HK1178881B - New co-crystals of agomelatine, a process for their preparation and pharmaceutical compositions containing them - Google Patents

Description

new co-crystals of agomelatine, process for their preparation and pharmaceutical compositions containing them

Technical Field

The invention relates to a new co-crystal of agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide of formula (I), a preparation method thereof and a pharmaceutical composition containing the same

Background

Agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide has valuable pharmacological properties.

In fact, it has a dual property, on the one hand an agonist of the receptors of the melatoninergic system and, on the other hand, 5-HT_2CAn antagonist of the receptor. Said properties make it active in the central nervous system and more particularly in the treatment of the following diseases: major depressive disorder, seasonal affective disorder, sleep disorder, cardiovascular disease, digestive system disease, insomnia and fatigue due to jet lag, appetite disorder and obesity.

Agomelatine, its preparation and its use in therapeutics have been described in european patent specification EP 0447285.

For the pharmaceutical value of this compound, a great deal of research work has been carried out, making it possible to isolate different polymorphic forms with various advantages, in particular with regard to purity, stability, reproducibility and formulation characteristics, which allow an extended shelf life without specific conditions with regard to temperature, light, humidity or oxygen levels.

Furthermore, for any active ingredient intended for administration to humans, it is very important to be able to control its dissolution rate, so as to promote rapid diffusion or, conversely, slow diffusion.

Disclosure of Invention

The applicant has now developed new co-crystals of agomelatine which make it possible to modify the dissolution rate of the active ingredient. The co-crystals according to the invention have an accelerated or retarded dissolution compared to the commercially available form described in patent specification EP1564202 and which is under the trademark TEFLONAnd (4) marketing. Thus, these new co-crystals with altered dissolution characteristics make it possible to consider new formulations that match the desired use.

A co-crystal is a crystalline complex consisting of at least two neutral molecules bound together by non-covalent interactions in the crystal lattice. The main difference between solvates and co-crystals relates to the physical state of the pure components: if one of the components is a liquid at ambient temperature, the molecular complex is a solvate; if all components are solid at ambient temperature, the term "eutectic" is used to refer to the compound. The main differences between solvates and co-crystals are: the co-crystals are significantly more stable than the solvates. The co-crystals are characterized by the method of obtaining the co-crystals and by the ordered three-dimensional structure, for example, as represented by X-ray diffraction diagrams. It is not possible a priori (a prior) to know whether two particular components will be able to form a co-crystal having a particular three-dimensional structure or will simply result in the juxtaposition of two powders. This particular three-dimensional structure has a direct relationship to the dissolution rate of the entity formed thereby.

The invention relates more particularly to new co-crystals of agomelatine (on the one hand) and an organic acid (on the other hand). The co-crystals according to the invention contain an organic acid which is in the solid state at ambient temperature.

The organic acids according to the invention are straight-chain or branched acids having from 2 to 10 carbon atoms. They have one or more COOH acid functions, and more preferably, 1, 2 or 3 acid functions. In addition to their acid functions, they may also have one or more ketone functions, one or more hydroxyl functions and/or one or more unsaturated bonds.

Among the organic acids which are components of the co-crystals according to the invention, mention may be made, for example and without limitation, of p-hydroxybenzoic acid, citric acid, oxalic acid, gallic acid, maleic acid, malonic acid, glutaric acid, glycolic acid, ketoglutaric acid, etc.

The ratio of the organic acid used is 0.25 to 4 molar equivalents, preferably 0.5 to 2 molar equivalents, relative to agomelatine.

More specifically, the present invention relates to the following co-crystals: agomelatine/p-hydroxybenzoic acid (2/1) and (1/2); agomelatine/citric acid (1/1); agomelatine/oxalic acid (2/1); agomelatine/gallic acid (2/1); agomelatine/maleic acid (1/1); agomelatine/malonic acid (1/1); agomelatine/glutaric acid (1/1); agomelatine/glycolic acid (1/1); agomelatine/ketoglutarate (1/1).

