FIELD OF THE INVENTION;

The present invention relates to a novel polymorph of Agomelatine and a process for the preparation thereof

BACKGROUND OF THE INVENTION:

Agomelatine is chemically known as N-[2-(7-methoxynaphthalen-l-yl)ethyl] acetamide, which is represented by a structural formula I

Agomelatine is an antidepressant developed by the pharmaceutical company Servier, marketed under the tradename, Valdoxan, Melitor, Thymanax. Agomelatine has dual effects by acting as an agonist of melatoninergic system receptors and as an antagonist of the 5-HT2c receptor. Its properties allow it to be active in the central nervous system, especially in the treatment of major depression, seasonal affective disorder, sleep disorder, cardiovascular diseases, insomnia and fatigue caused by jet lag, appetite disturbance, diseases of the digestive system and obesity. Agomelatine is the first melatoninergic antidepressant, and is effective for the treatment of depression, the improvement of sleep parameters and the maintenance of sexual function.

Agomelatine is first disclosed in US patent specification US 5,225,442 assigned to Adir et Compagnie and its preparation was also disclosed. Its use in therapeutics have been described in and EP 1 564 202.

Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scarming calorimetry (DSC) and Infrared spectrometry (IR).

Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other.

The prior art EP 0 447 285 Bl and Yous et al. (Journal of Medicinal Chemistry, 1992, 35 (8), 1484-1486) allows Agomelatine to be obtained in a particular crystalline form which has been described in Tinant et al. (Acta Cryst., 1994, C50, 907 910).

Bernard Tinant and Jean-Paul Declercq in Acta Cryst. (1994), C50, 907-910 disclose a full crystallographic investigation of the Agomelatine produced by Yous et al. The polymorph form of the product obtained by Yous et al. and analyzed by Tinant and Declercq is designated as the polymorph Form I of Agomelatine. Tinant and Declercq provide the full crystal data of this polymorph form, and regarding the identification of the polymorph Form I of Agomelatine, it is explicitly referred to Bernard Tinant and Jean-Paul Declercq in Acta Cryst. (1994), C50, 907-910. The most important crystal data is as follows: Mr = 243.30 Orthorhombic Pca2i a = 31 .501 (4) A b = 9.5280 (10) A c= 17.906 (2) A.

US patents US 7,498,465 B2, US 7,635,721 B2, US 7,645,905 B2, and US 7,358,395 82 have respectively disclosed the crystalline forms II, III, IV, V of Agomelatine and the preparations thereof US 20120004313 Al, have disclosed the crystalline form VI and WO 2011/050742 Al discloses the crystalline forms A, B and C.

Among these, crystalline Form II is prepared by recrystallization from ethanol and water; crystalline Form III is prepared by heating Agomelatine at llO'^C until complete melting occurs and then slowly cooling down until formation of the crystal; crystalline Form IV is prepared by heating Agomelatine at 110°C until complete melting occurs, followed by rapidly cooling dovm to 50-70°C and maintaining at 70°C for about 5 h until formation of the crystal occurs; crystalline Form V is prepared by so-called "high-energy" mechanical grinding of Agomelatine; crystalline Form VI is prepared by dissolving the Agomelatine in acetic acid and then adding into 0-25°C water to precipitate the crystal.

In view of the pharmaceutical value of Agomelatine, it is critical to obtain the said compound in a highly pure, and stable crystalline form as well as with good reproducibility so that it will be advantageous in pharmaceutical formulations and stable enough for long-term storage without specific requirements regarding temperature, light, humidity or oxygen levels.

OBJECTIVE OF THE INVENTION;

The main object of the present invention is to provide a novel polymorphic form of Agomelatine and a process for the preparation thereof, which is simple to implement and easily reproducible.

According to another object of the present invention is to provide pharmaceutical compositions comprising the novel crystalline form of Agomelatine.

SUMMARY OF THE INVENTION:

The main aspect of the present invention is to provide a novel polymorphic crystalline form of Agomelatine, herein now designated as Form R of Agomelatine.

The other aspect of the present invention is to provide a process for the preparation of Form R of Agomelatine.

According to another aspect of the present invention is to provide pharmaceutical compositions comprising Form R of Agomelatine.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is X-ray powder diffraction spectrum of Agomelatine crystalline form R.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to a novel crystalline form of Agomelatine designated as Agomelatine Form R characterized by peaks in the powder x-ray diffraction spectrum having 29 angle positions at about 11.8, 17.2, 17.5, 18.6, 19.7, 20.5, 21.9, 25.4 ± 0.2 degrees.

