CZ303789B6 - Process for preparing agomelatine crystal form and use thereof - Google Patents

Abstract

In the present invention, there is disclosed a process for preparing agomelatine of the general formula I in crystal form I, characterized by reflections of an X-ray powder diffraction pattern in the following positions: 11.92; 17.59; 18.41; 19.59; 19.82; 20.61; 21.86; 23.11 and 25.49 +- 0.2[deg.] 2[Theta] using radiation CuK{alpha} ([lambda]= 0.1542 nm (i.e. 1.542 A), wherein the preparation process comprises dissolving agomelatine at a temperature of at least 60 degC in an organic solvent being selected from the group consisting of aromatic hydrocarbons containing six to ten carbon atoms and their mixtures to achieve a saturated solution thereof and cooling the so prepared hot saturated solution without stirring. Another aspect of the present invention is cooling the solution spontaneously to ambient temperature without additional cooling.

Description

The invention relates to processes for the preparation of crystal form 1 of agomelatine.

BACKGROUND OF THE INVENTION

Agomelatine, N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide represented by Chemical Formula 1, (I) has valuable pharmacological properties, Agomelatine is the first melatonergic antidepressant. It is an MT ₂ and MT agonist, a receptor and a 5-HT _2c antagonist.

The preparation of agomelatine and its use have been described in EP 447 285.

Several polymorphic forms are known to agomelatine. The crystal structure of one of the polymorphic forms of agomelatine, later referred to as polymorph I, has been described in Acta Cryst., C: Crystal Struct. Commun. 50, 907 (1994) without mentioning how the single crystal was prepared. It cannot be ruled out that obtaining a single crystal of polymorphically pure Form I was a unique result, which the authors of the cited publication later failed to reproduce. To our knowledge, no procedure for the preparation of agomelatine Form I has been published by other authors.

The diffraction pattern obtained by the more common X-ray powder diffraction (XRPD) method describes polymorph II in the literature, for example in EP 1 564 202. Polymorph III is described in US 2006/270876, polymorph II, for example in EP 1 564 202. Polymorph III is described in US 2006/270876, polymorph IV in US 2006/270875, polymorph V in US2006 / 270877 and polymorph VI in US 2009/069434.

It is known that thermodynamically less stable (metastable) polymorphins, when reproducibly obtained in pure form, under conditions of use not subject to change in another more stable form, may be more advantageous for a particular technical application than their most stable form. Perhaps the best known example is diamond, which is a thermodynamically less stable form of carbon than much more available graphite.

In preparing solid dosage forms, a metastable polymorph may be preferable to a thermodynamically stable form, for example, where the stable form appears to have a lower solubility than is necessary for a given application. Metastable forms generally offer higher solubility and dissolution rate, but at the same time they are often more difficult than a thermodynamically stable form to meet the demanding purity and stability requirements of all active ingredients for pharmaceutical use in general.

Indeed, according to the principles of good manufacturing practice, the observance of which is controlled by the national authorities for the approval of medicinal products for human or veterinary use, it is necessary not only to reproduce and reliably obtain the active substance in specified chemical purity in its manufacture, as well as the stable polymorphic composition of the active ingredient throughout the shelf life of any pharmaceutical preparation containing the substance. Thus, the development of medicinal products containing the active substance in a metastable crystal modification, compared to the development of a stable form, entails an increased risk of failure associated with the threat of polymorphic instability of the active substance, i.e. converting the metastable modification into another, more stable solid form. as a result, for example, of the non-reproducible bioavailability of the active ingredient. Moreover, very often, in stability tests, the metastable solid form also appears to be less chemically stable than the most stable crystalline modification. Such behavior is particularly observed in amorphous modifications.

Agomelatine has not yet described a stable solid composition containing a crystal form other than Form 11.

Also, in the case of agomelatine, it has not yet been described whether, in addition to Form II, any other can be obtained in a sufficiently stable similar manner for pharmaceutical use. The present inventors have succeeded in solving the problem of obtaining a stable composition comprising a metastable form of agomelatine by formulating the composition using Form 1 obtained in a novel manner, or by using a new process for preparing an agomelatine composition to form new crystal forms of agomelatine.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of agomelatine of the formula I

in crystalline form I characterized by X-ray powder record reflections at positions 11.92; 17.59; 18.41; 19.59; 19.82; 20.61; 21.86; 23.11 and 25.49 ± 0.2 ° 2Θ using CuKa radiation (λ = 0.1542 nm (1.542 Å)), at 60 ° C agomelatine is dissolved in an organic solvent selected from the group consisting of aromatic hydrocarbons with six to ten carbons and mixtures thereof to a saturated solution and the prepared hot saturated solution cools without stirring. Another aspect of the present process is that the solution cools to ambient temperature spontaneously without additional cooling.