The invention also relates to a process for obtaining a co-crystal of agomelatine and an organic acid, in which:

-mixing the two components in the desired ratio in an organic solvent (1 equivalent of agomelatine/0.25-4 molar equivalents of organic acid);

-stirring and optionally heating the resulting solution at a temperature not exceeding the boiling point of the selected solvent;

-cooling the mixture under stirring and the co-crystal either naturally precipitating or precipitating after absorption in a second solvent;

-the obtained precipitate is filtered and dried.

In the process according to the invention, the solvent used is preferably an alcohol such as methanol or tert-butanol; ethers such as isopropyl ether or methyl tertiary butyl ether; or an aromatic hydrocarbon such as toluene. When a second solvent is used to accelerate precipitation of the co-crystal, benzonitrile is advantageously selected.

An alternative method involves co-milling the two components of the co-crystal. The co-grinding is preferably done in steel cylinders (steel jar). A variant of this process comprises adding an organic solvent during milling; in this case, the resulting co-crystals are then dried. Among the solvents used, mention may be made more particularly of alcohols such as ethanol or ethers such as isopropyl ether.

Milling is conveniently accomplished using balls that are not oxidizable. The grinding is done by means of vibration, preferably having a frequency of 20-30 Hz. The vibration may be applied for a period of time of 15 minutes to 3 hours.

Another alternative method comprises: the two solutions each containing one of the components are mixed and the resulting mixture is flash frozen at a very low temperature and the co-crystals thus obtained are then dried at the same low temperature. The two components are advantageously mixed in an organic solvent or an aqueous organic solvent. The freezing and drying are preferably carried out at-40 ℃ to-60 ℃ and more preferably at-40 ℃.

Another advantageous method according to the invention comprises: the powders of agomelatine and the acid are mixed in a mixer and then extruded by twin-screw extrusion without a die to obtain directly the solid granular product at the extruder outlet. Preferably, the screw profile (profile) used is a high shear profile, optionally with the use of mixing ingredients making it possible to improve the surface contact between the two components. The L/D parameters of the screws can vary from 10 to 40 and the rotational speeds are from 10 to 200 rpm. The temperatures used vary from 40 to 100 ℃.

In the process for preparing the co-crystals according to the invention, it is possible to use the compounds of formula (I) which have been obtained by any process, in particular the process described in EP 1564202.

The co-crystals according to the invention exhibit highly valuable properties in terms of two important parameters in the pharmaceutical industry, namely stability and dissolution. Dissolution of the active ingredient is an important property that can determine the rate of absorption of the active ingredient in the human body. It is an important step in the release process, which has a significant effect on the activity of the drug. In fact, in order to pass through a biological membrane or to be absorbed, the active ingredient must be molecularly dispersed (that is, dissolved) in the aqueous medium at the absorption site. The dissolution rate of the active ingredient is determined by its physico-chemical properties and also by the condition of the absorption medium. It is therefore important to have a form that is self-dominating (one with altered dissolution of the active ingredient) that makes it possible to obtain a higher or lower rapid dissolution of the active ingredient that is compatible with the intended use: a form with enhanced dissolution for immediate release formulations and a form with slower dissolution for delayed or sustained release formulations.

The co-crystals according to the invention fulfill this requirement, since compared to current pharmaceuticalsIn the form on the market, it is capable of modifying the dissolution rate of agomelatine and accelerating or reducing its dissolution up to 2 times. More particularly, with current drugsCompared to the dissolution rates of the marketed forms, the co-crystals according to the invention make it possible to modify the dissolution rate of the active ingredient by at least 25% under neutral (pH6.8) or acidic (0.01N HCl) conditions. It is therefore feasible to use the co-crystals according to the invention for the development of an immediate release pharmaceutical form in which the dissolution rate is increased relative to the currently commercially available forms, and for the development of a sustained release form in which the dissolution rate is retarded.

