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
"AN AMORPHOUS AGOMELATINE AND PROCESSES FOR PREPARING SAME."
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17thFloor, 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.

AN AMORPHOUS AGOMELATINE AND PROCESSES FOR PREPARING SAME
FIELD OF THE INVENTION:
The present invention relates to an amorphous form of agomelatine. The present invention further relate to a processes of preparing amorphous form of agomelatine and pharmaceutical composition thereof.
BACKGROUND OF THE INVENTION:
Chemically agomelatine is N-[2-(7-methoxy-l-naphthalenyl) ethyl] acetamide and is known from U.S. Patent No. 5,225,442 and is represented by compound of structural formula I.

The trade names of agomelatine are Valdoxan, Melitor, and Thymanax. Agomelatine is an antidepressant developed by the pharmaceutical company Servier.
U.S. patent No. 5,225,442 describes the crystallization of agomelatine in isopropyl ether solvent and resulting agomelatine has a melting point in the range of 109-110°C.
Tinant et ah, Acta. Cryst, 1994, C50, 90-910 discloses orthorhombic crystalline agomelatine
form, which is being characterized by following lattice parameters:
a = 31.501A, b = 9.5280A, c = 17.906A,
space group: Pca2,
number of molecules in the unit cell: 16
unit cell volume Vunit cell= 5374.3 A3

density: d = 1.20gm/cm3
U.S. patent No. 7,250,531 discloses agomelatine crystalline form II, which is being prepared by recrystallization of agomelatine in a mixture of ethanol and water [35: 65]. The agomelatine crystalline form II is monoclinic and having a melting point at 108°C.
U.S. patent No. 7,635,721 discloses crystalline form III of agomelatine, which is being prepared by heating agomelatine at 110°C until fully melted and then slowly cooled until recrystallization occurs.
U.S. patent No. 7,645,905 discloses crystalline form IV of agomelatine, which is being prepared by heating agomelatine at 110°C until the melting be completed, and is then rapidly cooled between 50°C and 70°C, and maintained for 5 hours at 70°C until crystallization.
U.S. patent No. 7,358,395 discloses crystalline form V of agomelatine, which is being prepared by subjecting agomelatine to high energy mechanical grinding for 6 hours. The agomelatine crystalline form V is also being prepared by heating agomelatine until completely melted and then immediately placed melted agomelatine at room temperature and simultaneously a small quantity of crystalline form V of agomelatine is added, and then the mixture is cooled until crystallization is complete to obtain agomelatine crystalline form V.
U.S. patent publication no. 2009/0069434 discloses crystalline form VI of agomelatine, which is being prepared by heating the solution of agomelatine in isopropyl ether at boiling temperature for 2 hours and then the resulting solution is cooled to 0°C and then resulting solids are filtered, dried under reduced pressure to get agomelatine crystalline form VI. The agomelatine crystalline form VI is also being prepared by recrystallization of agomelatine in a mixture of water and ethanol (50:50) at an ambient temperature under high pressure for 24 hours.
U.S. patent publication no. 2010/0036165 describes process of preparing crystalline form V by spray drying technique.

