AGOMELATINE POLYMORPHS AND PROCESSES INTRODUCTION

Aspects of the present application relate to crystalline forms of agomelatine, an amorphous solid disepersion of agomelatine, and processes for their preparation. In aspects, the application relates to the preparation of crystalline Form I of agomelatine. Further aspects relate to pharmaceutical compositions comprising polymorphic forms of agomelatine.

The drug compound having the adopted name "agomelatine" can be represented by structural formula (I), where each "Me" represents a methyl group, and it has a new pharmacological mechanism of action, which combines its melatonin MT1 and MT2 agonist properties with a serotonin 5-HT2c antagonist effect. The 5-HT2c receptor is considered a relevant target with regard to antidepressant therapy, as several currently used antidepressant drugs have 5-HT2C receptor antagonist properties.

Agomelatine is a non-hygroscopic white or almost white powder, practically insoluble in water and containing no asymmetric carbon atoms. A chemical name for agomelatine is N-[2-(7-methoxy-1-naphthylen-1-yl)ethyl]acetamide, and it is the active ingredient in VALDOXAN® tablets, sold for the treatment of major depressive episodes in adults.

U.S. Patent No. 5,225,442 discloses agomelatine, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and a method for the treatment of a living animal afflicted with treatable disorder of the melatoninergic system, comprising the step of administering to the living animal an effective amount of the compound. The patent also discloses a process for the preparation of agomelatine, involving the acetylation of 2-(7-methoxynaphth-1-yl)ethylamine with acetyl chloride in pyridine, and the obtained product is recrystallized in isopropyl ether. Agomelatine obtained in the patent has been characterized by its melting point, infrared (IR) spectrum, and 1H NMR spectrum.

A process for the preparation of agomelatine is also disclosed by S. Yous et al., "Novel Naphthalenic Ligands with High Affinity for the Melatonin Receptor," Journal of Medicinal Chemistry, Vol. 35(8), pages 1484-1486, 1992.

As stated at column 7, lines 38-42 of U.S. Patent No. 7,250,531: "The prior art EP 0 447 285 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)."

Journal of Medicinal chemistry 1994, 37, 3231-3239 discloses that agomelatine was obtained as a crystalline solid from a mixture of toluene/hexane in the ration of 2:1 having melting range 109-110°C.

This crystalline form that has been described in the above literature is designated herein as "Form I." A powder X-ray diffraction (PXRD) pattern of Form I is described in Chinese publications CN 101704763 A.

U.S. Patent No. 7,250,531 discloses crystalline Form II of agomelatine in a monoclinic crystal lattice. U.S. Patent No. 7,635,721 discloses crystalline Form III of agomelatine. U.S. Patent No. 7,645,905 discloses crystalline Form IV of agomelatine. U.S. Patent No. 7,358,395 discloses crystalline Form V of agomelatine. U.S. Patent Application Publication No. 2009/069434 A1 discloses crystalline Form VI of agomelatine.

International Application Publication No. WO 2010/102554 A1 also discloses crystalline Form VI of agomelatine. International Application Publication No. WO 2011/06387 A1 discloses Form A, Form B and Form C of agomelatine. Chinese patent application publication 101955440 A discloses crystalline Form X of agomelatine, and Chinese publications CN 101781226 A, CN 101774937 A and CN 102001959 A also disclose crystalline forms of agomelatine. Chinese publication CN 101870662A discloses ethylene glycol solvate and acetic acid solvates of agomelatine. International Application Publication No. WO 2011/06387 A1 discloses a process for the preparation of Form I of agomelatine. Chinese publications CN 101704763 A and CN 101921205 A also disclose a process for the preparation of Form I of agomelatine. International Application Publication No. WO2011/054917 A1 and WO2011/128413 A1 also disclose processes for the preparation of Form I of agomelatine.

The occurrence of different crystal forms, i.e., polymorphism, is a property of some compounds. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties, such as PXRD patterns, IR absorption spectra, melting points (MP), TGA curves, DSC curves, and solubilities.

Polymorphs are different solids having the same molecular structure, yet having distinct physical properties when compared to other polymorphs of the same structure. The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties. Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in recent articles, including A. Goho, "Tricky Business," Science News, August 21, 2004. In general, one cannot predict whether there will be more than one form for a compound, how many forms will eventually be discovered, or how to prepare any previously unidentified form.

There remains a need for additional polymorphic forms of agomelatine and for processes to prepare polymorphic forms in an environmentally-friendly, cost-effective, and industrially applicable manner.

SUMMARY

In an aspect, the application provides a process for the preparation of crystalline form I of agomelatine comprising:

a) dissolving agomelatine in a solvent selected from tetrahydrofuran, isopropyl acetate, 1,4-dioxane, chlorobenzene, chloroform to provide a solution;

b) adding an anti-solvent to the solution obtained in step a), wherein anti-solvent is selected from cyclohexane, methyl cyclohexane and n-heptane;

c) optionally seeding the solution or suspension obtained in step b) with the crystalline form I of agomelatine, and

d) isolating crystalline form I of agomelatine.