DETAILED DESCRIPTION OF THE INVENTION

In investigating the possibilities of obtaining a polymorphically stable pharmaceutical composition of agomelatine in which it would be contained in a metastable solid form, the present inventors first focused their attention on obtaining polymorphically pure crystal form I of agomelatine. It soon became apparent that the stable crystalline form II of agomelatine crystallized very easily from agomelatine solutions, so that by conventional means of obtaining solids in crystalline form, for example by slowly cooling a stirred saturated solution of agomelatine in an organic solvent, we obtained form II. Very rapid cooling of agomelatine solutions in organic solvents by spraying them on dry ice or liquid nitrogen or by very rapid evaporation of the solution

Although agomelatine in a spray drier was able to obtain Form 1, it was mixed with other polymorphic modifications of agomelatine.

Nevertheless, two ways of preventing crystallization of other forms of agomelatine and reproducible formation of pure polymorph I were found. The first is slow cooling of a hot saturated solution of agomelatine in a suitable solvent, avoiding agitation and possibly other vibrations and vibrations throughout crystal isolation device. By hot solution is meant a solution having a temperature of at least 60 ° C. Crystallization of Form I from the supersaturated solution obtained occurs spontaneously or by seeding with Form I after cooling the solution. Suitable solvents for this embodiment are aromatic hydrocarbons having six to ten carbons and mixtures thereof, e.g. toluene, ethylbenzene, cumene, tetralin or xylenes. A particularly preferred solvent for this variant is toluene. A preferred method of slow cooling is the spontaneous cooling of the hot solution.

A second variant of the process according to the invention is a very rapid decrease in the solubility of agomelatine caused by a rapid decrease in the temperature of the solution of agomelatine in the first solvent, accompanied by a further decrease in the solubility of agomelatine due to mixing the first solvent with a worse solvent. By the first agomelatine solvent is meant a solvent wherein at temperatures above 50 ° C a solubility of at least 1 kg per 10 l of agomelatine can be achieved, a worse solvent is a solvent in which the solubility of agomelatine at temperatures below 30 ° C is less than 1 kg per 100 L of solvent.

Examples of the first agomelatine solvents suitable for this variant of the process of the invention are aromatic hydrocarbons having six to ten carbons or mixtures thereof, e.g. toluene, ethylbenzene, cumene, tetralin or xylenes; aliphatic or cyclic esters of three to seven carbons such as 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 of three to nine carbons, e.g. acetone, butanone, methyl isobutyl ketone, cyclohexanone or acetophenone; aliphatic one to five carbon atoms, for example methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol or amyl alcohols; cyclic three to six carbon ethers or acetals such as tetrahydrofuran, methyletetrahydrofuran, dioxolane or dioxane; aliphatic or cycloaliphatic C3-C10 ether alcohols such as 2-methoxyethanol, diethylene glycol, triethylene glycol or tetrahydrofurfuryl alcohol and their methyl or ethyl ethers and acetates; polyethylene glycol having a molecular weight of up to 6000, halogen derivatives of two to seven carbons and one to three halogen atoms such as 1,2-dichloroethane, 1,1,1-trichloroethane or chlorobenzene; two to seven carbon nitriles such as acetonitrile, propionitrile, butyronitrile, adipodinitrile, succinodinitrile or benzonitrile; one to six carbon carbonates such as nitromethane, nitroethane, nitropropane or nitrobenzene; three to seven carbon 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 sulfur atom such as pyridine and pyridine base, morpholine, N-methylmorpholine or N, N-dimethylpropylenurea ( And dipolar aprotic solvents such as aliphatic or cyclic one to five carbon carboxylic amides, sulfoxides and sulfones such as dimethylsulfoxide, dimethylsulfone, sulfolane, tetramethylurea, formamide, N, N-dimethylformamide,,, Ν-dimethylacetamide or Nmethylpyrrolidone.

