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
"PROCESS OF PREPARING AGOMELATINE CRYSTALLINE FORM VI"
Enaltec Labs Pvt Ltd. an Indian Company, having its Registered Office at 17,hFloor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi JVIumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

PROCESS OF PREPARING AGOMELATINE CRYSTALLINE FORM VI
FIELD OF THE INVENTION:
The present invention relates to a process of preparing crystalline Form VI of agomelatine. The process comprises crystallizing agomelatine in water or a mixture of water and N, N;-dimethylformamide solvent.
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 al.M, Acta. Cryst, 1994, C50, 90-910 discloses orthorhombic crystalline agomelatine form, which is being characterized by following lattice parameters: a = 31.50lA,b = 9.5280A,c = 17.906A, space group; Pca2,
number of molecules in the unit cell: 16 unit cell volume Vuni 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 meeting 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.
Chinese patent publication no. W178122S 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 N. N'-dimethylformamide and water. The agomelatine crystal is being characterized by X-ray diffraction pattern having peaks at 12.84. 13.84, 16.14, 18.56, 19.12, 20.86, 21.20 and 23.84°20.
Indian Patent application no. 3249/MUM/2010 discloses thermally stable a and p crystalline forms of agomelatine. which are obtained by the crystallization of agomelatine in water.
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. The applicant of this patent has observed that crystalline form VI of agomelatine obtained by crystallization of agomelatine in a mixture of acetic acid and water is thermodynamically unstable due to the presence of traces amount of acetic acid in agomelatine crystalline form VI and being converted into agomelatine crystalline form II.
Accordingly, there is provided a process of preparing thermodynamically stable crystalline form VI of agomelatine.

SUMMARY OF THE INVENTION:
A object of the present invention is to provide a process of preparing thermodynamically stable crystalline form VI of agomelatine comprises crystallizing agomelatine in water or a mixture of water and N, N'-dimethylformamide solvent.
DETAILED DESCRIPTION OF THE INVENTION:
The agomelatine used for preparing crystalline form VI may be present in any other crystalline form such as Form II, III. IV, V, A, B. a and P as described above in the background of the invention.
The crystallization of agomelatine in water may be carried out by first melting agomelatine at a temperature in the range of 80°C to 150°C; pouring the melted agomelatine in water at a temperature in the range of 70°C to iOO°C and then agitating the resulting solution of agomelatine in water for a period of 30 minutes to 3 hours at a temperature in the range of 25°C to 35°C.
The crystallization of agomelatine in water may be carried out by dissolving agomelatine in water at a temperature in the range of 70°C to 100°C followed by the gradual cooling of resulting solution of agomelatine in water.
The graduai cooling of agomelatine solution described herein refers to the decrease of 2°C temperatures in 5 minutes of agomelatine solution in water.
The crystallization of agomelatine in water may also be carried out by dissolving agomelatine in 1 volume/weight to 5 volume/weight of M, N'-dimethylformamide; filtering the resulting solution through hyflow bed; adding 10 volume/weight to 30 volume/weight of water and then agitating the resulting solution of agomelatine in water and N, N'-dimethylformamide for a period of 30 minutes to 3 hours at a temperature in the range of 25°C to 35°C.

The agomelatine crystalline form VI obtained by the crystallization of agomelatine in water or a mixture of water and N. N'-dirnethylformarnide solvent may be characterized by X-ray diffraction pattern as depicted in Figure 1.
The agomelatine crystalline form VI obtained by the crystallization of agomelatine in water or a mixture of water and N. N:-dimethylformamide solvent may be characterized by data selected from the group comprising of X-ray diffraction pattern having following peaks:

Pos. [°2Theta] Area
[cts*°2Th.] d-spacing [A] Rel. Int. [%]
9.6078 16.50 9.19810 1.17
10.4899 26.83 8.42648 1.90
10.7951 50.79 8.18895 3.60
11.1546 140.10 7.92582 9.94
11.8465 724.46 7.46442 34.26
13.3407 31.06 6.63156 1.10
13.7333 28.78 6.44282 1.53
14.4506 22.11 6.12461 1.88
14.8624 92.42 5.95580 5.62
15.2919 68.81 5.78948 4.88
15.7605 14.52 5.61839 2.06
17.4948 642.70 5.06513 39.07
17.7941 110.30 4.98060 6.71
18.3114 496.60 4.84106 23.48
18.5174 107.17 4.78766 11.40
19.4982 1879.83 4.54899 100.00