In an aspect, the application provides a process for the preparation of crystalline form I of agomelatine comprising:

a) dissolving agomelatine in dimethylsulfoxide or 1,4-dioxane to provide a solution;

b) adding water to the solution obtained in step a), and

c) isolating crystalline form I of agomelatine.

In an aspect, the application provides a process for the preparation of crystalline form I of agomelatine comprising:

a) providing a solution of agomelatine in a solvent selected from tetrahydrofuran, methyl isobutyl ketone, isopropyl acetate, chloroform, or mixtures thereof;

b) adding the solution obtained in step a) to an anti-solvent selected from cyclohexane, methylcyclohexane, n-heptane, and

c) isolating crystalline form I of agomelatine.

In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks at about 6.3, 9.3, 10.5, 11.2, 11.9, 12.6, 13.3, 15.3, 17.2, 18.6, 19.0, and 22.1, ±0.2° 26.

In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks at about 6.6, 9.6, 12.8, 17.7, 19.3, 20.4, 22.4, 24.5, and 25.5, ±0.2° 26.

In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks at about 10.8, 12.2, 18.1, 20.8, 22.0, 23.6, and 25.3, ±0.2° 26.

In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks at about 8.8, 10.6, 12.8, 13.3, 14.9, 17.8, 19.3, 21.2, 23.2, 24.6, and 25.8, ±0.2° 26.

In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks at about 8.2, 12.4, 15.0, 17.4, 20.8, 24.1, and 25.2, ±0.2° 26.

In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks at about 8.2, 11.9, 12.5, 15.0, 17.4 and 25.2, ±0.2° 26.

In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern at about 12.1, 19.8, 20.7 and 25.6, ±0.2° 26.

In an aspect, the application provides an amorphous solid disepersion of agomelatine.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 depicts a PXRD pattern of agomelatine Form I, obtained by the procedure of Example 1.

Fig 2 depicts a PXRD pattern of agomelatine, obtained by the procedure of Example 31.

Fig 3 depicts a PXRD pattern of agomelatine, obtained by the procedure of Example 32.

Fig 4 depicts a PXRD pattern of agomelatine, obtained by the procedure of Example 33.

Fig 5 depicts a PXRD pattern of agomelatine, obtained by the procedure of Example 34.

Fig 6 depicts a PXRD pattern of agomelatine, obtained by the procedure of Example 36.

Fig 7 depicts a PXRD pattern of agomelatine, obtained by the procedure of Example 37.

Fig 8 depicts a PXRD pattern of agomelatine, obtained by the procedure of Example 38.

Fig 9 depicts a PXRD pattern of agomelatine, obtained by the procedure of Example 39.

DETAILED DESCRIPTION

In an aspect, the application provides a process for the preparation of crystalline form I of agomelatine comprising:

a) dissolving agomelatine in a solvent selected from tetrahydrofuran, isopropyl acetate, 1,4-dioxane, chlorobenzene, chloroform to provide a solution;

b) adding an anti-solvent to the solution obtained in step a), wherein anti-solvent is selected from cyclohexane, methyl cyclohexane and n-heptane;

c) optionally seeding the solution or suspension obtained in step b) with the crystalline form I of agomelatine, and

d) isolating crystalline form I of agomelatine.

Step a) involves preparation of a solution of agomelatine by dissolving agomelatine in a solvent selected from tetrahydrofuran, isopropyl acetate, 1,4-dioxane, chlorobenzene, chloroform to provide a solution. In embodiments, a solution of agomelatine can be prepared at any suitable temperatures, such as about 20°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.

In embodiments, a solution of agomelatine may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.

In embodiments of step b) anti-solvent may be added to the solution obtained in step a). The anti-solvent can be added to the solution drop-wise, lot wise in one lot or more lots or rapidly. The anti-solvents may be selected from cyclohexane, methylcyclohexane and n-heptane. In embodiments, the anti-solvent may be added to the solution at suitable temperatures such as about 0°C to about reflux temperature of the solvent.

In embodiments of step c) optionally the seed of crystalline form I of agomelatine may be added to the solution or suspension obtained in step b). In embodiments, the seed can be added before or after the addition of anti-solvent to the solution obtained in step-a). Preferably the seed can be added after the addition of the anti-solvent to the solution obtained in step a). The seed can be added as a solid or by making a slurry or suspension in anti-solvent used.

In embodiments, the slurry obtained by the precipitation comprising crystalline form I of agomelatine and solvent can be maintained at any suitable temperatures, such as about 0°C to about 50°C. In embodiments, the slurry comprising crystalline form I of agomelatine can be maintained for about 30 minutes to about 10 hours, or longer.