The powdered X-ray diffractogram (PXRD) of Agomelatine Form R is shown in figure 1. Agomelatine Form R may be identified and differentiated from the known polymorphs by its characteristic PXRD pattern.

The XRPD pattern of form R of Agomelatine with characteristic PXRD angles and relative intensities is shown in table 1:

Table 1: X-Ray Powder Diffraction (XRPD) pattern of form R of Agomelatine.

According to another aspect of the present invention, the process for the preparation of Agomelatine Form R, comprising the steps of: a) dissolving Agomelatine in a solvent; b) heating the solution obtained in step (a) to reflux and c) cooling the solution to 0-5°C to obtain crystalline form R of Agomelatine.

According to another embodiment of the present invention solvent is selected from the group comprising of water, methanol, ethanol, isopropyl alcohol, acetone or mixtures thereof.

The other embodiment of the present invention is to provide pharmaceutical compositions comprising Form R of Agomelatine.

The term "Pharmaceutical composition" refers to Agomelatine together with one or more appropriate inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention there may be mentioned, more especially, those which are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragees, granules, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions and disintegrable pastes.

The term "Agomelatine" used herein is any Agomelatine moiety containing substance that exhibits pharmaceutical activity and specifically includes Agomelatine free base or its pharmaceutically acceptable salts thereof or the pharmaceutically acceptable acid addition salts thereof and mixtures or combinations thereof.

Pharmaceutically acceptable salts of Agomelatine include salts prepared from pharmaceutically acceptable inorganic bases and organic bases, or acids including inorganic and organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts, and the like. Salts derived from organic bases include salts of primary, secondary, and tertiary amines, and substituted amines including naturally occurring substituted amines.

Salts derived from inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and the like, and with organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like. These lists are not all-inclusive, merely giving a few examples.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

The present invention can be illustrated in one of its embodiment by the following non- limiting examples.

EXAMPLES

EXAMPLE-1;

lOg of Agomelatine is added in 70 ml of IPA-water mixture (ratio 30: 70). And the solution was heated to reflux, to the solution 10 ml of IPA was added to get clear solution. The solution was filtered at hot condition. The filtrate was cooled to room temperature and further cooled to 0-5°C and was stirred for 1-2 hrs at O-S^C. Crystalline form of Agomelatine was filtered and washed with 20 ml of water. The product was dried at 50°C. Yield 9.5g.

EXAMPLE-2:

lOg of Agomelatine is added in 80 ml of IPA-water mixture (ratio 38:62). And the solution was heated to reflux and the solution was filtered. The filtrate was cooled to room temperature and further cooled to 0-5°C and was stirred for 1-2 hrs at 0-5°C Crystalline form of Agomelatine was filtered and washed with 20 ml of water. The product was dried at SO^C. Yield 9.5g.

EXAMPLE-3:

lOg of Agomelatine is added in 80 ml of acetone-water mixture (ratio 35:65). And the solution was heated to reflux and the solution was filtered. The filtrate was cooled to room temperature and further cooled to 0-5°C and was stirred for 1-2 hrs at 0-5°C Crystalline form of Agomelatine was filtered and washed with 20 ml of water. The product was dried at 50°C. Yield 9.2g.

EXAMPLE-4;

lOg of Agomelatine is added in 80 ml of ethanol-water mixture (ratio 40:60). And the solution was heated to reflux and the solution was filtered. The filtrate was cooled to room temperature and further cooled to 0-5°C and was stirred for 1-2 hrs at 0-5°C Crystalline form of Agomelatine was filtered and washed with 20 ml of water. The product was dried at 50°C. Yield 9.4 g.

We Claim:

1) The crystalline form R of Agomelatine, characterized by X-ray powder diffraction spectrum as depicted in figure I.

2) Agomelatine Form R characterized by peaks in the powder x-ray diffraction spectrum having 29 angle positions at 11.8, 17.2, 17.5, 18.6, 19.7, 20.5, 21.9, 25.4 ± 0.2 degrees.

3) The process for the preparation of Agomelatine Form R, comprising the steps of: a) dissolving Agomelatine in a solvent or a mixture thereof; b) heating the solution obtained in step (a) to reflux and c) cooling the solution to 0-5°C to obtain crystalline form R of Agomelatine.

4) The aqueous organic solvent according to claim 1, is selected from the group comprising of water, methanol, ethanol, isopropyl alcohol, acetone, mixtures thereof

5) A pharmaceutical composition comprising effective amount of crystalline form R of Agomelatine of claim 1, in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers.