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 FORMS OF AGOMELATINE"
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.

NOVEL POLYMORPHIC FORMS OF AGOMELATINE
FIELD OF THE INVENTION;
The present invention relates to novel polymorphs of agomelatine referred herein after as a and β crystalline form. The present invention further relate to a process of preparing a and β crystalline 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.

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 al, Acta. Cryst, 1994, C50, 90-910 discloses orthorhombic crystalline agomelatine
form, which is being characterized by following lattice parameters:
a = 31.501 A, 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.
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 dimethylformamide and water.
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.
Moreover, the all prior-art reported crystalline forms of agomelatine are formed by heating / melting the agomelatine or by the crystallization of agomelatine in organic solvents such as diisopropyl ether and, isopropanol/ n-hexane or by a crystallization of agomelatine in a mixture of water and organic solvents such as dimethylformamide and ethanol.
The applicant of this patent has observed that all reported prior-art polymorphic forms of agomelatine are unstable under drying at a temperature more than 40°C under reduced pressure and also the heating / melting of agomelatine resulted into the degradation of agomelatine and crystallization of agomelatine in organic solvent resulted residual solvents (dimethylformamide, ethanol, isopropanol, n-hexane and acetic acid) in final agomelatine active pharmaceutical ingredient and therefore there is a need in the art to develop a thermally stable polymorphic form of agomelatine without heating / drying of agomelatine; crystallization of agomelatine in organic solvent or a crystallization of agomelatine in a mixture of organic solvent and water.

Accordingly the present invention provides a and β crystalline forms of agomelatine, which are thermally stable and are obtained by the crystallization of agomelatine in water.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide novel polymorphs of agomelatine referred herein after as a and p crystalline forms of agomelatine.
A second aspect of the present invention is provides a processes of preparing α and β crystalline forms of agomelatine.
A third aspect of the present invention is to provide a pharmaceutical composition comprising α and β crystalline forms of agomelatine.
A fourth aspect of the present invention is to provide a process of preparing a crystalline form of agomelatine comprising the steps of:
a. dissolving agomelatine in 2 volume/weight of water at 98-100°C,
b. gradually cooling the reaction mixture up to 25°C and
c. isolating a crystalline form of agomelatine.
A fifth aspect of the present invention is to provide a process of preparing p crystalline form of agomelatine comprising the steps of:
a. dissolving agomelatine in 10 volume/weight of water at 100-103°C,
b. gradually cooling the reaction mixture up to 25°C and
c. isolating p crystalline form of agomelatine.
DETAIL DESCRIPTION OF THE INVENTION:
A a crystalline form of agomelatine may be characterized by X-ray diffraction pattern having peaks at 16.85, 18.30, 18.70, 19.63, 19.73, 20.12, 20.91, 21.80, 23.75, 23.87, 24.94, 25.59 and 33.68 ± 0.1 degrees two theta.

A a crystalline form of agomelatine may be characterized by X-ray diffraction pattern as depicted in Figure 1.
A a crystalline form of agomelatine may be characterized by X-ray diffraction pattern having following peaks:

Pos. [°2Th.] Height [cts] Area [cts*°2Th.] FWHM [°2Th.] d-spacing [A] Rel. Int. [%]
12.3897 56.64 24.65 0.3264 7.13835 3.08
13.0201 41.72 11.35 0.2040 6.79413 2.27
1S.0425 148.52 48.48 0.2448 5.88492 8.09
15.5363 96.72 26.31 0.2040 5.69896 5.27
16.5007 119.05 19.43 0.1224 5.36797 6.48
16.8598 706.31 134.48 0.1428 5.25444 38.47
17.6711 68.63 14.93 0.1632 5.01501 3.74
18.3007 1782.43 387.86 0.1632 4.84385 97.08
18.7087 986.46 214.65 0.1632 4.73913 53.73
19.6375 1048.43 114.07 0.0816 4.51703 57.10
19.7313 1389.96 151.23 0.0816 4.49578 75.70
20.1220 594.36 113.17 0.1428 4.40936 32.37
20.9126 466.68 63.47 0.1020 4.24441 25.42
21.8005 1836.03 449.46 0.1836 4.07351 100.00
23.1596 254.96 69.35 0.2040 3.83743 13.89
23.7584 940.74 127.94 0.1020 3.74206 51.24
23.8788 903.84 98.34 0.0816 3.72346 49.23
24.9435 534.47 43.61 0.0612 3.56689 29.11