Due to its activity in the central nervous system and microcirculation, the pharmaceutical forms containing the co-crystals according to the invention will be used for the treatment of stress (stress), sleep disorders, anxiety disorders and in particular generalized anxiety disorder, obsessive-compulsive disorder, mood disorders and in particular bipolar disorders, major depression, seasonal affective disorder, cardiovascular disorders, digestive disorders, insomnia and fatigue due to jetlag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, pain, psychotic disorders, epilepsy, diabetes, parkinson's disease, senile dementia, various disorders associated with normal or pathological ageing, migraine, memory loss, alzheimer's disease, and also for cerebral circulation disorders. In another active area, the co-crystals according to the invention will be able to be used for sexual dysfunction, as ovulation inhibitors and immunomodulators, and for the treatment of cancer.

The co-crystals according to the invention are preferably used for the treatment of major depressive disorder, seasonal affective disorder, sleep disorders, anxiety disorders, mood disorders, cardiovascular diseases, diseases of the digestive system, insomnia and fatigue caused by jet lag, appetite disorders and obesity.

The invention also relates to a pharmaceutical composition containing as active ingredient the co-crystals according to the invention together with one or more suitable, inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, such as tablets or dragees, granules, sublingual tablets, capsules, lozenges, suppositories, emulsions, ointments, dermal gels, injections, drinkable suspensions and chewing gums (chewinggums).

Useful dosages may be adjusted according to the nature and severity of the condition, the route of administration, and the age and weight of the patient. The dosage is 0.1 mg-1 g agomelatine per day, and the agomelatine is administrated once or more times.

Detailed Description

The following examples illustrate the invention but do not limit it in any way.

Example 1: process for preparation of agomelatine/citric acid (1/1)Eutectic crystals

Method A

3g of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide and 2.6g of citric acid were added to a 100-ml flask. 30ml of MeOH were added and the solution was stirred at ambient temperature for 20 h. After evaporation to dryness, the resulting white gum was taken up in 30ml of benzonitrile (added in 3ml portions). The resulting suspension was stirred until the conversion of the gum to crystals was complete. After filtration and washing with 20ml of benzonitrile, the solid obtained is dried at ambient temperature in vacuo. It is characterized by the melting point and the following X-ray powder diffractogram measured with a panalytical xpert Pro MPD diffractometer (copper on cathode) and expressed in interplanar spacing d, bragg angle 2 θ (expressed in ° ± 0.2) and relative intensity (expressed as a percentage with respect to the most intense line):

the bragg angle 2 θ (expressed in ° ± 0.2) of the X-ray powder diffraction pattern is characterized by: 5.21 °, 12.24 °, 17.07 °, 19.38 °, 20.69 °, 21.90 °, 22.81 °, 27.30 °.

Melting point: 126 heat-129 deg.C

Method B

316.59g agomelatine and 250g citric acid monohydrate were mixed in a Turbula type mixer for 10 minutes. The mixture was then extruded with twin-screw extrusion without a die to obtain a solid particulate product directly at the extruder outlet. A high shear screw profile is applied with the mixing ingredients to improve surface contact between the two components. The L/D parameter of the screw used was 19. For a measured feed rate of 300g/h, the rotation speed of the screw was 50 rpm. The extrusion temperature was 55 ℃. The obtained co-crystals are characterized by their X-ray powder diffraction pattern, which is identical to the pattern obtained by method a.

Example 2: eutectic of agomelatine/gallic acid (2/1)

A solution of 300.6mg of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide in 15ml of tert-butanol was slowly added to a 35ml aqueous solution of 106mg of gallic acid in a 250-ml flask. The mixture was stirred for 10 minutes, then the solution was frozen to-40 ℃ and dried at the same temperature for 2 days to give the title product, which was characterized by the melting point and the following X-ray powder diffraction pattern measured with a Panalytical Xpert Pro MPD diffractometer (copper on cathode) and expressed as interplanar spacing d, bragg angle 2 θ (expressed in ° ± 0.2) and relative intensity (expressed as a percentage relative to the strongest line):

the bragg angle 2 θ (expressed in ° ± 0.2) of the X-ray powder diffraction pattern is characterized by: 14.47 °, 17.68 °, 19.82 °, 22.33 °, 23.93 °.

