Forms of co-crystals of agomelatine and p toluenesulphonic acid, a process for their preparation and pharmaceutical compositions containing them

Abstract

The present invention relates to new forms of co-crystals of agomelatine and p-toluenesulphonic acid, to a process for their preparation and to pharmaceutical compositions containing them. The co-crystals according to the invention have better solubility than agomelatine and are therefore more suitable for the preparation of pharmaceutical compositions. They also have better stability and purity and, moreover, are obtained by a simple process which does not include any difficult steps. ##STR00001##

Claims

1. A Crystalline form of co-crystals of agomelatine and p-toluenesulphonic acid of formula (I): ##STR00004## wherein n represents 0 or 1.

2. The crystalline form according to claim 1, which is the co-crystal of agomelatine and p-toluenesulphonic acid monohydrate, having the following X-ray powder diffraction diagram expressed in terms of interplanar distance d, Bragg's angle 2 theta (expressed in 0.2), and relative intensity: TABLE-US-00007 2-Theta () exp. d () exp. Intensity (%) 6.9631 12.6846 77.52 9.4831 9.31871 16.21 12.8823 6.86648 100 13.9527 6.34201 23.16 14.1761 6.24258 16.06 15.1817 5.83128 13.38 15.379 5.75689 25 15.5788 5.68351 46.24 16.7156 5.29947 94.46 17.2926 5.12391 37.98 18.4671 4.80058 92.47 18.6356 4.75756 22.34 19.199 4.6192 25.69 19.6747 4.50857 35.74 20.1398 4.4055 28.53 21.6248 4.1062 14.93 22.0586 4.02643 52.23 22.2859 3.98587 99.09 23.2175 3.82799 15.22 23.9607 3.71092 32.37 25.1733 3.53485 42.09 26.0152 3.42233 16.64 27.7148 3.2162 39.29 28.23 3.15866 11.25 28.4033 3.13979 16.33 including the forms whose diffraction angles correspond to within 0.2.

3. The crystalline form according to claim 1, which is the co-crystal of agomelatine and p-toluenesulphonic acid, having the following X-ray powder diffraction diagram expressed in terms of interplanar distance d, Bragg's angle 2 theta (expressed in 0.2), and relative intensity: TABLE-US-00008 2-Theta () exp. d () exp. Intensity (%) 11.2964 7.82664 21.53 11.6596 7.58367 20.45 13.4436 6.58103 61.31 15.2416 5.80848 18.42 16.0185 5.52847 30.89 17.3473 5.10789 41.39 17.8289 4.97096 54.3 18.2535 4.85629 100 20.4891 4.33118 19.84 20.6912 4.28932 45.12 20.9516 4.23659 36.73 21.3088 4.16638 14.93 22.2998 3.98342 33.92 23.129 3.84244 24.66 23.4107 3.79685 12.89 23.6474 3.75938 12.34 23.9983 3.7052 12.8 including the forms whose diffraction angles correspond to within 0.2.

4. A process for obtaining the co-crystals of agomelatine and p-toluenesulphonic acid according to claim 1, wherein: agomelatine and p-toluenesulphonic acid monohydrate are mixed in an organic or aqueous-organic solvent in the desired proportions; the solution obtained is stirred and optionally heated at a temperature not greater than the boiling point of the chosen solvent; the mixture is cooled, with stirring, and the complex precipitates naturally or precipitates after being taken up in a second solvent; the precipitate obtained is filtered and dried; optionally, the precipitate is dried by heating.

5. A process for the preparation of the co-crystals of agomelatine and p-toluenesulphonic acid according to claim 1, wherein the two constituents are co-ground.

6. A process for the preparation of the co-crystals of agomelatine and p-toluenesulphonic acid according to claim 1, wherein the two constituents are mixed in an organic or aqueous-organic solvent and then frozen and dried at a very low temperature.

7. A process for the preparation of the co-crystals of agomelatine and p-toluenesulphonic acid according to claim 1, wherein the powders of agomelatine and the acid in question are mixed in a mixer and the mixture is then extruded by twin-screw extrusion without a die in order to obtain a solid grain directly at the outlet of the extruder.

8. A pharmaceutical composition comprising as active ingredient the co-crystals of agomelatine and p-toluenesulphonic acid according to claim 1, in combination with one or more inert, non-toxic, pharmaceutically acceptable carriers.

Description

(1) Representative examples of the present invention are illustrated with the corresponding figures in order better to evaluate the subject-matter, features and advantages thereof.

(2) FIG. 1: X-ray powder diffraction diagram of the agomelatine/p-toluenesulphonic acid (1/1) monohydrate co-crystal.

