WO2012097764A1

WO2012097764A1 - Metastable crystal forms of agomelatine

Info

Publication number: WO2012097764A1
Application number: PCT/CZ2012/000007
Authority: WO
Inventors: Jindrich Richter; Ludek Ridvan; Jaroslav Rezac; Ondrej Dammer
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2011-01-21
Filing date: 2012-01-17
Publication date: 2012-07-26
Anticipated expiration: 2013-07-21
Also published as: CZ201132A3; CZ303787B6

Abstract

The invention provides a method for the preparation of chemically and polymorphously stable composition of agomelatine, based on a metastable form of agomelatine represented by the chemical formula (1), as well as a reproducible method of preparation of the known metastable form 1 of agomelatine. Other aspects of the invention comprise new metastable crystal forms JR 1, JR2, JR3 and JR4 of agomelatine and their use in a polymorphously stable pharmaceutical composition.

Description

Metastable crystal forms of agomelatine Technical Field The invention relates to metastable crystal forms of agomelatine, which can be used for obtaining polymorphously and chemically stable pharmaceutical compositions and for preparing pharmaceutical formulations containing said composition, and methods of their preparation. Background Art

Agomelatine, N-[2-(7-methoxy- l -naphthyl)ethyl]acetamide represented by the chemical formula (I),

(I) has valuable pharmacological properties. Agomelatine is the first melatonergic antidepressant. It is an agonist of MT2 and MT] receptors and a 5-HT2_C antagonist.

Preparation of agomelatine and its use were described in EP 447285.

Several polymorphous forms of agomelatine are known. The crystalline structure of one of the polymorphous forms of agomelatine, later referred to as Polymorph I, was described in Acta Cryst., C: Crystal Struct. Commun. 50, 907 (1994) without a mention of the method the studied monocrystal was prepared with. It cannot be ruled out that obtaining one crystal of the polymorphously pure form I was an isolated result that the authors of the above mentioned publication have not later managed to reproduce any more. To the best of our knowledge no preparation method of agomelatine in the form I has been published by any other authors either. Polymorph II has been described in the literature by means of a diffraction pattern obtained by the more usual X-ray powder diffraction method (XRPD), and is mentioned in, e.g., EP 1564202. Polymorph III has been described in US 2006270876, polymorph IV in US 2006270875, polymorph V in US2006270877 and polymorph VI in US 2009069434.

It is known that thermodynamically less stable (metastable) polymorphs can, in case they can be successfully obtained in the pure form in a reproducible manner, under the conditions of use not undergoing change into other more stable forms, be more convenient for a certain technological application from the point of view of their properties than their most stable forms. Diamond, which is a thermodynamically less stable form of carbon than the much more readily available graphite, is probably the best known example.

In the preparation of solid dosage forms a metastable polymorph may be more convenient than the thermodynamically stable form, e.g. in cases where the stable form exhibits lower solubility than required for the given use. Metastable forms usually offer higher solubility as well as dissolution speed, but at the same time it is much more difficult with them than with the thermodynamically stable form to meet the demanding requirements posed on all active ingredients for pharmaceutical use concerning their purity and stability. In fact, according to the principles of the good manufacturing practice, the observance of which is inspected by authorities that decide on the approval of drugs for human or veterinary use in various countries, it is necessary not only to obtain the active substance in the specified chemical purity in a reproducible and reliable way during its production, but also to maintain said specified purity as well as stable polymorphous composition of the active substance during the whole shelf life of any pharmaceutical formulation containing said substance. Thus, compared to the development of a formulation based on the stable form, the development of therapeutic formulations containing the active substance in a metastable crystalline modification is accompanied by an increased risk of failure, associated with the danger of polymorphous instability of the active substance, i.e. of transformation of the metastable modification into another, more stable solid form, which would result in, e.g., non- reproducible bioavailability of the active substance. Moreover, the metastable polymorphous form often turns out to also be chemically less stable in stability tests, as compared to the most stable crystalline modification. Such behaviour is often observed especially in amorphous modifications.

No stable solid composition of agomelatine containing another crystal form than Form II has been described so far.

Nor has it been described for agomelatine whether, besides Form II, any other form can be obtained in a sufficiently stable form for pharmaceutical use. The authors of the present invention have succeeded in solving the problem of obtaining a stable composition containing a metastable form of agomelatine by formulating this composition with the use of Form I obtained by a new method, or by using a new procedure of preparing an agomelatine composition producing new crystal forms of agomelatine.