Examples of agomelatine second solvents ("precipitants") are water, C3-C25 liquid aliphatic and alicyclic hydrocarbons, and mixtures thereof such as pentane, hexane, heptane, cyclohexane, methylcyclohexane, decalin, gasoline or petroleum ether, C4-C10 aliphatic ethers with one oxygen atom such as diethyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether or dibutyl ether. In a second variant of the process for the preparation of the polymorphically pure Form I of the present invention, it is desirable that the first and second solvents together at the resulting crystallization temperature form a homogeneous mixture at least at the proportions of the two components. When a polar solvent is used as the first solvent over a wide range of water-miscible compositions such as a lower aliphatic alcohol,

Preferably, water may be used as a precipitant as an ether or an alcohol or ketone. Conversely, when an aromatic hydrocarbon is used to dissolve agomelatine, it is advantageous to use a precipitating agent selected from the group consisting of aliphatic and alicyclic hydrocarbons and mixtures thereof or from the group consisting of aliphatic ethers, or a mixed precipitate consisting of a mixture of two precipitants to achieve a sufficiently rapid decrease in solubility leading to polymorphically pure Form I. selected from these groups. Preferably, the solution of agomelatine in the first solvent is prepared at a temperature in excess of 60 ° C and sprayed into the precipitant at such a temperature that the temperature of the crystallization mixture during precipitation never exceeds 25 ° C, particularly preferably such that the crystallization temperature does not exceed 5 ° C. Noc: 2 ° C. The appropriate crystallization mode can be set and controlled by the amount and temperature of the precooling agent, the intensity of cooling and stirring during crystallization, and the concentration, temperature and rate of addition of the agomelatine solution.

When using solvent-precipitant pairs with such different polarities that the two solvents are not miscible in any ratio, such as methanol-heptane, dimethylsulfoxide-hexane, acetonitrile-heptane, dimethylformamide-cyclohexane, they were at the same ratio itself (without another solute such as agomelatine) provides a homogeneous mixture, observed crystallization, whereby a new metastable form of JR4 is formed instead of Form I. In carrying out the process of the invention, the formation of metastable forms of agomelatine other than Form 1 also contributes to reducing the temperature difference of the precipitation and precipitation solutions. Thus, for the preparation of polymorphically pure Form 1, it may be advantageous to use precipitants cooled down to the freezing point or even subcooled below the freezing point, optionally in the form of a heterogeneous mixture containing precipitant crystals in equilibrium with the liquid phase. Especially when water is used as a precipitant, the use of a mixture of water and ice is a preferred embodiment for the preparation of polymorphically pure Form I. The use of finely crushed ice or ice artificially prepared in finely crystalline form is a particularly preferred embodiment.

By measuring X-ray powder diffraction of the agomelatine Form I samples obtained by both variants of the method of the invention, the data given in Table 1 above was obtained.

Comparing the X-ray powder recordings of agomelatine Form I samples to the powder recordings calculated from the data in Acta Cryst., C: Crystal Struct. Commun. 50, 907 (1994), it has been shown that the preparation process of the invention provides agomelatine in the same crystal form as described in the above publication.

In a subsequent study of the properties of the prepared samples of polymorphically pure agomelatine in crystal form 1, it was found that the rate of conversion to constant modification II was highly dependent on both the manner in which the sample was prepared and the conditions to which it was subjected.

For example, it has been found that by heating the dry sample for several hours, a measurable amount of Form II in pure form I is already formed at temperatures above 60 ° C and when the Form I is stored in a wet state. For example, by mixing crystals of Form I in water, several percent of Form II was formed within hours. It has been found that the rate of conversion of Form I into Form II affects not only the liquid-to-crystal contact of the crystals, but also, in the case of water, the residual moisture occluded in the prepared crystalline substance. In a sample of polymorphically pure Form I, with a residual moisture content of 0.42% by weight, kept in a sealed container at room temperature, more than 5% of Form II was found after two months, whereas at less than 0.1% by four months Form II detected. Thus, it can be stated that crystallization of Form 1 free of Stop Form II must take place at temperatures below 60 ° C, but depending on the particular embodiment, it may be necessary to carry out downstream operations or the entire process at lower temperatures to ensure long-term polymorphic stability.

