FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"NOVEL POLYMORPHIC FORM OF DRONEDARONE HYDROCHLORIDE."
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at ]7thFloor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

NOVEL POLYMORPHIC FORM OF DRONEDARONE HYDROCHLORIDE
FIELD OF THE INVENTION
The present invention relates to novel polymorph of dronedarone hydrochloride hereinafter refer as crystalline form II. The present invention further relates to processes for preparing crystalline form II of dronedarone hydrochloride and pharmaceutical composition thereof.
BACKGROUND OF THE INVENTION:
Dronedarone hydrochloride is a benzofuran derivative having chemical name N-{2-butyl-3-[4-(3-dibutylaminopropoxy) benzoyl] benzofuran-5-yl} methanesulfonamide, hydrochloride is known from US Patent No. 5,223,510 and is represented by compound of structural formula I.

Dronedarone hydrochloride is sold in USA under the proprietary name of "MULTAQ". It is an antiarrhythmic agent and is indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) OR atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e.. age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter > 50mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted.
US Patent No. 5.223.510 describes the crystallization of dronedarone hydrochloride in acetone solvent and resulting dronedarone hydrochloride has a melting point at 143°C.

IP.com Journal (2010), 10(2B), 31 discloses amorphous form of dronedarone hydrochloride and crystalline form of dronedarone hydrochloride referred herein after as crystalline form I. The crystalline form I is characterized by data selected from a group consisting of: a powder XRD pattern having peaks at about 7.7, 8.1, 13.9,15.8, 21.5, 23.4, 26.2, 26.9 ± 0.2 degrees 2-theta.
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. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC") as well as by content of solvent in the crystalline form, 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 solutions, 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 solubilities.
The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. 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.
Therefore, there is a need for additional solid state forms of dronedarone hydrochloride.
The present applicant of the patent has surprisingly found a new crystalline polymorphic form of dronedarone hydrochloride, which is designated as form II.
SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide a novel polymorphic form of dronedarone hydrochloride hereinafter refer as crystalline form II.
A second aspect of the present invention is to provide processes for preparing crystalline form II of dronedarone hydrochloride.
A third aspect of the present invention is to provide a pharmaceutical composition comprising crystalline form II of dronedarone hydrochloride.
A fourth aspect of the present invention is to provide a process for preparing crystalline form II of dronedarone hydrochloride comprising the steps of:
a. providing a solution of dronedarone hydrochloride in an alcohol solvent,
b. stirring the solution obtained in step a for period of 30 minutes to 8 hours at a
temperature in the range of 0°C to 30°C and
c. isolating crystalline form II of dronedarone hydrochloride.
DETAIL DESCRIPTION OF THE INVENTION
A crystalline form II of dronedarone hydrochloride may be characterized by X-ray diffraction pattern having peaks at 1 1.6, 12.7, 13.5, 14.0, 15.4, 15.9, 18.6, 19.7,20.5, 20.9,21.1,21.3,22.4, 23.6, 24.1, 24.7, 25.7, 26.6, 27.4, 29.6 ± 0.2 degrees two theta.

A crystalline form II of dronedarone hydrochloride may be characterized by X-ray diffraction pattern as depicted in Figure 1.
A crystalline form 1\ of dronedarone hydrochloride may be characterized by X-ray diffraction pattern having following peaks:

Pos. [°2Th.] Height [cts] Area
[cts*°2Th.] FWHM
[°2Th.] d-spacing
[Å] ReLInt
[%]
11.6405 104.39 11.36 0.0816 7.59603 4.92
12.7766 235.77 25.65 0.0816 6.92306 11.11
13.3929 275.62 22.49 0.0612 6.60584 12.99
13.5997 832.36 113.20 0.1020 6.50582 39.23
14.0127 159.86 17.39 0.0816 6.31501 7.53
15.0391 354.39 38.56 0.0816 5.88623 16.70
15.4846 853.90 116.13 0.1020 5.71785 40.25
15.9725 627.49 85.34 0.1020 5.54428 29.58
16.3410 148.01 16.10 0.0816 5.42009 6.98
17.2436 93.71 20.39 0.1632 5.13836 4.42
17.8151 100.23 16.36 0.1224 4.97478 4.72
18.6124 294.24 80.03 0.2040 4.76343 13.87
19.3442 69.53 7.56 0.0816 4.58486 3.28
19.7828 534.12 145.28 0.2040 4.48419 25.18
20.1746 267.68 29.12 0.0816 4.39797 12.62
20.5175 353.30 76.88 0.1632 4.32525 16.65
20.9188 457.37 37.32 0.0612 4.24316 21.56
21.1794 1631.13 266.20 0.1224 4.19154 76.88