Melting point: 108-110 deg.C

Example 3: eutectic of agomelatine/maleic acid (1/1)

1g N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide and 482mg maleic acid were added to a 25-ml bottle that was not oxidizable. 2 stainless steel balls of 12mm diameter were added and the bottles were closed. Applying a vibration at a frequency of 30Hz for 60 minutes gives the title product, which is characterized by the melting point and the following X-ray powder diffractogram measured with the panalytical xpert Pro MPD diffractometer (copper on cathode) and expressed in interplanar spacing d, bragg angle 2 θ (expressed in ° ± 0.2) and relative intensity (expressed as a percentage with respect to the strongest line):

the bragg angle 2 θ (expressed in ° ± 0.2) of the X-ray powder diffraction pattern is characterized by: 11.30 degrees, 15.40 degrees, 17.28 degrees and 24.29 degrees.

Melting point: 73-75 deg.C

Example 4: eutectic of agomelatine/malonic acid (1/1)

A solution of 300mg of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide in 15ml of tert-butanol was slowly added to 35ml of an aqueous solution of 129mg of malonic acid placed in a 250-ml flask. The mixture was stirred for 30 minutes, then the solution was frozen to-40 ℃ and dried at the same temperature for 2 days to give the title product, which was characterized by the melting point and the following X-ray powder diffraction pattern measured with a Panalytical Xpert Pro MPD diffractometer (copper on cathode) and expressed as interplanar spacing d, bragg angle 2 θ (expressed in ° ± 0.2) and relative intensity (expressed as a percentage relative to the strongest line):

the bragg angle 2 θ (expressed in ° ± 0.2) of the X-ray powder diffraction pattern is characterized by: 10.47 °, 11.95 °, 14.78 °, 16.05 °, 22.32 °, 24.50 °, 25.05 °, 25.24 °, 27.38 °, 27.91 °.

Melting point: 67-68 deg.C

Example 5: co-crystals of agomelatine/p-hydroxybenzoic acid (2/1)

1g N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide and 283.8mg p-hydroxybenzoic acid were added to a 25-ml bottle, which was not oxidized. 2 stainless steel balls of 12mm diameter were added and the bottles were closed. 200 μ l of isopropyl ether was added. Vibration at a frequency of 30Hz was applied for 60 minutes to give the title product, which was characterized by the melting point and the following X-ray powder diffractogram measured with a Panalytical Xpert Pro MPD diffractometer (copper on cathode) and expressed in interplanar spacing d, bragg angle 2 θ (expressed in ° ± 0.2) and relative intensity (expressed as a percentage relative to the strongest line):

the bragg angle 2 θ (expressed in ° ± 0.2) of the X-ray powder diffraction pattern is characterized by: 13.16 °, 14.91 °, 17.37 °, 18.39 °, 18.93 °, 19.04 °, 19.65 °, 19.96 °, 20.25 °, 21.49 °, 25.00 °.

Melting point: 93-95 deg.C

Example 6: co-crystals of agomelatine/p-hydroxybenzoic acid (1/2)

1g N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide and 1.14g p-hydroxybenzoic acid and 250. mu.l isopropyl ether were added to a 25-ml bottle which was not oxidized. 2 stainless steel balls of 12mm diameter were added and the bottles were closed. Applying a vibration at a frequency of 30Hz for 120 minutes gives the title product, which is characterized by the melting point and the following X-ray powder diffractogram measured with the Panalytical XPert Pro MPD diffractometer (copper on cathode) and expressed in interplanar spacing d, Bragg angle 2 θ (expressed in ° + -0.2) and relative intensity (expressed as a percentage relative to the strongest line):

the bragg angle 2 θ (expressed in ° ± 0.2) of the X-ray powder diffraction pattern is characterized by: 9.50 °, 12.28 °, 14.00 °, 15.76 °, 16.18 °, 16.62 °, 17.56 °, 18.15 °, 19.96 °, 21.00 °, 21.30 °, 22.00 °, 22.97 °, 23.55 °, 23.76 °, 24.44 °, 26.09 °, 26.82 °, 28.42 °, 28.71 °, 29.85 °.

