DESC:Field of the invention

The present invention relates to an improved process for the preparation of pure crystalline form I of Agomelatine.

Background of the invention

The present invention relates to a process for preparing polymorph form I of agomelatine and a process for preparing medicaments with the polymorph form I of agomelatine, which includes the process for the preparation of the polymorph form I of agomelatine. The present invention also relates to the polymorph form I of agomelatine, which is obtainable by the new process and medicaments containing this polymorph form I of agomelatine.

Melatonin is a neurohormone that is physiologically synthesized principally in the pineal gland and is involved in the regulation of many physiological and pathophysiological processes such as sleep, seasonal disorders, depression and ageing. Melatonin exhibits its physiological actions by
activating G-protein-coupled melatonin receptors MT1 and MT2. Due to its involvement in several physiological and pathophysiological processes melatonin was considered as a possible therapeutically usable substance. However, the therapeutical usage of melatonin is limited by the fast metabolic degradation. The plasma half-life of melatonin is only about 15 minutes, which strongly restricts its therapeutical usability.

Research efforts have been made for structurally modified melatonin analogues which maintain the pharmacological activity of melatonin but which have improved pharmacokinetic properties. As a result of this research the bioisosterically modified melatonin analogue agomelatine attracted attention as a suitable therapeutic substance. Agomelatine has the chemical name N-[2-(7-methoxy-1 -naphthyl) ethyl]acetamide and has the following chemical structure:

Agomelatine, its preparation and use have first been described in EP-A 0 447 285. It is a pharmacological agent with a dual mechanism of action. Similar to melatonin, agomelatine is an agonist of the melatonergic MT1 and MT2 receptors and, additionally, an antagonist of the 5-HT2c receptors. In the following agomelatine has been extensively investigated.

S. Yous et al. in J. Med. Chem. 1992, 35, 1484-1486 describe a process for the preparation of agomelatine, wherein agomelatine is obtained from a biphasic medium of water and chloroform. 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:

C15H17N02
Mr=243.30
Orthorhombic
Pca2!
a=31.501(4)A
b=9.5280(10)A
c=17.906(2)A.
The density is D = 1203 kg . m-3, and the number of molecules in one cell is Z = 16.

Tinant and Declercq also disclose the fractional atomic coordinates and equivalent isotropic displacement parameters and selected geometric parameters as well as the hydrogen bonding geometry of this polymorph form. This data is included herein by reference.
EP 0 447 285 in example 1 also discloses a process for the preparation of agomelatine. In this process agomelatine is obtained by recrystallization from isopropyl ether. No information on the polymorph form can be found in EP 0 447 285.

Later publications consider that the agomelatine obtained according to EP 0 447 285 is the same polymorph form obtained by Yous et al. (e.g. US 2005/0182276) but no experimental data is provided. The known processes for obtaining the polymorph form I of agomelatine are considered as providing the polymorph form I of agomelatine not in a sufficiently reproducible and well- defined manner and with only poor filtrability (US 2005/0182276).

Furthermore, the polymorph form I of agomelatine obtained by the known processes tends to have a relatively high hygroscopicity, which is considered a disadvantage. It would be useful to have a process which produces agomelatine of form I with a low hygroscopicity.
Finally, the processes for producing agomelatine of polymorph form I of the prior art usually provide a very broad particle size distribution for the agomelatine. It would be useful to have a process which produces agomelatine of polymorph form I with a narrower particle size distribution. This would facilitate the preparation of pharmaceutical formulations with the agomelatine of form I.

Several processes have been developed to prepare agomelatine crystals to overcome the problems of the prior art processes. However, none of these processes produced the polymorph form I of agomelatine, but different new polymorph forms of agomelatine were obtained. In particular, an attempt to dissolve agomelatine in a water-soluble solvent that is essentially acceptable in pharmaceutical compositions, such as ethanol, and crystallizing the agomelatine by adding water to the solution resulted in a new polymorph form which was designated polymorph form II of agomelatine. This polymorph form II has a monoclinic crystal lattice and not an orthorhombic crystal lattice and a different space group (namely P2-¦/N). Form II has eight molecules in the unit cell and not 16 as the polymorph form I of agomelatine and has lattice parameters A = 20.0903 A, B = 9.3194 A and C = 15.4796 A. This polymorph form (polymorph form II) of agomelatine is described e.g. in EP-A 1 564 202 and US 2005/0182276. In the process developed in these documents the agomelatine is prepared in ethanol, and water is added to the hot ethanol to precipitate the agomelatine.