21.3708 2121.55 346.24 0.1224 4.15443 100.00
22.4058 396.58 53.94 0.1020 3.96481 18.69
23.1381 165.86 13.53 0.0612 3.84096 7.82
23.6547 918.62 149.92 0.1224 3.75822 43.30
24.1035 446.83 97.23 0.1632 3.68926 21.06
24.7976 273.45 37.19 0.1020 3.58754 12.89
25.0843 84.43 11.48 0.1020 3.54719 3.98
25.5078 171.89 14.03 0.0612 3.48925 8.10
25.7875 1169.22 159.01 0.1020 3.45204 55.11
25.8925 1427.27 232.93 0.1224 3.43827 67.27
26.6738 600.34 81.65 0.1020 3.33931 28.30
27.1278 166.52 45.29 0.2040 3.28444 7.85
27.4744 314.31 59.84 0.1428 3.24379 14.82
28.2026 178.87 19.46 0.0816 3.i6167 8.43
29.6159 216.85 35.39 0.1224 3.01393 10.22
29.9046 164.07 31.24 0.1428 2.98548 7.73
30.4505 91.08 19.82 0.1632 2.93320 4.29
30.8146 154.81 16.84 0.0816 2.89936 7.30
31.4158 202.74 22.06 0.0816 2.84523 9.56
32.1764 176.45 38.39 0.1632 2.77969 8.32
32.5009 173.69 56.69 0.2448 2.75268 8.19
34.5573 85.15 9.26 0.0816 2.59343 4.01
34.9126 146.67 47.87 0.2448 2.56785 6.91
35.1345 148.13 24.17 0.1224 2.55214 6.98

35.3738 103.26 11.24 0.0816 2.53542 4.87
36.0193 71.39 23.30 0.2448 2.49145 3.37
36.8483 55.38 24.10 0.3264 2.43728 2.61
37.5990 53.13 7.23 0.1020 2.39032 2.50
39.0546 124.57 16.94 0.1020 2.30452 5.87
A crystalline form II of dronedarone hydrochloride may be characterized by particle size data selected from a group consisting of X50 value of the crystal is from 1 to 200 microns.
The dronedarone base used in the present invention may be formed by methods known in the art such as those described in U.S.Patent nos. 5,223,510; 6,828,448; 6,846,936 and 7,312,345 which are incorporated herein by reference only.
A solution of dronedarone hydrochloride may be formed by reacting dronedarone base with alcoholic hydrochloride in an alcohol solvent at 0°C to 25°C.
The examples of alcohol solvents may include methanol, ethanol, n-propanol, isopropanol. n-butanol, isobutanol, pentanol or mixture(s) thereof.
The example of alcoholic hydrochloride solutions may include methanolic hydrochloride, ethanolic hydrochloride, isopropanolic hydrochloride or n-butanolic hydrochloride.
The alcoholic hydrochloride solution may contain hydrochloric acid in the range of 5% weight / weight to 15% weight / weight.
The crystalline form II of dronedarone hydrochloride may be formed by stirring the solution of dronedarone hydrochloride in an alcohol solvent at a temperature in the range of 0°C to 30°C for a period of 30 minutes to 8 hours.