(3) FIG. 2: DSC thermogram of the agomelatine/p-toluenesulphonic acid (1/1) monohydrate co-crystal.

(4) FIG. 3: X-ray powder diffraction diagram of the agomelatine/p-toluenesulphonic acid (1/1) co-crystal.

(5) FIG. 4: DSC thermogram of the agomelatine/p-toluenesulphonic acid (1/1) co-crystal.

EXAMPLE 1

Agomelatine/p-Toluenesulphonic Acid (1/1) Monohydrate Co-Crystal

(6) Procedure 1

(7) Agomelatine (5.00 g, 1 eq.) and p-toluenesulphonic acid monohydrate (3.92 g, 1 eq.) are placed in a reactor. 40 ml of tetrahydrofuran and 20 ml of hexane are added. The suspension is stirred under reflux for 0.5 hour until it becomes cloudy (if it does not become cloudy, further tetrahydrofuran is added until it is cloudy). The solution is cooled naturally to 5 C. and stirred for 0.5 hour, and then the suspension is filtered. The cake is dried for one hour in vacuo. 8.53 g of a white solid are obtained.

(8) Yield: 95.8%

(9) Melting point: 78 C.

(10) Procedure 2

(11) Agomelatine (5.00 g, 1 eq.) and p-toluenesulphonic acid monohydrate (3.952 g, 1 eq.) are introduced into a reactor. 40 ml of acetone and 10 ml of hexane are added. The suspension is stirred under reflux for 0.5 hour until it becomes cloudy (if it does not become cloudy, further acetone is added until it is cloudy). The solution is cooled naturally to 5 C. and stirred for 0.5 hour, and the suspension is then filtered. The cake is dried for one hour in vacuo. 8.06 g of a white solid are obtained.

(12) Yield: 90.4%

(13) Melting point: 78 C.

(14) Procedure 3

(15) Agomelatine (0.5 g) and p-toluenesulphonic acid monohydrate (0.392) are placed in a 50-ml non-oxidisable jar. Two stainless steel balls of 12 mm diameter are added and the jar is closed. Vibrations with a frequency of 30 Hz are applied for 15 minutes to yield, after drying overnight at ambient temperature, 0.881 g of solid.

(16) Melting point: 78 C.

(17) Procedure 4

(18) Agomelatine (0.5 g) and p-toluenesulphonic acid monohydrate (0.392) are placed in a 50-ml non-oxidisable jar. Two stainless steel balls of 12 mm diameter are added and the jar is closed. 100 l of methyl tert-butyl ether are added. Vibrations with a frequency of 30 Hz are applied for 30 minutes to yield, after drying overnight at ambient temperature, 0.883 g of solid.

(19) Melting point: 78 C.

(20) Procedure 5

(21) Agomelatine (5 g) and p-toluenesulphonic acid monohydrate (3.92 g) are placed in a 100-ml non-oxidisable jar. Two stainless steel balls of 12 mm diameter are added and the jar is closed. 100 l of methyl tert-butyl ether are added. Vibrations with a frequency of 30 Hz are applied for 30 minutes to yield, after drying overnight at ambient temperature, 8.83 g of solid.

(22) Melting point: 78 C.

EXAMPLE 2

Agomelatine/p-Toluenesulphonic Acid (1/1) Co-Crystal

(23) 2 g of the agomelatine/p-toluenesulphonic acid (1/1) monohydrate co-crystal obtained in Example 1 are heated at 85 C. for 4 hours. A white solid is obtained.

(24) Yield: 100%

(25) Melting point: 105 C.

(26) In the examples below it is possible to use commercially available agomelatine or agomelatine prepared by one of the methods described in the prior art.

EXAMPLE 3

Pharmaceutical Compositions: Capsules Containing a Dose of 25 mg of Agomelatine

(27) TABLE-US-00003 Formulation for the preparation of 1000 capsules each containing 25 mg of agomelatine Compound of Example 1 44.5 g Lactose (Spherolac 100) 85.2 g Starch 1500 25.5 g CMS-Na 8.5 g Ac-Di-Sol (FMC) 17 g Stearic acid 3.4 g

(28) TABLE-US-00004 Formulation for the preparation of 1000 capsules each containing 25 mg of agomelatine Compound of Example 2 42.7 g Lactose (Spherolac 100) 85.2 g Starch 1500 25.5 g CMS-Na 8.5 g Ac-Di-Sol (FMC) 17 g Stearic acid 3.4 g