Disclosure of Invention The present invention consists in preparing solid metastable crystal forms of agomelatine, which can be used for obtaining a polymorphously stable solid pharmaceutical composition of agomelatine, comprising a metastable solid form of agomelatine, or comprising a mixture of more such metastable forms, and a pharmaceutical formulation containing said pharmaceutical composition. It is understood, under a polymorphously stable composition or dosage form, such a composition or dosage form, in which, during its shelf life, no change of its polymorphous composition, i.e. no transformation of agomelatine into other polymorphous forms than those that were present at the time of release of the drug for sale, nor any change of the quantitative representation of the individual solid forms, occurs. The present invention further provides new crystal forms JRl , JR2, JR3 and JR4 of agomelatine and a method of preparing polymorphously stable metastable crystal forms of agomelatine, especially of crystal form I of agomelatine, characterized by typical reflections in the X-ray powder diffraction pattern presented in Table 1. Table 1 : Typical reflections of the X-ray powder diffraction pattern of Polymorph I of agomelatine in accordance with the invention

Another aspect of the invention provides a method of preparing crystal form I of agomelatine with the chemical and polymorphous purities and stability allowing obtaining of a polymorphousiy stable composition of agomelatine based on Form I and a method of preparing a polymorphousiy stable solid dosage form of agomelatine in accordance with the invention, based on a metastable solid form or a mixture of metastable solid forms of agomelatine.

Detailed description of the invention

When analyzing the possibilities of obtaining a polymorphousiy stable pharmaceutical composition of agomelatine in which substance would be contained in a metastable solid form, the authors of this invention first focused their attention on obtaining a polymorphousiy 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 polymorphous modifications of agomelatine.

In spite of this, we have finally succeeded in finding two ways how to prevent crystallization of other forms of agomelatine and achieve reproducible production of pure Polymorph I. The first one consists in slow cooling of a hot saturated solution of agomelatine in a suitable solvent under elimination of stirring or the presence of other shocks or vibrations of the whole crystallization apparatus. A hot solution is meant to include a solution at a temperature of at least 60°C. Crystallization of Form I from the obtained supersaturated solution occurs spontaneously or by seeding with Form I after cooling of the solution. Suitable solvents for this embodiment of the invention include aromatic hydrocarbons with six to ten carbon atoms and their mixtures, e.g. toluene, ethyl benzene, cumene, tetralin or xylenes. Toluene is an especially preferable solvent for this embodiment. Spontaneous cooling of the hot solution is an advantageous way of slow cooling.

The second variant of the method according to the invention involves a very quick reduction of solubility of agomelatine, caused by a quick decreasing of the temperature of the solution of agomelatine in the first solvent accompanied, by a further reduction of solubility of agomelatine due to mixing of the first solvent with a worse solvent, i.e. "precipitant". The first solvent of agomelatine refers to a solvent in which solubility of agomelatine of at least 1 kg per 10 L of the solvent can be achieved at temperatures above 50°C; the worse solvent meaning a solvent in which solubility of agomelatine at temperatures lower than 30°C is less than 1 kg per 100 L of the solvent.

Examples of the first solvents of agomelatine suitable for this variant of the method of the invention include aromatic hydrocarbons with six to ten carbon atoms or their mixtures, e.g. toluene, ethyl benzene, cumene, tetralin or xylenes; aliphatic or cyclic esters with three to seven carbon atoms, e.g. methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, ethyl propionate, γ-butyrolactone, δ-valerolactone, ethylene carbonate or propylene carbonate; aliphatic, alicyclic or aliphatic-aromatic ketones with three to nine carbon atoms, e.g. acetone, butanone, methyl isobutyl ketone, cyclohexanone or acetophenone; aliphatic one- to five-carbon alcohols, e.g. methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, 2-methyl- l -propanol, 2-methyl-2-propanol or amyl alcohols; cyclic ethers or acetals with three to six carbon atoms such as tetrahydrofuran, methyl tetrahydrofuran, dioxolane or dioxane; aliphatic or cycloaliphatic C3-C 10 ether-alcohols such as 2-methoxyethanol, diethylene glycol, triethylene glycol or tetrahydrofurfuryl alcohol and their methyl or ethyl ethers and acetates; polyethylene glycol with a relative molecular weight up to 6000, halogen derivatives with two to seven carbon atoms and one to three halogen atoms such as 1 ,2-dichloroethane, 1 , 1 , 1 -trichloroethane or chlorobenzene; nitriles with two to seven carbon atoms such as acetonitrile, propionitrile, butyronitrile, adipodinitrile, succinodinitrile or benzonitrile; nitro compounds with one to six carbon atoms such as nitromethane, nitroethane, nitropropane or nitrobenzene; five- or six-membered heterocycles with three to seven carbon atoms and one or two heteroatoms out of which at least one is nitrogen and the other heteroatom may be an atom of nitrogen, oxygen or sulphur, such as pyridine and pyridine bases, morpholine, N-methyl morpholine or Ν,Ν-dimethyl propylene urea (DMPU); and dipolar aprotic solvents such as aliphatic or cyclic one to five-carbon acid amides, sulfoxides and sulfones, e.g. dimethyl sulfoxide, dimethyl sulfone, sulfolane, tetramethylurea, formamide, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone. Examples of the other solvents ("precipitants") for agomelatine include water, C3-C25 liquid aliphatic and alicyclic hydrocarbons and their mixtures, such as e.g. pentane, hexane, heptane, cyclohexane, methyl cyclohexane, decaline, petrol or petroleum ether, C4-C 10 aliphatic ethers with one oxygen atom as diethyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether or dibutyl ether.