Melting point: 116 ℃ C. and 118 ℃ C

Example 7: eutectic of agomelatine/oxalic acid (2/1)

1g of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide and 185.5mg of oxalic acid were added to a 25-ml bottle which was not oxidized. 2 stainless steel balls of 12mm diameter were added and the bottles were closed. Applying a vibration at a frequency of 30Hz for 15 minutes gives the title product, which is characterized by the melting point and the following X-ray powder diffractogram measured with the panalytical xpert Pro MPD diffractometer (copper on cathode) and expressed in interplanar spacing d, bragg angle 2 θ (expressed in ° ± 0.2) and relative intensity (expressed as a percentage with respect to the strongest line):

the bragg angle 2 θ (expressed in ° ± 0.2) of the X-ray powder diffraction pattern is characterized by: 12.48 °, 13.80 °, 14.02 °, 14.22 °, 15.30 °, 15.43 °, 17.61 °, 17.82 °, 19.64 °, 19.77 °, 21.53 °, 21.72 °, 21.79 °, 21.97 °, 24.95 °, 25.39 °, 27.36 °, 27.47 °, 29.29 °, 29.77 °.

Melting point: 112.5-114.5 deg.C

Example 8: eutectic of agomelatine/glutaric acid (1/1)

1g N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide and 555mg glutaric acid were added to a 25-ml bottle which was not oxidizable. 2 stainless steel balls of 12mm diameter were added and the bottles were closed. Applying a vibration at a frequency of 30Hz for 60 minutes gives the title product, which is characterized by the melting point and the following X-ray powder diffractogram measured with the Panalytical XPert Pro MPD diffractometer (copper on cathode) and expressed in interplanar spacing d, Bragg angle 2 θ (expressed in ° + -0.2) and relative intensity (expressed as a percentage relative to the strongest line):

the bragg angle 2 θ (expressed in ° ± 0.2) of the X-ray powder diffraction pattern is characterized by: 9.59 °, 10.35 °, 11.96 °, 20.57 °, 21.65 °, 23.34 °.

Melting point: 74-75 deg.C

Example 9: eutectic of agomelatine/ketoglutarate (1/1)

1g N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide and 600mg ketoglutaric acid and 500. mu.l ethanol were added to a 25-ml unoxidizable bottle. 2 stainless steel balls of 12mm diameter were added and the bottles were closed. After drying overnight at 40 ℃ with application of vibration at a frequency of 30Hz for 15 minutes, the title product is obtained, which is characterized by the melting point and the following X-ray powder diffractogram measured with a Panalytical Xpert Pro MPD diffractometer (copper on cathode) and expressed as interplanar spacing d, bragg angle 2 θ (expressed in ° ± 0.2) and relative intensity (expressed as a percentage with respect to the strongest line):

the bragg angle 2 θ (expressed in ° ± 0.2) of the X-ray powder diffraction pattern is characterized by: 15.36 °, 16.34 °, 16.54 °, 19.24 °, 23.57 °, 23.90 °, 24.41 °.

Melting point: 94-96 deg.C

Example 10: eutectic of agomelatine/glycolic acid (1/1)

1g N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide and 319mg glycolic acid were added to a 25-ml bottle that was not oxidizable. 2 stainless steel balls of 12mm diameter were added and the bottles were closed. After drying overnight at 40 ℃ with application of vibration at a frequency of 30Hz for 15 minutes, the title product is obtained, which is characterized by the melting point and the following X-ray powder diffractogram measured with a Panalytical Xpert Pro MPD diffractometer (copper on cathode) and expressed as interplanar spacing d, bragg angle 2 θ (expressed in ° ± 0.2) and relative intensity (expressed as a percentage with respect to the strongest line):

the bragg angle 2 θ (expressed in ° ± 0.2) of the X-ray powder diffraction pattern is characterized by: 10.29 °, 14.11 °, 14.23 °, 17.98 °, 18.83 °, 19.51 °, 20.61 °, 23.96 °, 24.39 °, 26.44 °, 28.11 °, 29.52 °.