P.C.T publication no. 2010/102554 discloses crystalline form VI of agomelatine which is characterized by XRD pattern having peaks at 11.13, 11.82, 17.49, 18.29, 19.48, 19.72, 20.50, 21.76, 22.54, 22.97, 24.56, 25.36, 27.16 and 31.96 degree two-theta. The crystalline form VI of agomelatine is being prepared by dissolving agomelatine in acetic acid followed by the precipitation by the addition of water at a temperature in the range 0 to 25°C.
Chinese patent publication no. 101781225 discloses agomelatine crystalline form A; Chinese patent publication no. 101723844 discloses agomelatine crystalline form B and Chinese patent publication no. 101704763 discloses agomelatine type I crystal. The applicant of this patent has observed that agomelatine crystalline form A; agomelatine crystalline form B and agomelatine type I crystal are matching with the crystalline form VI of agomelatine disclosed in P.C.T publication no. 2010/102554.
Chinese patent publication no. 101774937 discloses novel crystal form of agomelatine, which is being formed by the crystallization of agomelatine from a mixture of isopropanol and n-hexane solvents.
Chinese patent publication no. 101781226 discloses agomelatine crystal, which is being formed by the crystallization of agomelatine from a mixture of dimethylforrnamide and water.
"Amorphous" refers to any solid substances which (i) lacks order in three dimensions, or (ii) exhibits order in less than three dimensions, order only over short distances (e.g., less than 10 A), or both. Thus, amorphous substances include partially crystalline materials and crystalline mesophases with, e.g. one- or two-dimensional translational order (liquid crystals), orientational disorder (orientationally disordered crystals), or conformational disorder (conformationally disordered crystals). Amorphous solids may be characterized by known techniques, including X-ray powder diffraction (XRPD) crystallography, solid state nuclear magnet resonance (ssNMR) spectroscopy, differential scanning calorimetry (DSC), or some combination of these techniques. As illustrated, below, amorphous solids give diffuse XRPD patterns, typically comprised of one or two broad peaks (i.e., peaks having base widths of about 5° 2θ or greater).

SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide an amorphous form of agomelatine.
A second aspect of the present invention is to provide a process for the preparation of agomelatine amorphous form comprising the steps of:
a. providing a solution of crystalline agomelatine in an organic solvent and
b. recovering agomelatine in the amorphous form from the solution thereof by the removal
of the solvent by spray-drying or freeze-drying technique.
Another aspect of the present invention is to provide substantially pure agomelatine amorphous form.
Another aspect of the present invention is to provide substantially pure agomelatine amorphous form obtained by spray-drying or freeze-drying of a solution of crystalline agomelatine in an organic solvent.
Another aspect of the present invention is to provide a process for the preparation of substantially pure agomelatine amorphous form comprising the steps of:
a. melting crystalline agomelatine and
b. recovering substantially pure agomelatine in the amorphous form.
Another aspect of the present invention is to provide a pharmaceutical composition comprising substantially pure amorphous form of agomelatine.
DETAIL DESCRIPTION OF THE INVENTION:
An amorphous form of agomelatine may be characterized by X-ray diffraction pattern as depicted in Figure 1.

The crystalline agomelatine used for the present invention may be prepared by methods known in the art such as those described in the background of the invention which are incorporated herein by reference only.
A solution of crystalline agomelatine in organic solvents may be prepared by dissolving crystalline agomelatine in an organic solvent at a temperature in the range of 20°C to 40°C.
Alternatively, such a solution may be obtained directly from a reaction in which agomelatine is formed.
Examples of organic solvent may include ketones, alcohols, esters, nitriles, halogenated aliphatic hydrocarbon solvents, ethers or mixtures thereof.
The ketone solvents may be selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof.
The alcohol solvents may be selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof.
The ester solvents may be selected from the group comprising of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof
The nitrile solvents may be selected from the group comprising of acetonitrile, propionitrile or mixture(s) thereof.
The halogenated aliphatic hydrocarbon solvents may be selected from the group comprising of dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof.

The ether solvents may be selected from the group comprising of tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s) thereof.
The solvent may be removed from the solution by a technique which includes, for example, spray drying and freeze drying.
In one aspect, agomelatine amorphous form may be recovered from the solution using a spray drying technique. A Mini-Spray Dryer (Model: Buchi 190, Switzerland) can be used. The Buchi 190 Mini-Spray Dryer operates on the principle of nozzle spraying in a parallel flow, i.e., the sprayed product and the drying gas flow in the same direction. The drying gas can be air or inert, gases such as nitrogen, argon and carbon dioxide,
In another aspect, agomelatine amorphous form may be recovered from the solution using a freeze drying technique. A freeze dryer (Model; Virtis Genesis SQ Freeze Dryer) can be used in this technique. The Virtis Genesis SQ Freeze Dryer operates on the principle of lyophilization, i.e., a process of stabilizing initially wet materials (aqueous solution or suspensions) by freezing them, then subliming the ice while simultaneously desorbing some of the bound moisture (primary drying). Following removal of the ice, desorption may be continued (secondary drying). This process may be carried out under vacuum.
The spray drying may be accomplished using a spray dryer which operates on the principle of nozzle spraying in a parallel flow, i.e., the sprayed product and the drying gas flow in the same direction. The drying gas can be air or one or more inert gases such as nitrogen, argon, and carbon dioxide. Moreover, the product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Dryer
The crystalline agomelatine may be melted at a temperature in the range of 105°C to 115°C.