Step d) involves the isolation of crystalline form I of agomelatine obtained in step c). In embodiments, crystalline form I of agomelatine can be isolated using any techniques, such as decantation, filtration by gravity or suction, centrifugation, or the solvent can be evaporated from the mass to obtain the desired product, and optionally the obtained solid can be washed with a solvent, such as an anti-solvent or the solvent, to reduce the amount of entrained impurities.

In embodiments, crystalline form I of agomelatine that is isolated can be dried at suitable temperatures, and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying temperatures and times will be sufficient to achieve desired product purity.

In an aspect, the application provides a process for the preparation of crystalline form I of agomelatine comprising:

a) dissolving agomelatine in dimethylsulfoxide or 1,4-dioxane to provide a solution;

b) adding water to the solution obtained in step a), and

c) isolating crystalline form I of agomelatine.

Step a) involves preparation of a solution of agomelatine by dissolving agomelatine in dimethylsulfoxide or 1,4-dioxane. In embodiments, a solution of agomelatine can be prepared at any suitable temperatures, such as about 20°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.

In embodiments, a solution of agomelatine may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.

In embodiments of step b) water may be added to the solution obtained in step a) to produce crystalline form I of agomelatine. Water can be added to the solution drop-wise, lot wise in one lot or more lots or rapidly. In embodiments, the water may be added to the solution at suitable temperatures such as about 0°C to about reflux temperature of the solvent.

In embodiments, the slurry obtained by the precipitation comprising crystalline form I of agomelatine and solvent can be maintained at any suitable temperatures, such as about 0°C to about 50°C. In embodiments, the slurry comprising crystalline form I of agomelatine can be maintained for about 30 minutes to about 10 hours, or longer.

Step c) involves the isolation of crystalline form I of agomelatine obtained in step b). In embodiments, crystalline form I of agomelatine can be isolated using any techniques, such as decantation, filtration by gravity or suction, centrifugation, or the solvent can be evaporated from the mass to obtain the desired product, and optionally the obtained solid can be washed with a solvent, such as an anti-solvent or the solvent, to reduce the amount of entrained impurities.

In embodiments, crystalline form I of agomelatine that is isolated can be dried at suitable temperatures, and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying temperatures and times will be sufficient to achieve desired product purity.

In an aspect, the application provides a process for the preparation of crystalline form I of agomelatine comprising:

a) providing a solution of agomelatine in a solvent selected tetrahydrofuran, methyl isobutyl ketone, isopropyl acetate, chloroform, or mixtures thereof;

b) adding the solution obtained in step a) to an anti-solvent selected from cyclohexane, methylcyclohexane, n-heptane, and

c) isolating crystalline form I of agomelatine.

Step a) involves the preparation of solution of agomelatine by dissolving agomealtine in a suitable inert solvent. The suitable solvent for making a solution can be selected from tetrahydrofuran, methyl isobutyl ketone, isopropyl acetate, chloroform, or mixtures thereof. In embodiments, a solution of agomelatine can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.

In embodiments, a solution of agomelatine may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.

In embodiments of step b) the solution obtained in step a) may be added to a suitable anti-solvent. The solution can be added to the anti-solvent drop-wise, lot wise in one lot or more lots or rapidly. The anti-solvents may be selected from cyclohexane, methylcyclohexane and n-heptane.

In embodiments, slurry obtained by the precipitation comprising crystalline form I of agomelatine and inert solvent can be maintained at any suitable temperatures, such as about -10°C to about 40°C, or about 0°C to about 25°C. In embodiments, slurry comprising crystalline form I of agomelatine can be maintained for about 30 minutes to about 10 hours, or longer.

In embodiments, the crystalline form I of agomelatine can be isolated using any techniques, such as decantation, filtration by gravity or suction, centrifugation, or the solvent can be evaporated from the mass to obtain the desired product, and optionally the solid can be washed with a solvent, such as an anti-solvent or the solvent, to reduce the amount of entrained impurities.

In embodiments, the crystalline form I of agomelatine that is isolated can be dried at suitable temperatures, and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying temperatures and times will be sufficient to achieve desired product purity.

In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks at about 6.3, 9.3, 10.5, 11.2, 11.9, 12.6, 13.3, 15.3, 17.2, 18.6, 19.0, and 22.1, ±0.2° 20. In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks located substantially as shown in Fig. 2.

In an aspect, the application provides processes for preparing the crystalline form of agomelatine characterized by a PXRD pattern having peaks located substantially as shown in Fig. 2, embodiments comprising: (a) dissolving agomelatine in acetic acid; (b) optionally, treating the solution with a decolorizing agent; and (c) precipitating the agomelatine by cooling the solution.

In embodiments, the solution of agomelatine can be prepared by adding acetic acid to agomelatine, or adding agomelatine to acetic acid, at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent. Stirring may be used to reduce the time required for the dissolution process. Optionally, additional organic solvent may be added to make the solution.