In the second variant of the procedure for preparation of polymorphously pure Form I according to the invention it is required that, at the resulting crystallization temperature, the first and the other solvent mutually form a homogeneous mixture in at least such a proportion of both constituents in which they are used in carrying out the method of preparation of Polymorph I according to the invention. If a polar solvent miscible with water in a broad range of composition is used as the first solvent, e.g. a lower aliphatic alcohol, an ether alcohol or ketone, water can conveniently be used as the precipitant. On the other hand, if an aromatic hydrocarbon is used to dissolve agomelatine, it is preferable to use a precipitant selected from the group consisting of aliphatic and alicyclic hydrocarbons and mixtures thereof or from the group consisting of aliphatic ethers, or a mixed precipitant constituted by a mixture of two precipitants selected from the above-mentioned groups to achieve a sufficiently fast reduction of solubility leading to the production of polymorphously pure Form I. It is convenient if the solution of agomelatine in the first solution is prepared at a temperature exceeding 60°C and sprayed into the precipitant at this temperature is such a way that the temperature of the crystallization mixture during the precipitation never exceeds 25°C, more preferably in such a way that the temperature during the crystallization do not exceed 5°C. A suitable crystallization regime may be set and controlled by the amount and pre-cooling temperature of the precipitant, intensity of the cooling and stirring during the crystallization as well as the concentration, temperature and rate of addition of the solution of agomelatine.

In case of using solvent - precipitant pairs with such a different polarity that both the solvents are not miscible in any proportion, such as the pairs methanol - heptane, dimethyl sulfoxide - hexane, acetonitrile - heptane, dimethyl formamide - cyclohexane, crystallizations were observed even at such proportion of both the constituents of the pair that by itself (without another dissolved constituent such as agomelatine) provides a homogeneous mixture in the result, where instead of form I a new metastable form JR4 was produced. Decreasing the temperature difference of the precipitating and precipitated solution in carrying out the method according to the invention also supports formation of other metastable forms of agomelatine than Form I. Thus, to prepare polymorphously pure Form I it may be convenient to use the precipitant cooled down to the solidification point or even overcooled below the solidification point, or in the form of a heterogeneous mixture containing crystals of the precipitant in equilibrium with the liquid phase. Especially where water is used as the precipitant, the use of a mixture of water and ice represents a preferable embodiment for preparation of polymorphously pure Form I. An especially advantageous embodiment of this method is represented by the use of finely crushed ice or artificially prepared ice in a fine crystal form.

Measurement of X-ray powder diffraction of samples of agomelatine of Form I obtained by means of both the variants of the method according to the invention provided data mentioned above in Table 1 .

A comparison of the X-ray powder diffraction patterns of the samples of agomelatine of Form I to that calculated from the data in Acta Cryst., C: Crystal Struct. Commun. 50, 907 (1994) has demonstrated that the method of preparation according to the invention provides agomelatine in the same crystal form as that described in the above mentioned publication. ·

It has been found out in the subsequent study of properties of the prepared samples of polymorphously pure agomelatine in crystal form I that the rate of transformation into the stable modification 11 strongly depended both on the method the sample was prepared with and the conditions it was then exposed to.