Other processes are also known for the preparation of crystal forms of agomelatine, but those processes lead to other polymorph forms of agomelatine. In particular, US 2009/0069434 discloses a process which leads to crystalline form VI of agomelatine, US 2006/0270876 discloses a process which leads to a polymorph form III of agomelatine, US 2006/0270877 discloses a process which leads to the polymorph form V of agomelatine, and US 2006/0270875 discloses a process which leads to the polymorph form IV of agomelatine. A polymorph form of agomelatine for use in a medicament should have excellent properties, such as crystallinity, polymorph stability, chemical stability and processability to pharmaceutical compositions.
Therefore, there exists a need in the art for a process for reliably and reproducibly producing the polymorph form I of agomelatine with good filterability and in a very high chemical and polymorph purity. The obtained polymorph form I of agomelatine ideally should have a very low hygroscopicity, and the agomelatine of form I should be obtained in crystals with a narrow particle size distribution.

Unexpectedly it was found that the polymorph form I of agomelatine can be reliably obtained by an easy process in excellent reproducibility using process of present invention The obtained polymorph form I of agomelatine has a chemical purity of preferably 98% or more, more preferably 99% or more, in particular 99.5% or more, such as 99.7% or more. The obtained polymorph from I of agomelatine preferably has a low hygroscopicity, and with the process of the invention agomelatine of polymorph form I is obtained in the form of crystals having a very narrow particle size distribution.

The present invention provides a process for the preparation of the polymorph form I of agomelatine, characterized by the powder diffraction diagram.
Description of the drawings
FIG. l depicts a powder X-ray diffractogram (PXRD) of crystalline Form I of Agomelatine
Object of the invention:

It is an object of the present invention is to provide a process for the preparation of Agomelatine in pure crystalline form I, comprising steps of

i) providing a solution of Agomelatine in organic amine or mixture there of
ii) adding solution of oraganic acid and water to the solution obtain in step i)
iii) optionally seeding crystals of form I
iv) isolating the crystals of the polymorphic form I of Agomelatine.

In another object of present invention, suitable organic acid in step i) is selected form the group of formic acid, acetic acid, propionic acid, butyric acid, lactic acid, more preferably propionic acid.

In another object of present invention organic amine in step iv) is selected form the group of primary amine such as t-butyl amine, ammonia, propyl amine, methyl amine; secondary amine such as diethylamine, dimethyamine, methylethylamine, tertiary amine such as triethyl amine; more preferably primary amine, more preferably primary amine i. e. t-butyl amine

Summary of the invention

It is an aspect of the present invention is to provide a process for the preparation of Agomelatine in pure crystalline form I, comprising steps of

i) providing a solution of Agomelatine in organic amine or mixture there of
ii) adding solution of oraganic acid and water to the solution obtain in step i)
iii) optionally seeding crystals of form I
iv) isolating the crystals of the polymorphic form I of Agomelatine.

Detailed description of the invention:
The authors of the present invention have focused their attention on obtaining a pure crystal form I of agomelatine. It has soon turned out that stable crystal form II of agomelatine crystallizes very easily from agomelatine solutions, such that Form II can be obtained by usual methods of obtaining solid substances in the crystal form, e.g. by slow cooling of a stirred saturated solution of agomelatine in an organic solvent. While it was possible, by very fast cooling of a solution of agomelatine in organic solvents by spraying them onto dry ice or into liquid nitrogen or by very quick evaporation of an agomelatine solution in a spray drier, to succeed in obtaining Form I, this was in a mixture with other crystalline form of agomelatine.

The agomelatine that is used in the process of the present invention for preparing the crystalline form I of agomelatine can have been prepared by any method known in the art, and it can be referred e.g. to the basic patent EP 0 447 285 or any of the other patents mentioned above which disclose processes for preparing agomelatine.

Further embodiment of the present invention is to provide process for the preparation of Agomelatine in pure crystalline form I, comprising the steps of

i) providing a solution of Agomelatine in organic amine or mixture there of
ii) adding solution of oraganic acid and water to the solution obtain in step i)
iii) optionally seeding crystals of form I
iv) isolating the crystals of the polymorphic form I of Agomelatine.

Furthermore, the crystals of polymorph form I of agomelatine obtained by the process of the present invention have a specific surface and are therefore less hygroscopic than the crystals of polymorph form I of agomelatine obtained by other processes.

Providing a solution in step i) include obtaining a solution of Agomelatine in organic amine as a final step in the preparation of the compound or dissolving Agomelatine in organic amine and water. Suitable organic amines that may be used for this step includes but are not limited to primary amine such as t-butyl amine, ammonia, propyl amine, methyl amine; secondary amine such as diethylamine, dimethyamine, methylethylamine, tertiary amine such as triethyl amine, tertiary butyl amine.