As for the chemical purity of the prepared samples of agomelatine in crystal modification 1, this also strongly depends on the chosen variant of the crystallization method. It has been found that crystallization from solvents which allow either the first variant by slow cooling of the hot solution (aromatic hydrocarbons) or the second variant in the form of rapid mixing of a solution of agomelatine in a first solvent with a low polar precipitant (examples of first solvents and low polar agglomerates mentioned above), preferably in the form of spraying a hot agomelatine solution into the chilled precipitator, provides a product of high chemical purity as measured by the high performance liquid chromatography (HPLC) method, but still after such drying under vacuum at 60 ° C the amount of organic solvents used, that it did not meet the limits set by the International Conference for Harmonization (ICH) or individual pharmacopoeias for the content of volatile organic compounds in the active substances. Thus, this method of crystallization of agomelatine Form I may serve as a preferred method for purifying agomelatine from organic impurities as determined by HPLC, but is generally not suitable as a final step in the manufacture of a pharmaceutically active substance for use in the manufacture of medicaments.

In contrast, a process variant of the invention utilizing the crystallization of agomelatine Form I by rapidly mixing a solution of agomelatine in a first solvent with water has generally proven less effective in reducing the content of organic impurities. On the other hand, this variant provides, after drying by conventional methods at temperatures below 60 ° C, agomelatine with a low residual solvent content, fully compliant with ICH regulations. This crystallization variant can be particularly advantageously used as a final purification step, optionally providing, in combination with the preceding crystallization of Form I from a non-aqueous medium, agomelatine in crystalline Form I, meeting all the above-mentioned requirements for the active drug substance.

It has surprisingly been found that, despite the presence of water in the crystallization medium, a polymorphically pure Form I can be obtained by a conventional drying process at temperatures below 60 ° C even in the product obtained by crystallization from aqueous mixtures, and that if this product is dried up to 0.1% by weight, remains polymorphically stable even in the long term.

Agomelatine in the long-term polymorphic stable form 1 obtained by the process of the invention was subsequently used to prepare pharmaceutical compositions which were tested for polymorphic and chemical stability. In addition, other possibilities for the preparation of compositions containing metastable solid forms of agomelatine have also been investigated and their stability tested in parallel with compositions based on pure form I. It has surprisingly been found that polymorphically stable compositions containing metastable forms of agomelatine can be prepared based on some other new metastable forms of agomelatine or mixtures thereof with form I.

In the crystallization experiments with agomelatine several new metastable forms of agomelatine were obtained and characterized. Form JR1, characterized by the typical XRPD reflections listed in Table 2, was obtained by remelting agomelatine in boiling water and slowly cooling the resulting emulsion. During rapid cooling, the form JR2 was formed in a similar way. Form JR3 was obtained by crystallization from aqueous acetic acid, while crystallization from anhydrous acetic acid resulted in a mixture of Form I and JR1.

-5GB 303789 B6

Table 2: typical X-ray reflections of powdered form of JR1 agomelatine

position [° 20] mezirovinná distance [nm] relative intensity [%] 10.71 0.8256 15.5 13.49 0.6557 3.5 16.31 0.5430 7.5 17.45 0.5078 4.7 18.00 0.4925 100.0 19.53 0.4542 10.0 20.27 0.4377 8.0 23.52 0.3779 23.0 25.09 0.3547 22.7 26.28 0.3388 10.4 29.74 0.3002 6.1 30.61 0.2918 3.6 34.60 0.2590 2.4

The compositions of the invention based on the metastable crystal form of agomelatine can be prepared by methods that limit or eliminate the use of solvents and temperatures of the processed material above 60 ° C. Suitable methods are direct compression and dry granulation techniques such as compacting. By direct compression is meant a production process wherein agomelatine prepared in a polymorphic metastable crystal form or as a polymorphic mixture of metastable crystal forms is homogenized with at least one solid excipient in one or more manufacturing steps and the resulting mixture is used to make tablets. By compacting is meant a production process, wherein agomelatine prepared in a polymorphic metastable crystal form or as a polymorphic mixture of metastable crystal forms is homogenized with at least one solid excipient in one or more manufacturing steps and subsequently compressed by compacting pressure into a compact mass web which is then ground a screening device for a defined particle size according to the mesh size of the screen. The resulting granulate can be used to produce solid dosage forms, for example tablets, capsules or sachets, either directly or after admixing one or more excipients. Tablets are the preferred dosage form.