For example, it has been found out that after several hours' heating of a dry sample a measurable amount of Form II is produced in pure Form I already at temperatures above 60°C and formation of a measurable amount of Form II was observed also at temperatures around 20°C if Form I was kept in a wet state. For example, several per cent of Form II were produced already in a few hours by stirring of crystals of Form I in water. It has been found out that the rate of transformation of Form I into Form II is influenced not only by the contact of the crystal with the solvent in the liquid state, but, in the case of water, also by the residual humidity occluded in the prepared crystalline substance. In a sample of polymorphously pure Form I with the residual humidity of 0.42% by weight, kept in a closed container at the laboratory temperature, more than 5% of Form II were found after two months, while no Form II was detected at a humidity below 0.1 % by weight even after four months of storage. Thus, the conclusion can be drawn that crystallization of Form I free of traces of Form II has to be carried out at temperatures below 60°C; however, depending on the particular embodiment it may be necessary to perform follow-up operations or the entire procedure at lower temperatures to ensure long-term polymorphous stability. As regards chemical purity of the prepared samples of agomelatine in crystalline modification I, it also significantly depends on the selected variant of the method of crystallization. It has been found out that crystallization from the solvents that enable either the first variant of embodiment by slow cooling of a hot solution (aromatic hydrocarbons), or the second variant in the form of fast mixing of a solution of agomelatine in the first solvent with a low-polarity precipitant (examples of the first solvents and low-polarity precipitants - see above), preferably in the form of spraying of a hot solution of agomelatine into a cold precipitant, provides a product of high chemical purity, measured by the method of High-Performance Liquid Chromatography (HPLC), which, however, even after long-term drying in vacuum at temperatures up to 60°C, still contained such high amounts of the used organic solvents that it did not meet the limits set forth by the International Conference for Harmonization (ICH) or by various pharmacopeiae for the content of volatile organic substance in active pharmaceutical ingredients. This means that this method of crystallization of Form I of agomelatine may serve as a convenient method of purification of agomelatine from organic impurities determinable by the HPLC method, but is not generally suitable as the final step of manufacture of a pharmaceutically active substance intended for us ein the production of therapeutic formulations. On the other hand the variant of the method according to the invention, using crystallization of Form I of agomelatine by quick mixing of a solution of agomelatine in the first solvent with water, has generally proved to be less efficient in reducing the content of organic impurities. However, after drying by common methods at temperatures below 60°C this method provides agomelatine with a low content of residual solvents, fully complying with ICH regulations. This variant of crystallization can especially conveniently be used as the final purification step providing, optionally in combination with preceding crystallization of Form I from a nonaqueous environment, agomelatine in crystal form I complying with all the above-mentioned requirements for an active pharmaceutical ingredient. At the same time it has been surprisingly shown that in spite of presence of water in the crystallization environment it is possible to obtain polymorphously pure Form I by means of a common drying procedure at temperatures below 60°C even in case of a product obtained by crystallization from aqueous mixtures, and that if this product is dried to a content of water lower than 0.1 % by weight, it remains polymorphously stable even in the long term.

Agomelatine in long-term polymorphously stable Form I, obtained by the method according to the invention was subsequently used for the preparation of pharmaceutical compositions, which were tested for polymorphous and chemical stability. Besides, other possibilities of preparation of compositions containing metastable solid forms of agomelatine were examined and their stability was tested in parallel with the compositions based on pure Form I. It has been surprisingly found out that polymorphously stable compositions containing metastable forms of agomelatine can also be prepared on the basis of some other, new metastable forms of agomelatine or their mixtures with Form I. In the crystallization experiments with agomelatine it has been possible to obtain and characterize several new metastable forms of agomelatine. Form JR1 , characterized by typical XRPD reflections presented in Table 2, was obtained by re-fusing agomelatine in boiling water and slow cooling of the resulting emulsion. Quick cooling provided Form JR2 in a similar way. Form JR3 was obtained by crystallization from aqueous acetic acid while crystallization from anhydrous acetic acid provided a mixture of Forms I and JR1 .

Table 2: Typical reflections of X-ray power pattern of Form JR1 of agomelatine

A composition according to the invention, based on a metastable crystal form of agomelatine, can be obtained by methods that limit or rule out the use of solvents and of temperatures of the processed material above 60°C. Suitable methods include direct compression and processes using dry granulation, e.g. compaction. Direct compression means a manufacturing method in which agomelatine, prepared in a polymorphously metastable crystal form or as a polymorphous mixture of metastable crystal forms, is homogenized with at least one solid excipient in one or several production steps and the resulting mixture is used for the production of tablets. Compaction means a production method in which agomelatine produced in a polymorphously metastable crystal form or as a polymorphous mixture of metastable crystal forms is homogenized with at least one solid excipient in one or more manufacturing steps and_. subsequently a strip of compact mass is produced by the action of pressure in a compactor, which is then ground in a sieving device to a defined particle size determined by the sieve mesh. The resulting granulate can either be used for the production of solid dosage forms, e.g. tablets, capsules or sachets, either directly or after admixing of one or more excipients. Tablets are a preferred dosage form.