19.7149 1638.17 4.49948 99.59
20.4329 160.17 4.34296 17.04
20.5297 149.11 4.32271 15.86
20.9418 68.88 4.23857 4.89
21.1764 66.81 4.19212 4.74
21.7604 431.19 4.08093 22.94
22.4114 189.71 3.96382 13.46
23.0107 458.78 3.86194 19.52
23.8230 125.08 3.73206 4.44
24.5636 194.46 3.62119 11.82
24.8704 65.38 3.57720 4.64
25.3955 456.22 3.50442 19.42
26.0318 77.73 3.42018 4.73
26.3143 53.94 3.38410 3.83
26.9823 132.41 3.30183 9.39
27.2374 41.78 3.27148 5.93
27.6086 42.17 3.22833 3.59
28.6157 31.84 3.11696 2.26
28.7927 28.01 3.09820 1.99
30.0653 95.70 2.96989 6.79
31.2420 92.78 2.86067 4.94
31.5168 97.69 2.83634 6.93
31.8894 182.66 2.80405 9.72
32.8811 73.43 2.72171 1.95

33.6661 22.78 2.66002 1.62
34.3966 36.43 2.60518 1.55
35.9060 10.47 2.49905 1.11
37.2627 45.57 2.41112 1.62
37.7704 101.04 2,37987 1.79
38.5013 27.85 2.33635 0.99
The agomelatine crystalline form VI obtained by the crystallization of agomelatine in water or a mixture of water and N, N'-dimethylformamide solvent may be characterized by infrared absorption spectra as depicted in Figure 2.
The agomelatine crystalline form VI obtained by the crystallization of agomelatine in water or a mixture of water and N. N'-dimethylformamide solvent may be characterized by following absorption peaks in infrared spectra: 3257.77 cm'1, 3078.39 cm"1, 2999.31 cm'1, 2968.45 cm"', 2939.52 cm"1, 2870.08 cm"1, 2835.36 cm"1, 2594.26 cm"1, 2426.45 cm"1, 2166.06 cm"1, 2129.41 cm"1, 2050.33 cm"1, 1913.39 cm"1, 1867.09 cm'1, 1809.23 cm"1, 1643.35 cm"1, 1625.99 cm"1. 1598.99 cm"1, 1554.63 cm"1, 1537.27 cm'1, 1512.19 cm'1, 1469.76 cm"1, 1444.68 cm"1, 1433.11 cm"1, 1363.67 cm"1, 1344.38 cm"1, 1298.09 cm"1, 1249.87 cm"1, 1215.15 cm"1, 1184.29 cm1, 1159.22 cm"1, 1134.14 cm"1, 1101.35 cm"1, 1082.07 cm"1, 1062.78 cm"1, 1031.92 cm"1, 966.34 cm"1, 908.47 cm"1, 860.25 cm"1, 846.75 cm"1, 833.25 cm"1, 756.10 cm"1, 732.95 cm"1, 698.23 cm"1, 675.09 cm"1, 644.22 cm"1, 611.43 cm"1, 588.29 cm"1, 551.64 cm"1, 522.71 cm"1, 509.21 cm"1, 474.49 cm"1, 433.98 cm"1.
The agomelatine crystalline form VI obtained by the crystallization of agomelatine in water or a mixture of water and N, N'-dimethylformamide solvent may be characterized by melting point in the range of 105°C to 108°C.