A composition based on a polymorphically stable mixture of metastable crystal forms of agomelatine can also be prepared such that a mixture of metastable crystal forms with at least one solid excipient is formed directly during the preparation process of the composition. This was achieved, for example, by rapid 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 solvent. Optionally, additional excipients may be added to the solid mixture obtained to prepare the final form, such as tabletting, capsule filling, tablet coating, and the like. For example, a tablet composition can be prepared by spraying an ethanolic solution of agomelatine and povidone onto a mixture of lactose, microcrystalline cellulose and crospovidone in a fluid granulation process, drying the granulate, admixing other excipients dry and tabletting.

Surprisingly, it has been found that even when the excipients used, such as cellulose or lactose, are not completely anhydrous, polymorphically stable compositions of agomelatine, whether based on a polymorphically pure form prepared in advance or a mixture of metastable forms formed directly in a process for preparing a solid dosage form. Also, the use of water in the final formulation operations, such as tablet coating, is not entirely excluded.

It has been found that the stability of the composition is also affected by the packaging and storage method used, especially at higher relative humidity (above 60%) and temperatures above 25 ° C. Choice

A suitable packaging method can help maintain the polymorphic stability of the composition of the invention even in adverse conditions such as distribution in countries with humid and warm climates. Because of the polymorphic stability of the prepared composition, it may be advantageous to use a material that prevents the access of air humidity to produce a pharmaceutical composition comprising the composition of the invention, or to perform packaging in a dry air or inert gas environment. These measures can be further combined with the use of a desiccant. A preferred embodiment of such a pharmaceutical composition comprising the composition of the invention, for example in the form of tablets or capsules, is for example a blister made of aluminum foil or a glass vial with a plastic closure containing a suitable moisture-absorbent desiccant.

BRIEF DESCRIPTION OF THE DRAWINGS

Giant. 1: X-ray powder record of the crystal form of JR1 Agomelatine.

Giant. 2: Comparison of powder X-ray patterns of crystal forms JR4, JR2, J1 and JR1 FIG. 3: X-ray powder record of crystal form JR3 of Agomelatine.

Measurement conditions: X'PERT PRO MPD PANalytical diffractometer with graphite monochromator, CuKa radiation used (λ = 0.1542 nm (1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measuring range: 2 to 40 ° 2Θ, step size: 0.01 ° 20, measurement was carried out on a flat sample with an area / thickness of 10 / 0.5 mm Programmable divergence irradiators with an irradiated sample area of 10 mm, Soller or 0.02 rad and an anti-diffuser were used to adjust the primary optics. The X'Celerator detector with maximum opening of the detection slot was used to adjust the secondary optics, a 0.02 rad Soller aperture and a 5.0 mm anti-dispersion aperture.

The invention is illustrated by the following examples. These examples are illustrative only and are not intended to limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of polymorphs

Agomelatine (1 g; 4 mmol) was dissolved in toluene (12 mL) hot. The resulting clear solution was concentrated by distillation of 2/3 toluene and freely cooled to room temperature over 2 hours. The precipitated crystalline product was isolated by filtration and dried under vacuum at 30 ° C and a pressure below 4 kPa for 7 days. Agomelatine crystalline form 1 was obtained in a yield of 0.45 g (45%) with a chemical purity of 99.9% (HPLC) and a residual toluene content of 1500 ppm.

Example 2

Preparation of polymorphs

Agomelatine (25 g; 0.1 mmol) was dissolved in toluene (125 mL) hot. The resulting clear solution was concentrated by distillation of 1/2 toluene and freely cooled to room temperature. The solution was then 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 under vacuum at 50 ° C and a pressure below 4 kPa for 7 days. Agomelatine crystalline form 1 was obtained in a yield of 22.8 g (91%) with chemical

-7EN 303789 B6 with a purity of 100% (HPLC) and a residual toluene content of 1500 ppm and a residual diisopropyl ether of 1070 ppm.

Example 3

Preparation of polymorph I

Agomelatine (0.25 g; 10 mmol) was melted in polyethylene glycol (PEG 600; 0.5 g) at 100 ° C. The resulting melt was cooled to 0 ° C. The solidified material was stirred in water (5 mL). The precipitated product was isolated by filtration. The product was dried for 7 days. Agomelatine crystalline form I was obtained in a yield of 0.1 g (45%) with a chemical purity of 99.8% (HPLC) and a high PEG 600 content.