A composition based on a polymorphously stable mixture of metastable crystal forms of agomelatine can also be prepared in such a way that a mixture of metastable crystal forms with at least one solid excipient is produced directly during the process of preparation of the composition. This could be achieved e.g. by quick drying of a solution of agomelatine dissolved together with a soluble polymeric excipient in an organic solvent in the presence of at least one solid excipient insoluble in the given solvent. Other excipients can be optimally added to the obtained solid mixture and preparation of the final form may be carried out, e.g. tabletting, filling of capsules, coating of tablets, and the like. A composition in the form of tablets can be prepared, e.g., by spraying of an ethanolic solution of agomelatine and povidone onto a mixture of lactose, microcrystalline cellulose and crospovidone in a process of fluid granulation, drying of the granulate, addition of other excipients in the dry state and tabletting.

It has been surprisingly found out that even if the excipients used, e.g. cellulose or lactose, are not completely anhydrous, they can be used for preparing polymorphously stable compositions of agomelatine, whether based on the polymorphously pure form prepared in advance, or on a mixture of metastable forms produced directly in the process of preparation of the solid dosage form. Use of water in the final operations of preparation of the dosage form, as e.g. coating of tablets, too, is not completely excluded. It has been found out that stability of the composition is also influenced, especially at higher values of relative air humidity (above 60%) and at temperatures above 25°C, by the methods of packing and storage used. The selection of a suitable packing method can help to maintain polymorphous stability of the composition according to the invention even under inconvenient conditions, such as distribution in countries with wet and hot climate. It may be preferable for polymorphous stability of the prepared composition to use a material that prevents access of air humidity for the production of a pharmaceutical formulation containing the composition according to the invention, or to pack the drug in an environment of dry air or an inert gas. These measures may be further combines with the use of a dessicant. A preferable embodiment of such a pharmaceutical formulation containing the composition according to the invention in the form of, e.g., tablets or capsules is represented by, e.g., a blister pack made of aluminium foil or a glass vial with a plastic cap that contains a suitable desiccant, absorbing moisture diffusing inside through the cap or during opening of the vial.

Brief Description of Drawings

Fig. 1 : X-ray powder diffraction pattern of crystal form JR1 of agomelatine.

Fig. 2 : Comparison of X-ray powder diffraction patterns of crystal forms JR4, JR2, 1, II and JR 1

Fig. 3 : X-ray powder diffraction pattern of crystal form JR3 of agomelatine.

Measurement conditions: X^'PERT PRO MPD PANalytical diffractometer with a graphite monochromator, radiation used CuKa (λ= 0.1542 nm ( 1 .542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40^° 2Θ, increment: 0.01 ° 20, the measurement was carried out with a flat sample with the area/thickness of 10/0.5 mm. For setting of the primary optics programmable divergence slits with the irradiated sample area of 10 mm, 0.02 rad Soller slits and a ¼° anti-dispersion slit were used. For setting of the secondary optics the X 'Celerator detector with the maximum opening of the detection slit, 0.02 rad Soller slits and a 5.0 anti-dispersion slit were used.

The invention is supported by means of the following examples. These working examples are only illustrative and do not limit the scope of the invention in any way. Working Examples Example 1

Preparation of Polymorph I

Agomelatine (1 g; 4 mmol) was dissolved in hot toluene ( 12 ml). The resulting clear solution was concentrated by distilling off 2/3 of toluene and freely cooled down to the laboratory temperature during 2 hours. The precipitatated crystalline product was isolated by filtration and dried in vacuo at 30°C and at a pressure below 4 kPa for 7 days. Agomelatine in crystal form 1 was obtained in the yield of 0.45 g (45%) with the chemical purity of 99.9% (HPLC) and the content of residual toluene of 1 500 ppm.

Example 2

Preparation of Polymorph I

Agomelatine (25 g; 0. 1 mol) was dissolved in hot toluene (125 ml). The resulting clear solution was concentrated by distilling off 1 /2 of toluene and freely cooled to the laboratory temperature. Then, the solution was poured into diisopropyl ether (250 ml) cooled to -6°C.

The mixture was stirred for 1 h and then the precipitated product was isolated by filtration.

The product was dried in vacuo at the temperature of 50°C and a pressure below 4 kPa for 7 days. Agomelatine in crystal form 1 was obtained in the yield of 22.8 g (91 %) with the chemical purity of 1 00% (HPLC) and the content of residual toluene of 1 500 ppm and residual diisopropyl ether of 1070 ppm.