The temperature at which solution of Agomelatine prepared in organic amine is cooled, is not particularly restricted, but usually the temperature is in the range of 100C to -80 0C, preferably 0 0C to -20 0C.
Step (ii) involves adding solution of organic acid and water to the solution obtains in step (i). Suitable organic acids that may be used for this step includes but are not limited to formic acid, acetic acid, propionic acid, butyric acid, lactic acid, preferred organic acid is propionic acid.
The process of step (ii) may be carried out in the presence of water, and the reaction may be carried out at temperature ranging from about 0ºC to about -60ºC, or about 0ºC to about -20ºC.
The solution obtained in step (iii) may be seeded with form I of Agomelatine crystals and may be cooled to a temperature below 10ºC to precipitate the solid. In embodiments, the solution may be cooled to temperatures about 0ºC to about 5ºC.
Step (iv) involves isolating the crystals of the polymorphic form I of Agomelatine.
Drying may be suitable carried out using any equipment at atmospheric pressure or under reduced pressures, at temperatures less than about 70ºC, less than about 50ºC less than about 30ºC and any other suitable temperatures. The drying may be carried out at any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours or longer.
The polymorphic form I of Agomelatine can be reliably obtained by an easy process in excellent reproducibility using process of present invention. The obtained polymorph form I of Agomelatine has a chemical purity of preferably 98% or more, more preferably 99% or more, in particular 99.5% or more, such as 99.8% or more. The obtained polymorphic form I of Agomelatine is pure crystalline form I, which is not contaminated with other crystalline form. The obtained polymorph from I of Agomelatine preferably has a low hygroscopic, and with the process of the invention Agomelatine of polymorph form I is obtained in the form of crystals having a very narrow particle size distribution
In the process of present invention seed crystal means crystals of form I of Agomelatine obtained by the prior art process or by the process of the present invention (Example I). It was also unexpectedly found that a very high reproducibility of the product characteristics can be obtained by seeding of the solution with seeds consisting of Agomelatine in crystalline form I.
The Agomelatine obtained by the process of the present invention is the polymorph form I of Agomelatine which is known from Acta Cryst. (1994), C50, 907-910. Regarding the details and the definition of the crystal form, it is referred to this document. The polymorph form I of Agomelatine can also be characterized by its powder diffraction diagram. An XRPD of form I that has been obtained by the process of the present invention is enclosed as figure I.

The following examples further explain the present invention, however examples are not restrictive.

Example I.
A Solution of propionic acid (48 ml) and water (70 ml) was cooled to 0 0C to -10 0C. A pre dissolved solution of Agomelatine in t-butyl amine and water was added to above solution at 0 0C to -10 0C. The crystallization started immediately and after the addition of solution of Agomelatine to the solution of propionic acid was complete, the reaction mixture was stirred at 0 0C to -10 0C for 30 minutes. Obtained crystals of form I were collected by filtration and dried for 10 hrs at 40-45 °C. HPLC purity 99.7 to 99.9%. XPRD: form 1 depicted in figure 1.

Example II
A Solution of propionic acid (48 ml) and water (70 ml) was cooled to 0 0C to -10 0C. This solution was seeded with crystals of Agomelatine Form-I (0.05g) at 0 0C to -10 0C. A pre dissolved solution of Agomelatine in t-butyl amine and water was added to above solution at 0 0C to -10 0C. The crystallization started immediately and after the addition of solution of Agomelatine to the solution of propionic acid was complete, the reaction mixture was stirred at 0 0C to -10 0C for 30 minutes. Obtained crystals of form I were collected by filtration and dried for 10 hrs at 40-45 °C. HPLC purity 99.7 to 99.9%. XPRD: form 1 depicted in figure 1.

Example III
A mixture of form I (100 g) and Di isopropyl ether (300 ml) was stirred at 50-60 °C for one hour. Cooled the reaction mixture at 10-20 °C and stirred. Obtained crystals of form II were collected by filtration and dried. Yield (97 g, 95 -97%). HPLC purity 99.7 to 99.9%.

Example IV
A mixture of form I (100 g) and cyclohexane (300 ml) was stirred at 50-60 °C for one hour. Cooled the reaction mixture at 10-20 °C and stirred. Obtained crystals of form II were collected by filtration and dried. Yield (97 g, 95 -97%). HPLC purity 99.7 to 99.9%.
,CLAIMS:
1. Process for the preparation of crystalline form I of Agomelating comprising the steps of
i) providing a solution of Agomelatine in organic amine or mixture there of
ii) adding solution of oraganic acid and water to the solution obtain in step (i)
iii) optionally seeding crystals of form I
iv) isolating the crystals of the polymorphic form I of Agomelatine.

2. A process of claim 1, where in organic amine is selected form the group consisting of primary amine such as t-butyl amine, ammonia, propyl amine, methyl amine; secondary amine such as diethylamine, dimethyamine, methylethylamine, tertiary amine such as triethyl amine;.

3. A process of claim 1, where in organic acid is selected for the group consisting of formic acid, acetic acid, propionic acid, butyric acid, lactic acid.