Optionally, the solution of agomelatine may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may optionally be treated with a decolorizing agent such as carbon, before the filtration.

In embodiments, the solution of agomelatine obtained can be maintained at any suitable temperatures below the temperature of solution formation, such as about -10°C to about 20°C, or about -5 to about 10°C, for crystallization.

The crystalline form of agomelatine can be isolated using any techniques known in the art for separating solids from liquids.

In embodiments, the crystalline form of agomelatine can be dried, if desired, at suitable temperatures, and at atmospheric or reduced pressures, for about 1-50 hours, or longer, using drying equipment known in the art.

In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks at about 6.6, 9.6, 12.8, 17.7, 19.3, 20.4, 22.4, 24.5, and 25.5, ±0.2° 29. In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks located substantially as shown in Fig. 3.

In an aspect, the application provides processes for preparing the crystalline form of agomelatine characterized by a PXRD pattern having peaks at 6.6, 9.6, 12.8, 17.7, 19.3, 20.4, 22.4, 24.5, and 25.5, ±0.2° 20, embodiments comprising: (a) dissolving agomelatine in isopropyl acetate; (b) optionally treating the solution with a decolorizing agent; and (c) precipitating the agomelatine by evaporating the solvent.

In embodiments, a solution of agomelatine can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the isopropyl acetate. Stirring may be used to reduce the time required for the dissolution process.

Optionally, the solution of agomelatine may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may optionally be treated with a decolorizing agent, such as carbon, before filtration.

In embodiments, the solution of agomelatine may be maintained for evaporation of the solvent at ambient temperatures. The removal of solvent may be carried out by keeping the solution open to the atmosphere for sufficient time.

In embodiments, the crystalline form of agomelatine above can be dried, if desired, at suitable temperatures, and at atmospheric or reduced pressures, for about 1-50 hours, or longer, using drying equipment known in the art.

In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks at about 10.8, 12.2, 18.1, 20.8, 22.0, 23.6, and 25.3, ±0.2° 20. In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks located substantially as shown in Fig. 4.

In an aspect, the application provides processes for preparing the crystalline form of agomelatine characterized by a PXRD pattern having peaks located substantially as shown in Fig. 4, embodiments comprising: (a) dissolving agomelatine in acetic acid; (b) optionally, treating the solution with a decolorizing agent; and (c) precipitating the agomelatine by evaporating the solvent.

In embodiments, a solution of agomelatine can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the acetic acid. Stirring may be used to reduce the time required for the dissolution process.

Optionally, the solution of agomelatine may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may optionally be treated with a decolorizing agent, such as carbon, before filtration.

In embodiments, the clear solution of agomelatine from the above step is maintained for evaporation of the solvent at ambient temperatures. The removal of solvent may be carried out by keeping the solution open to the atmosphere for sufficient time.

In embodiments, the crystalline form of agomelatine above can be dried, if desired, at suitable temperatures, and at atmospheric or reduced pressures, for about 1-50 hours, or longer, using drying equipment known in the art.

In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks at about 8.8, 10.6, 12.8, 13.3, 14.9, 17.8, 19.3, 21.2, 23.2, 24.6, and 25.8, ±0.2° 26. In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks located substantially as shown in Fig. 5.

In an aspect, the application provides processes for preparing the crystalline form of agomelatine characterized by a PXRD pattern having peaks located substantially as shown in Fig. 5, embodiments comprising: (a) dissolving agomelatine in formamide; (b) optionally, treating the solution with a decolorizing agent; and (c) precipitating the agomelatine by cooling the solution.

In an aspect, the application provides processes for preparing the above crystalline form of agomelatine characterized by a PXRD pattern having peaks located substantially as shown in Fig. 5, comprising: (a) slurrying agomelatine in formamide; and (b) isolating the agomelatine.

In embodiments, a solution of agomelatine can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the formamide. Stirring may be used to reduce the time required for the dissolution process.

In embodiments, the solution of agomelatine may be filtered to make it clear and free of unwanted particles. In embodiments, the solution may optionally be treated with a decolorizing agent, such as carbon, before filtration.

In embodiments, the clear solution of agomelatine is cooled to about -40 to about -30°C, for precipitation of the crystalline form.

The crystalline form of agomelatine can be isolated using techniques known in the art for separating solids from liquids.

If desired, the crystalline form of agomelatine can be dried at suitable temperatures, and at atmospheric or reduced pressures, for about 1-50 hours, or longer, using drying equipment known in the art.

In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks at about 8.2, 12.4, 15.0, 17.4, 20.8, 24.1, and 25.2, ±0.2° 29. In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks located substantially as shown in Fig. 6.

In an aspect, the application provides processes for preparing the crystalline form of agomelatine characterized by a PXRD pattern having peaks located substantially as shown in Fig. 6, embodiments comprising: (a) dissolving agomelatine in acetic acid; (b) optionally, treating the solution with a decolorizing agent; and (c) precipitating the agomelatine by cooling the solution.