Example 3

Preparation of Polymorph I

Agomelatine (0.25 g; 10 mol) was thawed in polyethylene glycol (PEG 600; 0.5 g) at the temperature of 1 00°C. The resulting fusion was cooled down to 0°C. The solidified mass was stirred up in water (5 ml). The pecipitated product was isolated by filtration. The product was dried freely for 7 days. Agomelatine in crystal form 1 was obtained in the yield of 0.1 g (45%) with the chemical purity of 99.8% (HPLC) and high content of PEG 600. Example 4

Preparation of Polymorph I

Agomelatine (0.5 g; 10 mol) was thawed in polyethylene glycol (PEG 1 500; 0.5 g) at the temperature of 100°C. Cold water ( 1 0 ml) was poured into the resulting fusion. The precipitated product was isolated by filtration. The product was dried freely for 7 days. Agomelatine in crystal form I was obtained in the yield of 0.21 g (84%) with the chemical purity of 99.7% (HPLC) and high content of PEG 1 500 (determined by the method of nuclear magnetic resonance (NMR)). Example 5

Preparation of Polymorph I

Agomelatine (362 g; 1 .5 mmol) was dissolved in methanol ( 1 100 ml) at a temperature of about 50°C. The resulting clear solution was cooled to the laboratory temperature and added to a vigorously stirred mixture of water ( 1 850 ml) and ice ( 1 850 g) during 30 minutes. The resulting thick white suspension was stirred for another 30 minutes. The precipitated crystalline product was isolated by filtration and dried freely at the laboratory temperature for 7 days. Agomelatine in crystal form I was obtained in the yield of 349.3 g (96.5%) with the chemical purity of 1 00% (HPLC) and water content of 0.07% and the content of residual methanol of 1 50 ppm. DSC : Tonset 98°C, Tpeak 99.7°C.

Example 6

Preparation of Polymorph JR1 :

Agomelatine (0.5 g) is added to boiling, intensively stirred distilled water ( 1 0 ml). The resulting emulsion is stirred under boiling for 5 minutes and then cooled under intensive stirring to the laboratory temperature during 20 minutes. The resulting suspension is filtered and the obtained product is dried in a stream of air. Melting point 92.4-95°C.

Example 7

Preparation of Polymorph JR2

Agomelatine (0.5 g) is added to boiling, intensively stirred distilled water (10 ml). The resulting emulsion is stirred under boiling for 5 minutes and then cooled under intensive stirring to the laboratory temperature during 2 minutes. The resulting suspension is filtered and the obtained product is dried in a stream of air. Melting point 96-99.2°C. Example 8

Preparation of Polymorph JR3

Agomelatine ( 1 g; 4. 1 mmol) is dissolved in hot acetic acid (5 ml, 80%) and the resulting clear solution is cooled freely to the laboratory temperature. The crystallized product is aspirated and dried freely. Agomelatine, crystal form JR3 is obtained in the yield of 0.85 g (85%) with the chemical purity of 100% (HPLC).

Example 9

Preparation of Polymorph JR4

Agomelatine ( 1 g) is dissolved in methanol (1 ml) and poured into n-heptane (5 ml) at 0°C under stirring. After stirring for 30 minutes the crystals are aspirated and washed with n- heptane.

Example 10

Preparation of a composition based on a polymorphously stable mixture of crystal forms of agomelatine