The agomelatine amorphous form may be recovered by the steps of cooling and milling of melted agomelatine. The milling of melted agomelatine may be carried out in a clay mortar and pestle.
The cooling of melted agomelatine may be carried out up to the temperature in the range of 20-30°C.
The agomelatine amorphous form obtained by the present invention may be additionally dried at a temperature in the range of 40°C to 60°C for 40 minutes to 6 hours.
The term "substantially pure agomelatine amorphous form" described herein referred to agomelatine amorphous form having more than 99% purity as determined by HPLC technique.
The pharmaceutical composition comprising substantially pure amorphous form of agomelatine and one or more pharmaceutically acceptable carriers, excipients or diluents.
BRIEF DESCRIPTION OF THE DRAWING:
Figure 1 depicts X-ray diffraction pattern of amorphous form of agomelatine
X-Ray Powder Diffraction (XRPD) pattern of the product of Examples 1 to 2 was obtained on D 8 -Advance, Bruker AXE, Germany, diffractometer equipped with Scintillation detector using Copper Ka (λ= 1.5406 A) radiation with scanning range between 2.00-39.98°2θ at scanning speed of 2o/min.

EXAMLES:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the processes of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of substantially pure amorphous form of agomelatine.
Crystalline agomelatine (10 gm) was placed in to an oven at 110°C for 40 minutes. The melted
agomelatine was cooled to 25°C and then it was milled in a clay mortar and pestle to get title
compound.
Yield: 9.8 gm
Purity: 99.94% (By HPLC)
Example 2: Preparation of substantially pure amorphous form of agomelatine.
Crystalline agomelatine (10 gm) was dissolved in methanol (60 ml) at 25-30°C. The clear
solution was subjected to spray drying in a mini spray dryer at an inlet temperature of 60°C and
an outlet temperature of 40°C with a feed rate of 15 ml/minute, agomelatine in an amorphous
form was thus isolated.
Yield: 9.5 gm
Purity: 99.98% (By HPLC)

WE CLAIM:
1. An amorphous form of agomelatine is characterized by X-ray diffraction pattern as depicted in Figure 1.
2. A process for the preparation of agomelatine amorphous form comprising the steps of:
a. providing a solution of crystalline agomelatine in an organic solvent and
b. recovering agomelatine in the amorphous form from the solution thereof by the
removal of the solvent by spray-drying or freeze-drying technique.
3. The process according to claim no. 2 wherein, a solution of crystalline agomelatine in organic solvents is prepared by dissolving crystalline agomelatine in an organic solvent at a temperature in the range of 20°C to 40°C.
4. The process according to claim nos. 2 and 3 wherein, examples of organic solvent is selected from the group comprising of ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof; alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof; ester solvents such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof; nitrile solvents such as acetonitrile, propionitrile or mixture(s) thereof; halogenated aliphatic hydrocarbon solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof; ether solvents such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s) thereof.
5. The process according to claim no.2 wherein, amorphous agomelatine is recovered from the solution by spray drying or by freeze drying.

6. A substantially pure agomelatine amorphous form obtained by spray-drying or freeze-drying of a solution of crystalline agomelatine in an organic solvent.
7. A process for the preparation of substantially pure agomelatine amorphous form comprising the steps of:
a. melting crystalline agomelatine and
b. recovering substantially pure agomelatine in the amorphous form.
8. The process according to claim no. 7 wherein, crystalline agomelatine is melted at a temperature in the range of 105°C to 115°C.
9. The process according to claim no. 7 wherein, agomelatine amorphous form is recovered by the steps of cooling and milling of melted agomelatine.
10. A pharmaceutical composition comprising substantially pure amorphous form of agomelatine and one or more pharmaceutically acceptable carriers, excipients or diluents.