25.5995 717.46 312.24 0.3264 3.47695 39.08
26.6841 244.31 93.03 0.2856 3.33804 13.31
27.6958 107.40 29.21 0.2040 3.21836 5.85
28.0617 228.25 62.09 0.2040 3.17722 12.43
28.7545 109.65 35.79 0.2448 3.10222 5.97
29.2906 166.74 63.50 0.2856 3.04666 9.08
29.9438 300.99 98.24 0.2448 2.98166 16.39
30.3738 286.26 93.44 0.2448 2.94042 15.59
31.8123 121.25 79.15 0.4896 2.81067 6.60
33.6898 526.95 100.33 0.1428 2.65820 28.70
34.9777 147.11 64.02 0.3264 2.56322 8.01
35.7208 163.50 53.37 0.2448 2.51158 8.91
36.2426 125.88 41.09 0.2448 2.47661 6.86
37.5466 46.27 25.17 0.4080 2.39354 2.52
38.2232 157.51 25.71 0.1224 2.35271 8.58
39.2769 121.76 66.24 0.4080 2.29199 6.63
A a crystalline form of agomelatine may be characterized by infra-red spectrum as depicted in Figure 3.
A p crystalline form of agomelatine may be characterized by infra-red spectrum as depicted in Figure 4.
A β crystalline form of agomelatine may be characterized by X-ray diffraction pattern having peaks at 10.55, 17.85, 19.37, 20.07, 23.39, 24.96 and 26.11 ± 0.1 degrees two theta.

A β crystalline form of agomelatine may be characterized by X-ray diffraction pattern as depicted in Figure 2.
A β crystalline form of agomelatine may be characterized by X-ray diffraction pattern having following peaks:

Pos. [°2Th.] Height [cts] Area [cts*°2Th.] FWHM [°2Th.] d-spacing [A] Rel. Int. [%]
10.5569 3488.31 948.82 0.2040 8.37314 16.72
10.9934 158.11 43.01 0.2040 8.04166 0.76
13.3699 965.69 183.87 0.1428 6.61712 4.63
13.9968 374.76 183.48 0.3672 6.32215 1.80
16.1664 1986.26 432.21 0.1632 5.47821 9.52
17.3137 1111.42 272.08 0.1836 5.11771 5.33
17.8503 20861.99 6809.35 0.2448 4.96506 100.00
18.6897 385.63 83.91 0.1632 4.74391 1.85
19.3723 2198.79 837.30 0.2856 4.57827 10.54
20.0753 2300.25 563.10 0.1836 4.41951 11.03
21.1672 596.54 81.13 0.1020 4.19392 2.86
23.3961 4702.23 1662.71 0.2652 3.79919 22.54
23.7712 678.31 55.35 0.0612 3.74007 3.25
24.9698 4710.89 1665.77 0.2652 3.56319 22.58
25.9851 1710.63 : 186.12 0.0816 3.42623 8.20
26.1119 2375.65 452.32 0.1428 3.40988 11.39
26.4561 456.13 99.25 0.1632 3.36629 2.19
28.3608 522.94 56.90 0.0816 3.14439 2.51

29.6313 1124.08 275.17 0.1836 3.01239 5.39
30.2386 649.97 70.72 0.0816 2.95326 3.12
30.5235 914.11 124.32 0.1020 2.92634 4.38
31.7850 181.83 24.73 0.1020 2.81302 0.87
32.9350 513.23 69.80 0.1020 2.71738 2.46
34.3204 529.21 86.37 0.1224 2.61079 2.54
34.4937 497.57 81.20 0.1224 2.59807 2.39
36.1938 237.65 19.39 0.0612 . 2.47983 1.14
39.5945 350.57 38.14 0.0816 2.27433 1.68
Agomelatine used for the present invention may be formed by methods disclosed in the art such as those described in U.S. Patent nos. 5,225,442; 7,250,531; 7,635,721; 7,645,905 or 7,358,395 which are incorporated herein by reference only.
The a crystalline form of agomelatine may be formed by dissolving agomelatine in 2 volume / weight of water at 98-100°C and then resulting solution may be cooled gradually up to 25°C and then resulting solids may be filtered, washed with water and dried at 45°C for 1 hour under reduced pressure.
The solution of agomelatine in water may be cooled in 30 minutes to 60 minutes.
The β crystalline form of agomelatine may be formed by dissolving agomelatine in 10 volume / weight of water at 100-103oC and then resulting solution may be cooled gradually up to 25°C and then resulting solids may be filtered, washed with water and dried at 50-55°C for 1 hour under reduced pressure.
A pharmaceutical composition of agomelatine comprising a crystalline form of agomelatine and pharmaceutically acceptable excipients