Microcrystalline cellulose (65.7 g), lactose monohydrate (198.8 g) and crospovidone (8 g) were charged into a fluid granulator. This mixture of three excipients was heated up in the granulator to 27°C by the flow of input air (at 55°C). Agomelatine (77.5 g), Polymorph II and povidone (25. 1 g) were dissolved in absolute ethanol in a beaker under intensive stirring ( 1 5 min). After achieving the temperature of 27°C in the granulator, spraying of the fluidizing mixture of the excipients with the ethanolic solution of agomelatine and povidone K30 was started using a peristaltic pump and a nozzle connected to pressurized air at the pressure of 250 kPa (2.5 bar). The spraying process took 60 min. Then, the resulting granulate was dried by the flow of input air (having the temperature of 55°C throughout the spraying and drying periods) for 20 min until the granulate temperature of 34°C was obtained. The temperature of the product in the granulator ranged from 27°C to 31 °C during the spraying and from 3 1 °C to 34°C during the drying. The dried granulate was sieved through a sieve with the mesh size of 0.8 mm. The humidity of the granulate, measured as the drying loss at 105°C, 10 min, was 1 .4%. Further excipients colloidal silicon dioxide (3.2 g) and crospovidone (1 1 .4 g) were added by sieving to the granulate (33 1 .9 g). The mixture was homogenized for 12 min. Then, sieved stearic acid glidant (5.6 g) was added to the mixture and the mixture was homogenized for 3 min. The humidity of the tabletting matter, measured as the drying loss at 105°C, 10 min, was 1 .7%. The tabletting matter produced in the above mentioned way was used for the production of oblong-shaped cores with the weight of 129.2 mg (122- 1 34 mg specification), hardness of 99 N (at least 40 N specification), disintegration of 3 min (max. 15 min specification), dimensions of 9 x 4.5 mm (length x width). These cores were then coated with a pre-prepared coating suspension on the basis of hydroxypropyl methyl cellulose. The suspension was prepared by dissolving hydroxypropyl methyl cellulose (61 .2 g) in hot (80°C) water (300 g) under intensive stirring ( 1 5 min), after the dissolution polyethylene glycol (14.7 g) was added under intensive stirring (5 min) until dissolution. Separately, titanium dioxide (7.8 g), talc ( 1 5.6 g) and yellow ferric oxide (3 g) were suspended in water (100 g, laboratory temperature). Then, both parts of the suspension were mixed and water was added (200 g, laboratory temperature). The cores were put into the drum of a coating device, heated up by the flow of input air (at 60°C) to the output air temperature of 50°C; immediately after that spraying with the coating suspension was started using a peristaltic pump and a nozzle connected to pressurized air at the pressure of 100- 125 kPa ( 1 - 1 .25 bar). The input air temperature was maintained at 60 °C throughout the spraying period (60 min) and in the range of 45°C to 55°C throughout the drying period ( 10 min). The final average weight of the coated tablets was 1 30.7 mg ( 126- 138 mg specification), the hardness 1 02 N (at least 40 N specification), disintegration 5 min (max. 30 min specification). A mixture of Polymorph 1 and Polymorph JR1 was detected in the coated tablets.

Example 11

Preparation of a composition based on a polvmorphously pure metastable form of agomelatine Agomelatine ( 192.8 g) Polymorph I, lactose monohydrate (494.5 g), microcrystalline cellulose ( 1 63.5 g), povidone 30 (62.5 g), colloidal silicon dioxide (4 g) and crospovidone (20 g) were sieved through a sieve with the mesh size of 0.8 mm, stirred for 10 min and then, sieved (through 0.8 mm) magnesium stearate (5 g) was added and the mixture was stirred for 2 min. The homogenized mixture was granulated in a compactor at the pressure of 4.5 MPa (45 bar), the granulate was sieved through a sieve with the mesh size of 0.8 mm. The humidity of the granulate, measured as a drying loss at 105 °C, 10 min, was 2.3 %. Sieved (mesh size 0.8 mm) colloidal silicon dioxide (4.8 g) and crospovidone (3 1 .4 g) were added to the granulate (91 7.8 g). The mixture was stirred for 12 min. Then, sieved (mesh size 0.8 mm) stearic acid ( 1 5.2 g) and magnesium stearate (6.3 g) were added. The mixture was stirred for 3 min. The humidity of the resulting tabletting matter, measured as the drying loss at 105 °C, 10 min, was 2.3 %. The resulting tabletting matter was used for the production of oblong-shaped cores with the weight of 1 34.8 mg ( 124- 1 36 mg specification), hardness of 69 N (at least 40 N specification), disintegration of 5 min (max. 15 min specification), dimensions of 9 x 4.5 mm (length x width). These cores were then coated with a pre-prepared coating suspension on the basis of hydroxypropyl methyl cellulose prepared in advance. The suspension was prepared by dissolution of hydroxypropyl methyl cellulose (61 .2 g) in hot (80°C) water (300 g) under intensive stirring ( 1 5 min); after the dissolution polyethylene glycol (14.7 g) was added under intensive stirring (5 min) until dissolution. Separately, titanium dioxide (7.8 g), talc ( 1 5.6 g) and yellow ferric oxide (3 g) were suspended in water ( 1 00 g, laboratory temperature). Then, both parts of the suspension were mixed and water was added (200 g, laboratory temperature). The cores were put in the drum of a coating device, heated up by the flow of input air (at 60°C) to the output air temperature of 50°C, immediately after that spraying with the coating suspension was started using a peristaltic pump and a nozzle connected to pressurized air at the pressure of 1 00- 125 kPa ( 1 - 1 .25 bar). The input air temperature was maintained at 60 °C throughout the spraying period (60 min) at 60 °C and in the range of 45°C to 55°C throughout the drying period (1 0 min). The final average weight of the coated tablets was 137.4 mg ( 128- 140 mg specification), the hardness 97 N (at least 40 N specification), disintegration 9 min (max. 30 min specification). Polymorph I was detected In the coated tablets.