EXAMPLE 4

Pharmaceutical Compositions: Tablets Each Containing a Dose of 25 mg of Agomelatine

(29) Formulation for the preparation of 1000 tablets each containing 25 mg of agomelatine: Compound of Example 1 . . . 44.5 g Lactose monohydrate . . . 115 g Magnesium stearate . . . 2 g Maize starch . . . 33 g Maltodextrins . . . 15 g Anhydrous colloidal silica . . . 1 g Pregelatinised maize starch, Type A . . . 9 g

(30) Formulation for the preparation of 1000 tablets each containing 25 mg of agomelatine: Compound of Example 2 . . . 42.7 g Lactose monohydrate . . . 115 g Magnesium stearate . . . 2 g Maize starch . . . 33 g Maltodextrins . . . 15 g Anhydrous colloidal silica . . . 1 g Pregelatinised maize starch, Type A . . . 9 g
Detection Methods and Results
1. Purity of the Samples

(31) Chromatography conditions: C18 column; mobile phase: phosphate buffer 10 mmol/L (adjusted to pH 7.0 with NaOH): acetonitrile 2:7 (v/v); temperature of the column: 40 C.; detection wavelength: 220 nm; internal standard method used with the compound of Examples 1 and 2.

(32) 1 mg/ml solutions of the compounds of the invention are prepared with the mobile phase. 10 l of each solution are injected into the liquid chromatography system and the chromatograms are recorded.

(33) The compounds of Examples 1 and 2 have purities greater than or equal to 99%.

(34) 2. Stability

(35) Samples of the compounds of Examples 1 and 2 are placed in incubators at 40 C. for 30 days in order to determine their stability by HPLC. The results are presented in Table 3:

(36) TABLE-US-00005 TABLE 3 25 C., 40 C., 50 C. 70 C. 60% RH OB 75% RH OB CB CB Compound of Stable Stable Stable Stable Example 1 Compound of Changes Changes Changes Stable Example 2 into the into the into the monohydrate monohydrate monohydrate RH: relative humidity; OB: open bottle; CB: closed bottle
3. Solubility in Water

(37) By means of an external standard method, the compounds of Examples 1 and 2 are tested by HPLC and compared with agomelatine of form II. The results are presented in Table 4 in the form of % increase in solubility relative to the solubility of agomelatine of form II:

(38) TABLE-US-00006 TABLE 4 Solubility (increase versus agomelatine form II) Sample in water in 0.1N HCl in a buffer pH 6.8 Compound of +41% +50% +49% Example 1 Compound of +35% +45% +60% Example 2

(39) The results show that the co-crystals of agomelatine and p-toluenesulphonic acid of the present invention have greater solubility than agomelatine of form II per se in water, in 0.1N HCl, which is similar to human gastric fluids, or in a buffer at pH 6.8. These results show that the co-crystals have a far better potential in terms of bioavailability than agomelatine of form II.

(40) 4. DSC Analyses

(41) Approximately 5-10 mg of the compounds of Examples 1 and 2 are weighed into an aluminium crucible closed with a pierced (non-hermetic) aluminium lid, unless specified otherwise. The sample is introduced into a TA Q1000 device (equipped with a cooler), cooled and maintained at 25 C. After thermal stabilisation, the sample and the reference are heated from 200 C. to 250 C. at a rate of 10 C./min and the response to the heat flow is recorded. Nitrogen is used as the purge gas, at a flow rate of 100 cm.sup.3/min.

(42) The DSC thermograms obtained with the compounds of Examples 1 and 2 are shown in FIGS. 2 and 4.

(43) 5. Analysis of the Crystalline Structure

(44) The conditions of measurement of the X-ray powder diffraction diagrams of the products of Examples 1 and 2 are as follows:

(45) Approximately 50 mg of the compounds of Examples 1 and 2 are placed between two Kapton films and fixed to the sample support. The sample is then placed in a PANALYTICAL XPERT-PRO MPD diffractometer in transmission mode under the following conditions: Parameters of the generator: 45 kV/40 mA Configuration theta/theta Anode: Cu K-Alpha1 [] 1.54060 K-Alpha2 [] 1.54443 K-Beta [] 1.39225 K-A2/K-A1 ratio 0.50000 Scanning mode: continuous from 3 to 55 (Bragg's angle 2 theta) Step [2Th.] 0.0170 Step duration [s] 35.5301 Starting angle [2Th.] 3.0034 Finishing angle [2Th.] 54.9894 Rotation: yes

(46) The X-ray powder diffraction diagrams obtained for Examples 1 and 2 are shown in FIGS. 1 and 3.