The agomelatine crystalline form VI obtained by the crystallization of agomelatine in water or a mixture of water and N, N'-dimethylformamide solvent may be isolated by the steps of filtration, centrifugation, washing, drying and combination thereof.
The agomelatine crystalline form VI obtained by the crystallization of agomelatine in water or a mixture of water and N, N'-dimethylformamide solvent may be washed with 2 volume/weight to 15 volume/weight of water.
The agomelatine crystalline form VI obtained by the crystallization of agomelatine in water or a mixture of water and N, N'-dimethylformamide solvent may be dried at a temperature in the range of 30°C to 60°C under reduced pressure.
The agomelatine crystalline form VI obtained by the crystallization of agomelatine in water or a mixture of water and N, N'-dimethylformamide solvent may be dried in equipment such as a rotary dryer, tray dryer, vacuum oven, air oven, humidity dryer, fluidized bed dryer, spin flash dryer, flash dryer,, or combinations thereof.
The water content of agomelatine crystalline form VI may be in the range of 0.01% weight/weight to 0.50% weight/weight as determined by Karl Fisher technique.
The chemical purity of agomelatine crystalline form VI may be in the range of 99.50% to 99,99% as determined by HPLC technique.
The agomelatine crystalline form VI obtained by the crystallization of agomelatine in water or a mixture of water and N. N'-dimethylformamide solvent may have less than 0.01% weight / weight of agomelatine crystalline form II.
The agomelatine crystalline form VI obtained by the crystallization of agomelatine in water or a mixture of water and N, N'-dimethylformamide solvent is stable when stored at a temperature in the range of 25°C to 40°C for atleast six months.

The agomelatine crystalline form VI obtained by the crystallization of agomelatine in water or a mixture of water and N. N'-dimethylformamide solvent is stable and not converted into the agomelatine crystalline form II as compared to the agomelatine crystalline form VI obtained from the crystallization of agomelatine in acetic acid and water.
The percentage of agomelatine crystalline form II in agomelatine crystalline form VI obtained by the process comprises crystallization of agomelatine in water or a mixture of water and N. N'-dimethylformamide solvent and by the process comprises crystallization of agomelatine in acetic acid and water after one day, one month and six months when stored at 40°C is as follows:

Product Description % of Agomelatine % of Agomelatine % of Agomelatine % of Agomelatine
Form II (Initially Form II after one Form 11 after one Form II after six
when stored at day (when stored at month (when stored months (when
40°C) 40°C) at 40°C) stored at 40°C)
Agomelatine Nil Nil Nil Nil
crystalline form VI
obtained by the
crystallization of
agomelatine in
water or a mixture
of water and N, N'-
dimethylformamide
solvent
Agomelatine Nil 0.5% weight/weight 5% weight/weight 15% weight/weight
crystalline form VI
obtained from the
crystallization of
agomelatine in
acetic acid and
water

The limit of detection (LOD) of agomelatine crystalline form II in agomelatine crystalline form VI is 0.01 % weight/weight measured by X-ray diffraction method.
The limit of quantitation (LOQ) of agomelatine crystalline form II in agomelatine crystalline form VI is 0.10% weight/weight measured by X-ray diffraction method.
BRIEF DESCRIPTION OF THE DRAWING:
Figure 1 depicts the X-ray diffraction pattern of agomelatine crystalline form VI Figure 2 depicts the IR absorption spectra of agomelatine crystalline form VI
X-Ray Powder Diffraction (XRPD) pattern of agomelatine crystalline form VI are obtained on D 8 -Advance, Bruker AXE, Germany, diffractometer equipped with Scintillation detector using Copper Ka (X,= 1.5406 A) radiation with scanning range between 2.00-39.98°20 at scanning speed of 2<7min.
IR absorption spectra of agomelatine crystalline form VI are obtained by triturating agomelatine (3mg) with dry potassium bromide (lOOmg) and fill this mixture into DRS sample holder to record IR spectrum
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope or spirit of the invention.
EXAMPLES:
EXAMPLE I: PREPARATION OF AGOMELATINE CRYSTALLINE FORM VI
The agomelatine (lOOgm) was melted at I45°C and the resulting melted agomelatine was poured into hot water (1200ml) at 95-100°C in 2 minutes. The resulting agomelatine solution in water was agitated for 15 minutes at 95~100oC and then it was cooled to 25°C in next 45 minutes and