In embodiments, a solution of agomelatine can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the acetic acid. Stirring may be used to reduce the time required for the dissolution process.

In embodiments, the solution of agomelatine may be filtered to make it clear and free of unwanted particles. In embodiments, the solution may optionally be treated with a decolorizing agent, such as carbon, before filtration.

In embodiments, the clear solution of agomelatine is cooled to about -10 to about 10°C, for precipitation of the crystalline form.

The crystalline form of agomelatine can be isolated using techniques known in the art for separating solids from liquids.

If desired, the crystalline form of agomelatine can be dried at suitable temperatures, and at atmospheric or reduced pressures, for about 1-50 hours, or longer, using drying equipment known in the art.

In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks at about 8.2, 11.9, 12.5, 15.0, 17.4 and 25.2, ±0.2° 26. In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks located substantially as shown in Fig. 7.

In an aspect, the application provides processes for preparing the crystalline form of agomelatine characterized by a PXRD pattern having peaks located substantially as shown in Fig. 7, embodiments comprising: (a) dissolving agomelatine in acetic acid; (b) optionally, treating the solution with a decolorizing agent; and (c) precipitating the agomelatine by cooling the solution.

In embodiments, a solution of agomelatine can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the acetic acid. Stirring may be used to reduce the time required for the dissolution process.

In embodiments, the solution of agomelatine may be filtered to make it clear and free of unwanted particles. In embodiments, the solution may optionally be treated with a decolorizing agent, such as carbon, before filtration.

In embodiments, the clear solution of agomelatine is cooled to about -40 to about -30°C, for precipitation of the crystalline form.

The crystalline form of agomelatine can be isolated using techniques known in the art for separating solids from liquids.

If desired, the crystalline form of agomelatine can be dried at suitable temperatures, and at atmospheric or reduced pressures, for about 1-50 hours, or longer, using drying equipment known in the art.

In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks at about 12.1, 19.8, 20.7 and 25.6, ±0.2° 26. In an aspect, the application provides a crystalline form of agomelatine, characterized by a PXRD pattern having peaks located substantially as shown in Fig. 8.

In an aspect, the application provides processes for preparing the crystalline form of agomelatine characterized by a PXRD pattern having peaks located substantially as shown in Fig. 8, embodiments comprising: (a) dissolving agomelatine in n-butyl acetate; (b) optionally, treating the solution with a decolorizing agent; and (c) precipitating the agomelatine by cooling the solution.

In embodiments, a solution of agomelatine can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the n-butyl acetate. Stirring may be used to reduce the time required for the dissolution process.

In embodiments, the solution of agomelatine may be filtered to make it clear and free of unwanted particles. In embodiments, the solution may optionally be treated with a decolorizing agent, such as carbon, before filtration.

In embodiments, the clear solution of agomelatine is cooled to about -40 to about -30°C, for precipitation of the crystalline form.

The crystalline form of agomelatine can be isolated using techniques known in the art for separating solids from liquids.

If desired, the crystalline form of agomelatine can be dried at suitable temperatures, and at atmospheric or reduced pressures, for about 1-50 hours, or longer, using drying equipment known in the art.

In an aspect, the application provides an amorphous solid dispersion of agomelatine together with a pharmaceutical^ acceptable excipient.

In an aspect, the application provides processes for preparing amorphous solid dispersion of agomelatine, embodiments comprising: (a) providing a solution of agomelatine and a pharmaceutically acceptable excipient, in a solvent; (b) optionally, treating the solution with a decolorizing agent; and (c) removing the solvent.

Agomelatine and excipients can be dissolved in any solvents that are inert to the solutes. Examples of such solvents include, but are not limited to: alcohol solvents; ketone solvents; halogenated hydrocarbon solvents; ester solvents; ether solvents; nitrile solvents; polar aprotic solvents; or mixtures thereof.

In embodiments, the excipient that is used does not have any adverse effect on the drug. Examples of excipients that can be used for the preparation of an amorphous form of agomelatine include, but are not limited to, one or more of polyvinylpyrrolidones, povidone, cellulose, methylcelluloses, hydroxypropyl methylcelluloses, etc.

In embodiments, a solution of agomelatine can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent. Stirring may be used to reduce the time required for the dissolution process.

The excipient can be dissolved separately in a solvent, and its solution mixed with the drug solution. Alternatively, the excipient can be dissolved in the drug solution.

In embodiments, solutions comprising agomelatine, optionally also containing the excipient, may be filtered to make them clear and free of unwanted particles. In embodiments, the solutions may optionally be treated with a decolorizing agent, such as carbon, before filtration.