Example 4

Preparation of polymorph I

Agomelatine (0.25 g; 10 mmol) was melted in polyethylene glycol (PEG 1500; 0.5 g) at 100 ° C. Cold water (10 mL) was poured into the resulting melt. The precipitated product was isolated by filtration. The product was dried freely for 7 days. Agomelatine crystalline Form I was obtained in a yield of 0.21 g (84%) with a chemical purity of 99.7% (HPLC) and a high PEG 1500 content (determined by nuclear magnetic resonance (NMR) method).

Example 5

Preparation of polymorph I

Agomelatine (362 g; 1.5 mmol) was dissolved in methanol (1100 mL) at about 50 ° C. The resulting clear solution was cooled to room temperature and added to a vigorously stirred mixture of water (1850 mL) and ice (1850 g) over 30 minutes. The resulting thick white suspension was further stirred for an additional 30 minutes. The precipitated crystalline product was isolated by filtration and dried freely at room temperature for 7 days. Agomelatine crystalline form 1 was obtained in a yield of 349.3 g (96.5%) with a chemical purity of 100% (HPLC) and a water content of 0.07% and a residual methanol content of 150 ppm. DSC: Tonset 98 ° C, Tpeak 99.7 ° C.

Example 6

Preparation of JR1 polymorph:

Agomelatine (0.5 g) was added to boiling, vigorously stirred distilled water (10 mL). The resulting emulsion is stirred under boiling for 5 minutes and then cooled to room temperature over 20 minutes with vigorous stirring. The resulting suspension was filtered off and the product obtained was dried in a stream of air. Melting point 92.4-95 ° C.

Example 7

Preparation of polymorph JR2

Agomelatine (0.5 g) was added to boiling, vigorously stirred distilled water (10 mL). The resulting emulsion is stirred under boiling for 5 minutes and then cooled with vigorous stirring

B6 minutes to room temperature. The resulting suspension was filtered off and the product obtained was dried in a stream of air. Melting point 96-99.2 ° C.

Example 8

Preparation of JR3 polymorph

Agomelatine (1 g; 4.1 mmol) was dissolved in acetic acid (5 mL, 80%) hot and the clear solution obtained was allowed to cool freely to room temperature. The crystallized product is filtered off with suction and freely dried. The agomelatine crystalline form of JR3 was obtained in a yield of 0.85 g (85%) with a chemical purity of 100% (HPLC).

Example 9

Preparation of JR4 polymorph

Agomelatine (1 g) was dissolved in methanol (1 mL) and poured with stirring into n-heptane (5 mL) at 0 ° C. After stirring for 30 min, the crystals were aspirated and washed with n-heptane.

Example 10

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

Microcrystalline cellulose (65.7 g), lactose monohydrate (198.8 g) and crospovidone (8 g) were introduced into the fluidized bed granulator. The mixture of the three excipients was heated in the granulator to a temperature of 27 ° C by flowing inlet air (55 ° C). Agomelatine (77.5 g), polymorph and povidone (25.1 g) were dissolved in absolute beakers in vigorous ethanol with vigorous stirring (15 min). After reaching a temperature in the granulator of 27 ° C, spraying of the fluidizing excipient mixture with ethanol solution of agomelatine and povidone K30 was started by means of a peristaltic pump and a nozzle connected to a pressure of 250 kPa (2.5 bar). The spraying process took 60 min. Thereafter, the resulting granulate was dried for 20 minutes with flowing inlet air (for the entire time of spraying and drying at 55 ° C) until the granulate temperature reached 34 ° C. The product temperature in the granulator was between 27 and 31 ° C for the spraying period and between 31 and 34 ° C for the drying period. The dried granulate was sieved through a 0.8 mm sieve. The moisture content of the granulate measured as loss on drying at 105 ° C for 10 min was 1.4%. Colloidal silica (3.2 g) and crospovidone (11.4 g) were sieved to the granulate (331.9 g). The mixture was homogenized for 12 min. The sieved stearic glidant (5.6 g) was then admixed to this mixture and homogenized for 3 min. The moisture content of the tablet, measured as loss on drying at 105 ° C, 10 min, was 1.7%. The above-described tablet was used to produce oblong cores weighing 129.2 mg (specifications 122 to 134 mg), strength 99 N (specifications min. 40 N), disintegration 3 min (specifications max. 15 min), dimensions 9 x 4.5 mm (length x width). These cores were then coated with a pre-prepared coating suspension based on hydroxypropyl methylcellulose. The suspension was prepared by dissolving hydroxypropyl methylcellulose (61.2 g) in warm (80 ° C) water (300 g) with vigorous stirring (15 min), after dissolution polyethylene glycol (14.7 g) was added under vigorous stirring (5 min) to dissolution. In particular, titanium dioxide (7.8 g), talc (15.6 g) and yellow iron oxide (3 g) were suspended in water (100 g, room temperature). Then the two parts of the suspension were mixed and water (200 g, room temperature) was added. The cores were placed in a coating drum heated by the incoming air (60 ° C) to an outlet air temperature of 50 ° C, immediately after which the coating slurry was sprayed with a peristaltic pump and a nozzle connected to a pressure of 100 to 125 kPa (1 to 1.25 bar). The inlet air temperature was maintained between 45 and 55 ° C for the entire spray time (60 min) and 60 ° C and for the drying time (10 min).