Melting point: 75-77 ℃.

Example 11: measurement of dissolution of cocrystal

Dissolution measurements of the obtained co-crystals were done with the aid of a microdis analyzer (pION) in acidic and neutral medium at 37 ℃ with a stirring speed of 700 rpm. The results obtained are collated in the following table and are indicated as being on the marketThe percentage increase in dissolution of the co-crystal compared to the dissolution obtained with agomelatine form II contained in the form:

	0.01N HCl	buffer pH6.8
			Compound of example 1	+25%	+70%
Compound of example 2	+37%	+29%
			Compound of example 5	+97%	+89%
Compound of example 6	+19%	+46%
			Compound of example 7	+1.5%	+33%

The results obtained show an increase in dissolution of the co-crystals of 33% to 97% under at least one of the two conditions tested (acidic or neutral).

	0.01N HCl	Buffer pH6.8
			Compound of example 3	-26%	-4%
Compound of example 4	-55%	-21%
			Compound of example 8	-42%	-29%
Compound of example 9	-47%	-32%
			Compound of example 10	-30%	-30%

The results obtained show a reduction in dissolution of the co-crystals of 26% to 55% under at least one of the two conditions tested (acidic or neutral).

Example 12: accelerated release pharmaceutical composition

Formulation for the preparation of 1000 tablets containing 25mg agomelatine per tablet:

example 13: delayed release pharmaceutical composition

Formulation for preparing 1000 tablets containing 25mg of active ingredient per tablet:

Claims (8)

1. Co-crystal of agomelatine, characterized in that it consists of agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide of formula (I)

And an organic acid in a solid state at ambient temperature, wherein the co-crystal is selected from:

n- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide/p-hydroxybenzoic acid, wherein the molar ratio of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide to p-hydroxybenzoic acid is 2/1, and has the following Bragg angle 2 θ in the X-ray powder diffraction pattern, expressed as ° ± 0.2: 13.16 °, 14.91 °, 17.37 °, 18.39 °, 18.93 °, 19.04 °, 19.65 °, 19.96 °, 20.25 °, 21.49 °, 25.00 °;

n- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide/p-hydroxybenzoic acid, wherein the molar ratio of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide to p-hydroxybenzoic acid is 1/2, and has the following Bragg angle 2 θ in the X-ray powder diffraction pattern, expressed as ° ± 0.2: 9.50 °, 12.28 °, 14.00 °, 15.76 °, 16.18 °, 16.62 °, 17.56 °, 18.15 °, 19.96 °, 21.00 °, 21.30 °, 22.00 °, 22.97 °, 23.55 °, 23.76 °, 24.44 °, 26.09 °, 26.82 °, 28.42 °, 28.71 °, 29.85 °;

n- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide/citric acid, wherein the molar ratio of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide to citric acid is 1/1, having the following Bragg angle 2 θ in the X-ray powder diffraction pattern, expressed in ° ± 0.2: 5.21 °, 12.24 °, 17.07 °, 19.38 °, 20.69 °, 21.90 °, 22.81 °, 27.30 °;

n- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide/oxalic acid, wherein the molar ratio of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide to oxalic acid is 2/1, having the following Bragg angle 2 θ in the X-ray powder diffraction pattern, expressed as ° ± 0.2: 12.48 °, 13.80 °, 14.02 °, 14.22 °, 15.30 °, 15.43 °, 17.61 °, 17.82 °, 19.64 °, 19.77 °, 21.53 °, 21.72 °, 21.79 °, 21.97 °, 24.95 °, 25.39 °, 27.36 °, 27.47 °, 29.29 °, 29.77 °;

n- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide/gallic acid, wherein the molar ratio of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide to gallic acid is 2/1, having the following Bragg angle 2 θ in the X-ray powder diffraction pattern, expressed in ° ± 0.2: 14.47 °, 17.68 °, 19.82 °, 22.33 °, 23.93 °;

n- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide/maleic acid, wherein the molar ratio of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide to maleic acid is 1/1, having the following Bragg angle 2 θ in the X-ray powder diffraction pattern, expressed in ° ± 0.2: 11.30 °, 15.40 °, 17.28 °, 24.29 °;

n- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide/malonic acid, wherein the molar ratio of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide to malonic acid is 1/1, having the following Bragg angle 2 θ in the X-ray powder diffraction pattern, expressed in ° ± 0.2: 10.47 °, 11.95 °, 14.78 °, 16.05 °, 22.32 °, 24.50 °, 25.05 °, 25.24 °, 27.38 °, 27.91 °;

n- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide/glutaric acid wherein the molar ratio of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide to glutaric acid is 1/1, having the following Bragg angle 2 θ in the X-ray powder diffraction pattern, expressed in ° ± 0.2: 9.59 °, 10.35 °, 11.96 °, 20.57 °, 21.65 °, 23.34 °;

n- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide/glycolic acid, wherein the molar ratio of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide to glycolic acid is 1/1, having the following Bragg angle 2 θ in the X-ray powder diffraction pattern, expressed in ° ± 0.2: 10.29 °, 14.11 °, 14.23 °, 17.98 °, 18.83 °, 19.51 °, 20.61 °, 23.96 °, 24.39 °, 26.44 °, 28.11 °, 29.52 °; and

n- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide/ketoglutaric acid, wherein the molar ratio of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide to ketoglutaric acid is 1/1, having the following Bragg angle 2 θ in the X-ray powder diffraction pattern, expressed in ° ± 0.2: 15.36 °, 16.34 °, 16.54 °, 19.24 °, 23.57 °, 23.90 °, 24.41 °.

2. A pharmaceutical composition comprising the co-crystal according to claim 1 as an active ingredient, together with one or more pharmaceutically acceptable, inert, non-toxic carriers.

3. Use of a pharmaceutical composition according to claim 2 for the manufacture of a medicament for the treatment of disorders of the melatoninergic system.

4. Use of a pharmaceutical composition according to claim 2 for the preparation of a medicament for the treatment of stress, sleep disorders, anxiety obsessive compulsive disorders, mood disorders, major depression, seasonal affective disorders, cardiovascular disease, digestive system diseases, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, pain, psychotic disorders, epilepsy, diabetes, parkinson's disease, senile dementia, various disorders associated with normal or pathological ageing, migraine, memory loss, alzheimer's disease, cerebral circulation disorders and sexual dysfunction, and as ovulation inhibitors and immunomodulators and in the treatment of cancer.

5. Use of a pharmaceutical composition according to claim 2 for the preparation of a medicament for the treatment of insomnia and fatigue caused by generalized anxiety disorder, bipolar disorder or jet lag.

6. Use of the co-crystal according to claim 1 for the preparation of a medicament for the treatment of disorders of the melatoninergic system.

7. Use of the co-crystal of claim 1 in the manufacture of a medicament for the treatment of stress, sleep disorders, anxiety disorders, obsessive-compulsive disorders, mood disorders, major depression, seasonal affective disorders, cardiovascular disease, digestive system disease, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, pain, psychotic disorders, epilepsy, diabetes, parkinson's disease, senile dementia, various disorders associated with normal or pathological ageing, migraine, memory loss, alzheimer's disease, cerebral circulation disorders, and also for sexual dysfunction and as ovulation inhibitors and immunomodulators, and for the treatment of cancer.

8. Use of the co-crystal of claim 1 in the manufacture of a medicament for the treatment of insomnia and fatigue caused by generalized anxiety disorder, bipolar disorder or jet lag.