In embodiments, the solvent can be removed by any techniques known in the art such as lyophilization, freeze drying, spray drying, thin film drying, flash drying, etc.
Fig. 9 illustrates the PXRD pattern of amorphous agomelatine, obtained by a process of the present application.

In embodiments, agomelatine which is used as the starting material can be prepared by any method, including methods known in the art, and optionally can be purified using any method known in the art to enhance its chemical purity.

Agomelatine obtained according to processes of the present application can be milled or micronized by any process known in the art, such as ball milling, jet milling, wet milling etc., to produce desired particle sizes and particle size distributions.

X-ray powder diffraction patterns described herein were generated using a Bruker AXS D8 Advance powder X-ray diffractometer, with a copper K-alpha radiation source. Generally, a diffraction angle (20) in powder X-ray diffractometry may have an error in the range of ±0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2°. Accordingly, the present invention includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (20) ±0.2° of 6.3°" means "having a diffraction peak at a diffraction angle (20) of 6.1° to 6.5°. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peak relationships and the peak locations are characteristic for a specific polymorphic form. The relative intensities of the PXRD peaks can vary somewhat, depending on factors such as the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrumental variation and other factors can slightly affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by plus or minus about 0.2°. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a filter is used or not).

An aspect of the present application provides pharmaceutical compositions containing a therapeutically effective amount of agomelatine, together with one or more pharmaceutical^ acceptable excipients.

The pharmaceutical compositions comprising agomelatine of the invention together with one or more pharmaceutical^ acceptable excipients may be formulated as: solid oral dosage forms, such as, but not limited to: powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze-dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate-controlling substances to form matrix or reservoir systems, or combinations of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated powder coated, enteric coated, or modified release coated.

Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to, any one or more of: diluents such as starches, pregelatinized starches, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic, cationic, and neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film-formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

DEFINITIONS

The following definitions are used in connection with the disclosure of the present application, unless the context indicates otherwise. In general, the number of carbon atoms present in a given group or compound is designated "Cx-Cy", where x and y are the lower and upper limits, respectively. For example, a group designated as "CrC6" contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.

The following abbreviations and acronyms are used herein and have the indicated definitions:

An "alcohol" is an organic compound containing a carbon bound to a hydroxyl group. "Ci-C6 alcohols" include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, and the like.

An "ester" is an organic compound containing a carboxyl group -(C=0)-0-bonded to two other carbon atoms. "C3-C6 esters" include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and the like.

An "ether" is an organic compound containing an oxygen atom -O- bonded to two other carbon atoms. "C2-C6 ethers" include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, and the like.

A "halogenated hydrocarbon" is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, and the like.

A "ketone" is an organic compound containing a carbonyl group -(C=0)-bonded to two other carbon atoms. "C3-C6 ketones" include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, and the like.

A "nitrile" is an organic compound containing a cyano-(C=N) bonded to another carbon atom. "C2-C6 nitriles" include, but are not limited to, acetonitrile, propionitrile, butanenitrile, and the like.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES Example 1: Preparation of agomelatine Form I: Agomelatine (500 mg) and dimethyl sulfoxide (0.5 mL) are charged into a round bottom flask at 27°C. The mixture is heated to 80°C to obtain a clear solution. Water (15 mL) is added at 80°C. The mass is cooled to 27°C. The formed solid is collected by filtration and washed with water (5 mL), and then dried under vacuum at 55°C for 3 hours. Yield: 410 mg. The PXRD pattern is shown in Fig. 1.

Example 2: Preparation of agomelatine Form I: Agomelatine (500 mg) and methanol (1.5 mL) are charged into a round bottom flask at 27°C. The mixture is heated to 58°C to obtain a clear solution. The solution is rapidly cooled to -35°C. The formed solid material is recovered by scraping the product from the round bottom flask.

Example 3: Preparation of agomelatine Form I: Agomelatine (500 mg) and formamide (18 mL) are charged into a round bottom flask at 27°C. The mixture is stirred at 27°C to obtain a clear solution. The solution is filtered to remove undesired particles. Water (45 mL) is cooled to 5°C in another flask, and the formamide solution is added to the flask containing water at 5°C. The mass is stirred for 15 minutes at 5°C. The formed solid is collected by filtration and washed with water (10 mL), and then is suction dried for 5 minutes. Yield: 410 mg (wet). Example 4: Preparation of agomelatine Form I: Agomelatine (500 mg) and 1,4 dioxane (3 mL) are charged into a round bottom flask at 27°C. The mixture is stirred at 27°C to obtain a clear solution. The solution is filtered to remove undesired particles. Water (15 mL) is added to the solution at 27°C and stirred for 5 minutes at the same temperature. The formed solid is collected by filtration and washed with water (10 ml_), and then is suction dried for 5 minutes. Yield: 410 mg (wet). Example 5: Preparation of agomelatine Form I: Agomelatine (500 mg) and 1, 4 dioxane (3 mL) are charged into a round bottom flask at 27°C. The mixture is stirred at 27°C to obtain a clear solution. The solution is filtered to remove undesired particles. Methylcyclohexane (15 mL) is added to the solution at 27°C and the mass is stirred for 5 minutes at the same temperature. The formed solid is collected by filtration and washed with methylcyclohexane (10 mL), and then suction dried for 5 minutes. Yield: 420 mg (wet).