then again it was agitated at 25°C to 30°C for 1 hour. The resulting solids were filtered, washed
with water (200ml) and dried at 46°C under reduced pressure.
Yield: 80gm
Purity: 99.70% (By HPLC method)
Powder X-ray diffraction pattern is substantially in accordance with Figure 1
IR absorption spectra is substantially in accordance with Figure 2
EXAMPLE 2: PREPARATION OF AGOMELATINE CRYSTALLINE FORM VI
The agomelatine (lOOgm) was dissolved in N. N'-dimethyiformamide (200ml) at 25°C and the resulting hazy solution was filtered through hyflow bed. The hyflow bed was washed with N, N'-dimethyJformamide (10ml) and then the resulting solution of agomelatine in K N'-dimethyiformamide was added into water (2.51itres) in 30 minutes. The resulting solution of agomelatine in N, N:-dimethylformamide and water solvents was agitated for 45 minutes at 25-30°C and then the resulting solids were filtered, washed with 1 litre water and dried at 30°C for 48 hours. Yield: 92gm
Purity: 99.98% (By HPLC)
Powder X-ray diffraction pattern is substantially in accordance with Figure 1 IR absorption spectra is substantially in accordance with Figure 2

WE CLAIM:
1. A process of preparing crystalline Form VI of agomelatine comprises crystallizing agomelatine in water or a mixture of water and N, N'-dimethylforrnamide solvent.
2. The process according to claim no. 1 wherein the crystallization of agomelatine in water is carried out by first melting agomelatine at a temperature in the range of 80°C to 150°C; pouring the melted agomelatine in water at a temperature in the range of 70°C to 100°C and then agitating the resulting solution of agomelatine in water for a period of 30 minutes to 3 hours at a temperature in the range of25°C to 35°C.
3. The process according to claim no.I wherein crystallization of agomelatine in water is carried out by dissolving agomelatine in water at a temperature in the range of 70°C to ]00°C followed by the gradual cooling (decrease of 2°C temperatures in 5 minutes of agomelatine solution in water) of resulting solution of agomelatine in water.
4. The process according to claim no. 1 wherein crystallization of agomelatine in water is carried out by dissolving agomelatine in 1 volume/weight to 5 volume/weight of N, N:-dimethylformamide; filtering the resulting solution through hyflow bed; adding 10 volume/weight to 30 volume/weight of water and then agitating the resulting solution of agomelatine in water and M, N'-dimethylformamide for a period of 30 minutes to 3 hours at a temperature in the range of 25°C to 35°C.
5. The process according to claim no. I wherein crystalline Form VI of agomelatine obtained by the crystallization of agomelatine in water or a mixture of water and N, N'-dimethylformamide solvent is characterized by X-ray diffraction pattern as depicted in Figure 1 and infrared absorption spectra as depicted in Figure 2.
6. The process according to claim no. 1 wherein crystalline Form VI of agomelatine obtained by the crystallization of agomelatine in water or a mixture of water and N, N'-dimethylformamide solvent is characterized by melting point in the range of 105°C to 108°C.
7. The process according to claim no. 1 wherein agomelatine crystalline form VI obtained by the crystallization of agomelatine in water or a mixture of water and N. N'-dimethylformamide solvent is isolated by the steps of filtration, centrifugation, washing. drying and combination thereof.

8. The process according to claim no.l wherein agomelatine crystalline form VI obtained by the crystallization of agomelatine in water or a mixture of water and N, N'-dimethylformamide solvent is washed with 2 volume/weight to 15 volume/weight of water.
9. The process according to claim no. 1 wherein agomelatine crystalline form VI obtained by the crystallization of agomelatine in water or a mixture of water and N. N:-dimethylformamide solvent is dried at a temperature in the range of 30°C to 60°C under reduced pressure.
10. The process according to claim no. I wherein agomelatine crystalline form V[ obtained by the crystallization of agomelatine in water or a mixture of water and 1M, N:-dimethylformamide solvent is stable when stored at a temperature in the range of 25°C to 40°C for atleast six months and not converted into agomelatine crystalline form ]].