-9EN 303789 B6

The final average weight of the coated tablets was 130.7 mg (specification 126-138 mg), strength 102 N (specification min. 40 N), disintegration 5 min (specification max. 30 min). A mixture of polymorph I and polymorph JR1 was detected in the coated tablets.

Example 11

Preparation of a composition based on a polymorphically pure unstable form of agomelatine

Agomelatine (192.8 g) polymorph 1, lactose monohydrate (494.5 g), microcrystalline cellulose (163.5 g), povidone K30 (62.5 g), colloidal silica (4 g) and crospovidone (20 g) Magnesium stearate (5 g) was sieved (over 0.8 mm) and the mixture was stirred for 2 min. The homogenized mixture was granulated on a compactor at a pressure of 45 bar, the granulate was sieved through a 0.8 mm sieve. The moisture content of the granulate measured as loss on drying at 105 ° C, 10 min was 2.3%. To the granulate (917.8 g) sieved (0.8 mm mesh size) raw materials colloidal silica (4.8 g) and crospovidone (31.4 g) were added. The mixture was stirred for 12 min. The sieved (0.8 mm mesh size) stearic acid (15.2 g) and magnesium stearate (6.3 g) were then added. The mixture was stirred for 3 min. The moisture content of the resulting pulp measured by drying loss at 105 ° C for 10 min was 2.3%. The resulting tablet was used to produce oblong cores of weight

134.8 mg (specifications 124 to 136 mg), strength 69 N (specifications min. 40 N), disintegration 5 min (specifications max. 15 min), dimensions 9 x 4.5 mm (length x width). These cores were then coated with a pre-prepared coating suspension based on hydroxypropyl methylcellulose. The suspension was prepared by dissolving hydroxypropyl methylcellulose (61.2 g) in warm (80 ° C) water (300 g) with vigorous stirring (15 min), after dissolution polyethylene glycol (14.7 g) was added under vigorous stirring (5 min) to dissolution. In particular, titanium dioxide (7.8 g), talc (15.6 g) and yellow iron oxide (3 g) were suspended in water (100 g, room temperature). Then the two parts of the suspension were mixed and water (200 g, room temperature) was added. The cores were placed in a coating drum heated by inlet air (60 ° C) to an outlet air temperature of 50 ° C, then spray coating was started using a peristaltic pump and a nozzle connected to a pressurized air of 100 to 125 kPa (1 to 1.25 bar). The inlet air temperature was maintained between 45-55 ° C for the entire spray time (60 min) and 60 ° C and for the drying time (10 min). The final average weight of the coated tablets was 137.4 mg (specification 128-140 mg), strength 97 N (specification min. 40 N), disintegration 9 min (specification max. 30 min). A polymorph was detected in the coated tablets

Claims (3)

PATENT CLAIMS A process for the preparation of agomelatine of formula I (I) in crystalline form I characterized by X-ray powder record reflections at positions 11.92; 17.59; 18.41; 19.59; 19.82; 20.61; 21.86; 23.11 and 25.49 ± 0.2 ° 2Θ using CuKa radiation - 10EN 303789 B6 λ = 0,1542 ηιη, characterized in that agomelatine is dissolved at a temperature of at least 60 ° C in an organic solvent selected from the group consisting of six to ten carbons of aromatic hydrocarbons and mixtures thereof into a saturated solution and prepared hot saturated the solution was allowed to cool without stirring. Method according to claim 1, characterized in that the solution cools spontaneously without additional cooling to ambient temperature. Process according to Claims 1 to 2, characterized in that toluene is also used as the solvent.