Example 6: Preparation of agomelatine Form I: N-heptane (30 mL) is charged into a round bottom flask at 27°C and cooled to 10°C. A solution of agomelatine (500 mg) in isopropyl acetate (10 mL) is added to the n-heptane at 12°C and stirred for 30 minutes at the same temperature. The formed solid is collected by filtration and washed with n-heptane (20 mL), and then dried under vacuum at 52°C for 2 hours. Yield: 370 mg.

Example 7: Preparation of agomelatine Form I: Water (15 mL) is charged into a round bottom flask at 27°C and cooled to 10°C. A solution of agomelatine (500 mg) in methanol (3 mL) is added to the water at 12°C and stirred for 30 minutes at the same temperature. The formed solid is collected by filtration and washed with water (10 mL), and then dried under vacuum at 50°C for 2 hours. Yield: 360 mg. Examples 8-15: Preparation of agomelatine Form I: Agomelatine (0.5 g) and a solvent are charged into a round bottom flask. The mixture is stirred to obtain a clear solution. If required, the mixture is heated to obtain a clear solution. An anti-solvent (15 mL) is added to the solution. The mass is maintained to precipitate a solid (if required, using cooling) and the formed solid is collected by filtration, washed with a small quantity of anti-solvent, and then dried to produce agomelatine Form I. The following examples illustrate the preparation of Form I of agomelatine, following this procedure.

Examples 16-30: Preparation of agomelatine Form I: Agomelatine (0.5 g) and a solvent are charged into a round bottom flask. The mixture is stirred to obtain a clear solution. If required, the mixture is heated to obtain a clear solution. The solution is added to an anti-solvent. The mass is maintained to precipitate the solid (if required, using cooling) and the formed solid is collected by filtration, washed with a small quantity of anti-solvent, and then dried to produce agomelatine Form I. The following examples illustrate the preparation of Form I of agomelatine following this procedure.

Example 31: Preparation of a crystalline form of agomelatine: Agomelatine (2.0 g) and glacial acetic acid (2 mL) are charged into a round bottom flask at 27°C. The mixture is heated to 55°C to obtain a clear solution. The solution is maintained at 0-5°C for 12 hours. The formed solid is separated by filtration and dried under vacuum at 70°C for 5 hours. Yield: 1.95 g. The PXRD pattern is shown in Fig. 2. Example 32: Preparation of a crystalline form of agomelatine: Agomelatine (100 mg) and isopropyl acetate (3 mL) are charged into a test tube at 27°C. The test tube is shaken to obtain a solution. The solution is exposed to the atmosphere at 27°C for 18 hours, for the evaporation of solvent. Yield: 72 mg. The PXRD pattern is shown in Fig. 3.

Example 33: Preparation of a crystalline form of agomelatine: Agomelatine (100 mg) and glacial acetic acid (0.8 mL) are charged into a test tube at 27°C. The test tube is shaken to obtain a solution. The solution is exposed to the atmosphere at 27°C for 18 hours, for the evaporation of solvent. Yield: 68 mg; The PXRD pattern is shown in Fig. 4.

Example 34: Preparation of a crystalline form of agomelatine: Agomelatine (500 mg) and formamide (1 mL) are charged into a round bottom flask at 27°C. The mixture is heated to 85°C to obtain a clear solution. The solution is cooled to -35°C and maintained at the same temperature for 10 minutes. The formed solid is separated by filtration and dried at 27°C for 2 days. Yield: 485 mg. The PXRD pattern is shown in Fig. 5.

Example 35: Preparation of a crystalline form of agomelatine: Agomelatine (500 mg) and formamide (15 mL) are charged into a round bottom flask at 27°C. The mixture is stirred at 27°C for 24 hours. The solid is collected by filtration and washed with formamide (2 mL), and then suction dried for 5 minutes. Yield: 495 mg (wet). Example 36: Preparation of a crystalline form of agomelatine: Agomelatine (1.0 g) and glacial acetic acid (2 mL) are charged into a round bottom flask at 27°C. The mixture is heated to 55°C to obtain a clear solution. The solution is kept in refrigerator at 0-5°C for 17 hours. Yield: 1.2 g (wet). The PXRD pattern is shown in Fig. 6.

Example 37: Preparation of a crystalline form of agomelatine: Agomelatine (0.5 g) and glacial acetic acid (0.3 mL) are charged into a beaker at 27°C. The mixture is heated to 83°C to obtain a clear solution. The solution is cooled to -40°C for 10 minutes. The formed solid is kept for drying at 27°C for 24 hours and further dried under vacuum at 55°C for 3 hours. Yield: 0.48 g (wet). The PXRD pattern is shown in Fig. 7.