Claims

A method of preparing agomelatine of formula I

(I)

in crystal form I, characterized by reflections of an X-ray powder diffraction pattern in the following positions: 1 1 .92; 1 7.59; 1 8.41 ; 19.59; 1 9.82; 20.61 ; 21 .86; 23. 1 1 and 25.49± 0.2° 2Θ using radiation CuKa (λ= 0. 1 542 nm ( 1 .542 A), characterized in that agomelatine is dissolved in an organic solvent selected from a group consisting of aromatic hydrocarbons with six to ten carbon atoms and their mixtures at a temperature of at least 60°C to a saturated solution and the prepared hot saturated solution cools down without stirring.

The method according to claim 1 , characterized in that said solution cools down spontaneously without additional cooling to the ambient temperature.

The method according to claims 1 or 2, characterized in that the solvent is toluene.

A method of preparing agomelatine of formula I

(I) in crystal form 1, characterized by reflections of an X-ray powder diffraction pattern in the following positions: 1 1 .92; 1 7.59; 1 8.41 ; 19.59; 19.82; 20.61 ; 21 .86; 23.1 1 and 25.49± 0.2° 2Θ using radiation CuK (λ= 0. 1 542 nm ( 1 .542 A), characterized in that agomelatine is dissolved in a first solvent selected from the group consisting of aromatic hydrocarbons C6-C 10 and their mixtures; aliphatic or cyclic esters C3-C 10; aliphatic, alicyclic and aliphatic-aromatic ketones C3-C9; aliphatic alcohols C1 -C5; cyclic C3-C6 ethers and acetals; aliphatic and cycloaliphatic C3-C 10 ether-alcohols and their methyl or ethyl ethers and acetates; polyethylene glycol with a relative molecular weight up to 6000; C2-C7 halogen derivatives with one to three halogen atoms; C2-C7 nitriles; C 1 -C6 nitro compounds; C3-C7 five- or six-membered heterocycles with one or two heteroatoms of which at least one is nitrogen and the other heteroatom may be a nitrogen, oxygen or sulphur atom; and C 1 -C5 aliphatic and cyclic acid amides, sulfoxides and sulfones, and the prepared solution is mixed with a second solvent selected from the group consisting of water, C3-C25 liquid aliphatic and alicyclic hydrocarbons and their mixtures and C4-C 10 aliphatic ethers with one oxygen atom.

The method according to claim 4, characterized in that said first and second solvents are mutually miscible in any proportion.

The method according to claims 4 or 5, characterized in that said second solvent is water.

The method according to claims 4 or 5, characterized in that said second solvent is selected from the group consisting of C3-C25 liquid aliphatic and alicyclic hydrocarbons and their mixtures and C4-C 1 0 aliphatic ethers with one oxygen atom.

The method according to any one of claims 4-7, characterized in that a solution of agomelatine in the first solvent having a temperature above 60°C is added to the second solvent such that the temperature of the resulting crystallization mixture does not exceed 25°C during the crystallization. The method according to claim 8, characterized in that the temperature of the crystallization mixture does not exceed 5°C during the crystallization.

The method according to claim 9, characterized in that the second solvent is in the form of a heterogeneous mixture containing crystals of the precipitant in equilibrium with the l iquid phase.

Use of agomelatine in Form 1, prepared according to any one of the preceding claims, for the preparation of another crystal form of agomelatine.

Use of agomelatine in Form I. prepared according to any one of the preceding claims, for the preparation of a pharmaceutical composition.

1 3. Crystal form JRl of agomelatine, having the following characteristic peaks in an X-ray powder diffraction pattern: 10.7; 16.3 ; 1 8.0; 19.5 ; 23.5; 25.1 and 26.3 ± 0.2^° 2Θ.

14. The agomelatine crystal form JR l according to claim 1 3 , characterized by reflections of the X-ray powder diffraction pattern in the following positions: 10.71 ; 1 3.49; 16.3 1 ; 1 7.45; 1 8.00; 1 9.53 ; 20.27; 23.52; 25.09; 26.28; 29.74; 30.61 and 34.60 ± 0.2° 2Θ.

Use of agomelatine in Form JRl according to claims 13 or 14 for the preparation of a pharmaceutical composition.