A pharmaceutical composition of agomelatine comprising p crystalline form of agomelatine and pharmaceutically acceptable excipients
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1 depicts X-ray diffraction pattern of a crystalline form of agomelatine Figure 2 depicts X-ray diffraction pattern of (3 crystalline form of agomelatine Figure 3 depicts infra-red spectra of a crystalline form of agomelatine Figure 4 depicts infra-red spectra of p crystalline form of agomelatine
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 [A]: 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.

EXAMLES:
In the following examples, 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 a crystalline form of agomelatine
Agomelatine (2gm) was dissolved in water (4ml) at 98-100°C and resulting transparent solution
was stirred 10 minutes at 98-100°C and then it was cooled to 25°C in 60 minutes. The resulting
solids were filtered, washed with water (2ml) and dried at 45°C under reduced pressure.
Yield: l.8gm
XRD: As depicted in Figure 1
IR: As depicted in Figure 3
Purity: 99.86% (By HPLC)
Melting Point: 106.1°C to 107.1°C
Example 2: Preparation of p crystalline form of agomelatine
Agomelatine (10gm) was dissolved in water (100ml) at 100-103°C and resulting transparent
solution was stirred 15 minutes at 100-103°C and then it was cooled to 25°C in 120 minutes. The
resulting solids were filtered, washed with water (20ml) and dried at 50-55°C under reduced
pressure.
Yield: 9.8gm
XRD: As depicted in Figure 2
IR: As depicted in Figure 4
Purity: 99.94% (By HPLC)
Melting Point: 105°Cto 107°C
Example 3: Preparation of p crystalline form of agomelatine
Agomelatine (50gm) was dissolved in water (100ml) at 100-103°C and resulting transparent solution was stirred 15 minutes at 100-103°C and then it was cooled to 25°C in 120 minutes. The resulting suspension was added water (400ml) and it was further heated to 100°C. The resulting

solution was refluxed 20minutes at 100°C and then it was cooled to 25°C. The resulting solids
were filtered, washed with water (100ml) and dried at 50-55°C under reduced pressure.
Yield: 45gm
XRD: As depicted in Figure 2
IR: As depicted in Figure 4
Purity: 99.9%% (By HPLC)
Melting Point: 105°C to 107°C

WE CLAIM:
1. A compound which is a a crystalline form of agomelatine having substantially the same X-ray diffraction pattern as shown in Figure. 1,
2. The compound of claim 1, having X-ray diffraction pattern comprising the peaks at 16.85, 18.30, 18.70, 19.63, 19.73, 20.12, 20.91, 21.80, 23.75, 23.87, 24.94, 25.59 and 33.68 ± 0.1 degrees two theta.
3. The compound of claim 1, having substantially the same infrared spectrum as shown in Figure. 3.
4. A process of preparing a crystalline form of agomelatine comprising the steps of:
a. dissolving agomelatine in 2 volume / weight of water at 98-100°C,
b. resulting solution is cooled gradually up to 25°C and
c. resulting solids is filtered, washed with water and dried at 45°C for 1 hour under
reduced pressure.
5. A compound which is a p crystalline form of agomelatine having substantially the same X-ray diffraction pattern as shown in Figure. 3.
6. The compound of claim 5, having X-ray diffraction pattern comprising the peaks at 10.55, 17.85, 19.37, 20.07, 23.39, 24.96 and 26.11 ±0,1 degrees two theta.
7. The compound of claim 5, having substantially the same infrared spectrum as shown in Figure. 4.
8. A process of preparing p crystalline form of agomelatine comprising the steps of:
a. dissolving agomelatine in 10 volume / weight of water at 100-103°C,
b. resulting solution is cooled gradually up to 25°C,
c. resulting solids is filtered, washed with water and dried at 50-5 5 °C for 1 hour under
reduced pressure.

9. A pharmaceutical composition of agomelatine comprising a crystalline form of agomelatine and pharmaceutically acceptable excipients.
10. A pharmaceutical composition of agomelatine comprising p crystalline form of agomelatine and pharmaceutically acceptable excipients.