The crystalline form II of dronedarone hydrochloride may be isolated by the steps of filtration. centrifugation, washing, drying or the combinations thereof.
The isolated crystalline form II of dronedarone hydrochloride may be dried at a temperature in the range of 40°C to 110°C for a period of 2 hours to 8 hours under reduced pressure.
A pharmaceutical composition of dronedarone hydrochloride comprising crystalline form II of dronedarone hydrochloride and pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE DRAWING:
Figure 1 illustrates a powder X-ray diffraction pattern of dronedarone hydrochloride crystalline form II.
XRD diffraction measurement was performed on X-Ray powder diffractometer Bruker D8
Advance powder diffractometer with the detector Lynxeye (Bruker). The analysis conditions
were as follows:
Scan range [°2-theta]: 2-39.98;
Scan mode: continuous;
Step size [°2-theta]: 0.0170°;
Scan step time[s]: 51.04 seconds;
Sample spin: 15 rpm;
Sample holder: glass;
Measurement Temperature [°C]: 25
Anode Material: Cu
K-Alpha[Å]: 1.54060
Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The sample might be mixed with n-dodecane in order to avoid the environment contamination by airborne particles coming from the powder. The ground sample or

its suspension with n-dodecane was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.
EXAMPLE:
In the following example, the preferred embodiments 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 II of dronedarone hydrochloride
A solution of dronedarone (10gm) in isopropanol (110ml) was added isopropanolic hydrochloric acid (9.4ml, 7% weight / weight) and then it was stirred for 1 hour at 20-25°C. The resulting solution was cooled to 10°C and then it was stirred for 2 hours at 10-15°C. The resulting solids were filtered, washed with chilled isopropanol (10ml) and dried at 45-50°C for 4 hours to get title compound. Yield: 10.6gm Purity: 99.9% (By HPLC) XRD: As depicted in Figure 1

WE CLAIM:
1. A compound which is crystalline form II of dronedarone hydrochloride having substantially the same X-ray diffraction pattern as depicted in Figure 1.
2. The compound of claim no. 1 is further characterized by X-ray diffraction pattern comprising peaks at 11.6, 12.7, 13.5, 14.0, 15.4, 15.9, 18.6, 19.7,20.5,20.9,21.1,21.3, 22.4, 23.6, 24.1, 24.7, 25.7, 26.6, 27.4, 29.6 ± 0.2 degrees two theta.
3. The compound of claim no. 1 is further characterized by particle size data selected from a group consisting of X50 value of the crystal is from 1 to 200 microns.
4. A process for preparing crystalline form IT of dronedarone hydrochloride comprising the steps of:
a. providing a solution of dronedarone hydrochloride in an alcohol solvent,
b. stirring the solution obtained in step a for period of 30 minutes to 8 hours at a
temperature in the range of 0°C to 30°C and
c. isolating crystalline form il of dronedarone hydrochloride.
5. The process according to claim no. 4, wherein a solution of dronedarone hydrochloride is formed by reacting dronedarone base with an alcoholic hydrochloride such as methanolic hydrochloride, ethanolic hydrochloride, isopropanolic hydrochloride or n-butanolic hydrochloride in an alcohol solvent such as methanol, ethanol, n-propanol. isopropanol. n-butanol, isobutanol, pentanol or mixture(s) thereof at a temperature in the range of 0°C to 25°C.
6. The process according to claim no. 5, wherein an alcoholic hydrochloride solution contain hydrochloric acid in the range of 5% weight/weight to 15% weight/weight.
7. The process according to claim no. 4, wherein crystalline form II of dronedarone hydrochloride is formed by stirring the solution of dronedarone hydrochloride in an

alcohol solvent at a temperature in the range of 0°C to 30°C for a period of 30 minutes to 8 hours.
8. The process according to claim no. 4, wherein crystalline form IT of dronedarone hydrochloride is isolated by the steps of filtration, centrifugation, washing, drying or the combinations thereof.
9. The process according to claim no. 8, wherein crystalline form 11 of dronedarone hydrochloride is dried at a temperature in the range of 40°C to 110°C for a period of 2 hours to 8 hours under reduced pressure.
10. A pharmaceutical composition of dronedarone hydrochloride comprising crystalline form II of dronedarone hydrochloride and pharmaceutically acceptable excipients.