorphous form after storage for a period of 3 months at 25°C.

The term “stable” as used in this specification preferably means that the Dofetilide retains polymorphic stability for at least three months, more preferably for at least 6 months.

In further embodiment the conversion of crystalline form W1 of Dofetilide to other crystalline forms of Dofetilide is disclosed.

Another embodiment discloses pharmaceutical compositions comprising crystalline form W1 of Dofetilide in combination with one or more pharmaceutically acceptable carriers, diluents, excipients.

The pharmaceutical compositions may be prepared in a manner well known in the pharmaceutical art. The carrier or excipient may be a solid, semi-solid or liquid material that can serve as a vehicle or medium for the active ingredient. The compositions may be administered in the form of oral, parenteral, transdermal or any other route of administration.

Another embodiment discloses the crystalline form W1 of Dofetilide having 90% of the particles less than 45 microns. The particle size may be measured by any suitable method preferably the laser diffraction technique can be used for the measurement of particle size of the active ingredient alone or in the composition.

The particle size of the active ingredient is determined by measuring the characteristic equivalent sphere diameter, by laser diffraction using a Malvern apparatus. The parameter taken into consideration was VD (volume diameter) in microns of 90% of the particles.

Advantageously at least 90% of the particles have a volume diameter lower than 45 microns, preferably lower than 45 microns, more preferably lower than 30 microns, most preferably lower than 15 microns.

The crystalline form W1 of Dofetilide may be micronized in a suitable milling device such as ball milling, jet milling or milling using a high pressure homogenizer or by other techniques such as spray drying to achieve the desired particle size.

Another embodiment discloses pharmaceutical composition comprising crystalline W1 of Dofetilide having 90% of the particles less than 45 microns.

The embodiments of the specification are further illustrated by way of following examples, which do not limit the scope of the claims. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the claims.

Examples

Example-1: Preparation of N-[4-(2-[2-[4-(methanesulphonamido) phenoxy]-N-methyl ethylamino} ethyl) phenyl] methanesulphonamide

To the solution of N-methyl-N-[2-(4-aminophenoxy)ethyl]-4-aminophenethylamine (100 gm) in acetonitrile (800 mL), N-methyl morpholine (116 mL) was added drop wise the solution of methane sulphonyl chloride (88.40 gm) in acetonitrile (200 mL) at temperature of about 0°C to 5 °C. After completion of the reaction, charged water (1L) and distilled out the solvent, after distillation charged isopropyl alcohol (1.0 lit) and water (100 mL) and stirred the reaction mixture, followed by heating the reaction mixture at temperature 75°C to 85 °C to get clear solution. The reaction mixture was cooled to temperature of about 25°C to 35 °C. The slurry was filtered to provide the title compound.
Yield: 100 gm
HPLC Purity: 99.7 %

Example-2: Preparation of crystalline form W1 of Dofetilide

Charged Dofetilide (10.0 g) to a stirred solution of isopropyl acetate (100 ml) and water (10 ml) and heat to get a clear solution. The mixture was treated with charcoal to remove color impurities and refluxed at temperature 70°C t0 80°C for a period of 30 minutes. The reaction mixture is filtered through hyflo pad and cooled to ambient temperature and stirred. The reaction mixture is granulated for 6 hours. The precipitate obtained was filtered, washed with isopropyl acetate and dried under vacuum at temperature 60°C to provide the title compound.
Yield: 6.80 gm
HPLC Purity: 99.37 %

Example-3: Preparation of crystalline form W1 Dofetilide

Charged Dofetilide (1.2 kg) to a stirred solution of isopropyl alcohol (7.0 L) and water (1.0L) and heat to get a clear solution. The mixture was treated with charcoal to remove color impurities and refluxed at temperature 70°C t0 80°C for a period of 30 minutes. The reaction mixture is filtered through hyflo pad and cooled to ambient temperature and stirred. The reaction mixture is granulated for 6 hours. The precipitate obtained was filtered, washed with isopropyl alcohol and dried under vacuum at temperature 70°C to provide the title compound.
Yield: 1.08 kg
HPLC Purity: 99.76 %
Moisture Content: 1.19 % w/w