Example 38: Preparation of a crystalline form of agomelatine: Agomelatine (0.5 g) and n-butyl acetate (2 mL) are charged into a beaker at 27°C. The mixture is heated to obtain a clear solution. The solution is cooled to -30°C for 10 minutes. Yield: 0.48 g (wet). The PXRD pattern is shown in Fig. 8.

Example 39: Preparation of amorphous solid dispersion of agomelatine with povidone: Agomelatine (3 g), povidone (3 g), and dichloromethane (100 mL) are charged into a round bottom flask at 28°C. The mixture is stirred to obtain a clear solution. The solution is filtered to remove undesired particles. The solution is spray-dried to obtain amorphous agomelatine. Yield: 3.4 g. The PXRD pattern is shown in Fig. 9.

Example 40: Preparation of agomelatine Form I: Agomelatine (5.0 g) and isopropyl acetate (50 mL) are charged into a round bottom flask at 28°C. The mixture is stirred and heated to 48°C to obtain a clear solution. The solution is filtered to remove undesired particles. The filtrate is taken in a flask and cooled to 17°C. N-heptane (150 mL) cooled to 15°C is added to the solution at 17°C in one lot and the obtained slurry is stirred for 40 minutes at 17°C. The precipitated solid is collected by filtration and washed with n-heptane (10 mL), dried under vacuum at 40°C for 1 hour. Yield: 3.7 g.

Example 41: Preparation of agomelatine Form I: Agomelatine (10 g) and isopropyl acetate (100 mL) are charged into a round bottom flask at 28°C. The mixture is stirred and heated to 52°C to obtain a clear solution. The solution is filtered to remove undesired particles. The filtrate is taken in a flask and cooled to 19°C. N-heptane (20 mL) cooled to 16°C and seed of crystalline form I (500 mg) are added to the solution at 19°C and the obtained slurry is stirred for 5 minutes at 19°C. The remaining quantity of n-heptane (280 mL) cooled to 16°C is added to the slurry and stirred for 1 hour at 19°C. The precipitated solid is collected by filtration and washed with n-heptane (10 mL), dried under vacuum at 30°C for 5 hours. Yield: 7.6 g.

We Claim:

1. A process for the preparation of crystalline form I of agomelatine comprising:

a) providing a solution of agomelatine in a solvent selected from tetrahydrofuran, isopropyl acetate, 1,4-dioxane, chlorobenzene, chloroform to provide a solution;

b) adding an anti-solvent to the solution obtained in step a), wherein anti-solvent is selected from cyclohexane, methylcyclohexane and n-heptane;

c) optionally seeding the solution or suspension obtained in step b) with crystalline form I of agomelatine, and

d) isolating crystalline form I of agomelatine.

2. A process according to claim 1 wherein the solvent is isopropyl acetate.

3. A process according to claim 1 and 2 wherein the anti-solvent is n-heptane.

4. A process for the preparation of crystalline form I of agomelatine comprising:

a) providing a solution of agomelatine in isopropyl acetate;

b) adding n-heptane to the solution obtained in step a),

c) optionally seeding the solution or suspension obtained in step b) with crystalline form I of agomelatine, and

c) isolating crystalline Form I of agomelatine.

5. A process for the preparation of crystalline form I of agomelatine comprising:

a) providing a solution of agomelatine in dimethylsulfoxide or 1,4-dioxane;

b) adding water to the solution obtained in step a), and

c) isolating crystalline Form I of agomelatine.

6. A process for the preparation of crystalline form I of agomelatine comprising:

a) providing a solution of agomelatine in a solvent selected from tetrahydrofuran, methyl isobutyl ketone, isopropyl acetate, chloroform, or mixtures thereof;

b) adding the solution obtained in step a) to an anti-solvent selected cyclohexane, methylcyclohexane, n-heptane, and

c) isolating crystalline form I of agomelatine.

7. An amorphous solid dispersion of agomelatine together with one or more pharmaceutical acceptable carriers.

8. An amorphous solid dispersion of agomelatine of claim 7, wherein the pharmaceutical acceptable carrier is povidone.

9. A process for preparing the amorphous solid dispersion of agomelatine of any
of claims 7 and 8, comprising:

a) providing a solution of agomelatine in combination with one or more pharmaceutically acceptable carriers in a solvent or mixture of solvents;

b) removing the solvent from the solution or suspension obtained in step a), and

c) isolating amorphous solid dispersion of agomelatine together with one or more pharmaceutically acceptable carrier.

10. A solid pharmaceutical formulation comprising the amorphous solid dispersion
of agomelatine of claim 7 to 9 or crystalline form I agomelatine obtained according to
any of the claims 1 to 6 and one or more pharmaceutically acceptable carrier.