WO2015013903A1

WO2015013903A1 - NEW AGOMELATINE p-TOLUENESULFONIC ACID CO-CRYSTAL FORMS AND PREPARATION THEREOF

Info

Publication number: WO2015013903A1
Application number: PCT/CN2013/080472
Authority: WO
Inventors: Hanbin Shan; Yuhui SHEN; Ying Luo; Philippe Letellier; Michael Lynch
Original assignee: Shanghai Institute of Pharmaceutical Industry; Laboratoires Servier SAS
Current assignee: Shanghai Institute of Pharmaceutical Industry; Laboratoires Servier SAS
Priority date: 2013-07-31
Filing date: 2013-07-31
Publication date: 2015-02-05
Anticipated expiration: 2016-01-31

Abstract

The present invention relates to the p-toluenesulfonic acid co-crystals of agomelatine of formula (I), preparation and use thereof, and to pharmaceutical composition containing it. The p-toluenesulfonic acid co-crystals of agomelatine obtained through the present method has significant increased solubility than agomelatine, and therefore is more suitable for manufacturing pharmaceutical formulations. In addition, the product enjoys good stability and purity. Using the present method, product of high purity can be obtained through a simple process, free of any complicated steps.

Description

NEW AGOMELATINE j-TOLUENESULFONIC ACID CO-CRYSTAL FORMS AND

PREPARATION THEREOF

Technical Field

The present invention relates to new crystalline forms of ?-toluenesulfonic acid co-crystals of agomelatine, their preparation and uses thereof, and to pharmaceutical composition containing them.

Technical Background

Agomelatine, or N-[2-(7-methoxy-l-naphthyl)ethyl]-acetamide, has the structure of formula (II)

It is marketed under the trade name of Valdoxan® or Thymanax® by the French company Servier as a melatonin agonist and antagonist of 5HT₂c receptor. It is the first melatonin type anti-depressant, indicated for depression, improving sleep and sexual function. The preparation process and therapeutic use of agomelatine has been described in European patent specification EP0447285 and EP 1564202.

In view of its pharmaceutical value, it is important to produce the compound or a complex thereof with better purity, solubility and reproducibility.

The preparation process of a j-toluenesulfonic acid co-crystal of agomelatine has been reported in CN 102702041 , wherein the structure of said /?-toluenesulfonic acid co-crystal was identified by 'HNMPV, the product obtained in said invention was amorphous.

Summary of the Invention

Amorphous form presents several drawbacks in terms of pharmaceutics such as wall sticking, poor flowability and stability, and it is of great interest to have a well-defined crystalline form of an entity. The object of the present invention is to provide crystalline forms of -toluenesulfonic acid co- crystals of agomelatine, featuring excellent solubility, stability and purity, making them favourable for use in the manufacture of pharmaceutical formulations containing agomelatine.

The present invention provides crystalline forms of p-toluenesulfonic acid co-crystals of agomelatine of formula (I):

wherein n represents 0 or 1.

The preferred embodiments of the invention are the agomelatine sulfonic acids co-crystal as follows: agomelatine/p-toluenesulfonic acid (1/1) monohydrate co-crystal, agomelatine/^-toluenesulfonic acid (1/1) co-crystal.

Agomelatine/ />-toluenesulfonic acid (1/1) monohydrate co-crystal has been characterized by the main-ray powder diffraction diagram given in Figure 1, measured using a Panalytical Xpert Pro MPD diffractometer (copper anticathode). The main ray data are expressed in terms of interplanar distance d, Bragg's angle 2 theta (expressed in °+0.2), and relative intensity (expressed as a percentage relative to the most intense line) and are listed in Table 1 :

Tablel: Table of diffraction peaks for agomelatine / -toluenesulfonic acid (1/1) monohydrate co- crystal

When the crystal of the present invention is measured by X-ray diffraction, there may be measurement errors for the recorded peaks sometimes due to the equipment or conditions applied. Specifically, for example, the 2Θ value has sometimes an error of about ± 0.2, and has sometimes an error of about ± 0.1 even if very precise technical equipment is used. Therefore, the measurement error should be taken into account when identifying the structure of each crystal. The diffraction pattern was indexed and crystal lattice parameters and space group were determined using HighScore Plus (indexing method: Treor), confirming the purity of the crystalline phase. Space group (No.): P 21 21 21 (19)

Lattice parameters:

a = 13.7359(3) A

b = 25.3716(6) A

c = 6.4487(1) A

a = 90°

β= 90°

γ= 90°

V (A3)= 2247.4 A³

The agomelatine / /?-toluenesulfonic acid (1/1) monohydrate co-crystal is further characterized by its differential scanning calorimetry (DSC) thermogram shown in Figure 2, which shows a broad endothermic event corresponding to a dehydration and melt with an onset temperature of approximately 78°C (and a peak temperature around 87°C).

The invention also relates to agomelatine/ /?-toluenesulfonic acid (1/1) co-crystal which has been characterized by the main ray powder diffraction diagram given in Figure 3, measured using a Panalytical Xpert Pro MPD diffractometer (copper anticathode). The main ray data are expressed in terms of interplanar distance d, Bragg's angle 2 theta (expressed in °±0.2), and relative intensity (expressed as a percentage relative to the most intense line) and are listed in Table 2:

Table 2: Table of diffraction peaks for agomelatine/p-toluenesulfonic acid (1/1) co-crystal

2-Theta (°) exp. d (A) 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 When the crystal of the present invention is measured by X-ray diffraction, there may be measurement errors for the recorded peaks sometimes due to the equipment or conditions applied. Specifically, for example, the 2Θ value has sometimes an error of about ± 0.2, and has sometimes an error of about ± 0.1 even if very precise technical equipment is used. Therefore, the measurement error should be taken into account when identifying the structure of each crystal.

The diffraction pattern was indexed and crystal lattice parameters and space group were determined using HighScore Plus (indexing method : Treor), confirming the purity of the crystalline phase. Space group (No.): P 2 1∑_\ (19)

Lattice parameters :

a = 8.6683 (3) A

b = 30.360 (1) A

c = 8.0982 (4) A

a = 90°

β= 90°

γ= 90°

V (A³)= 2131.2 A³

The agomelatine/ />-toluenesulfonic acid (1/1) co-crystal is further characterized by its differential scanning calonmetry (DSC) thermogram shown in Figure 4, which shows an endothermic event corresponding to a melt with an onset temperature of approximately 105°C.

The present invention further provides a method for the preparation of said agomelatine / p- toluenesulfonic acid (1/1) co-crystal monohydrate and agomelatine / /?-toluenesulfonic acid (1/1) co- crystal wherein:

agomelatine and /^-toluenesulfonic acid monohydrate are mixed in an 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 selected solvent;

the mixture is cooled, with stirring, and the co-crystal precipitates naturally or precipitates after taking up in a second solvent;

the precipitate obtained is filtered off and dried;

optionally, the precipitate is dried under heating.

In the process according to the invention, the solvent used is preferably an ether such as, for example, diisopropyl ether, tetrahydrofuran, dioxane or methyl tert-butyl ether, or an aromatic hydrocarbon such as, for example, toluene. When a second solvent is used in order to promote precipitation of the co-crystal, the solvent used is preferably an alcohol such as, for example, methanol, ethanol or tert-butanol, or an alkane such as, for example, n-hexane or n-heptane, or benzonitrile.

An alternative process comprises co-grinding of the two constituants of the co-crystal form. The co- grinding is preferably carried out in a steel jar. A variant of this process comprises adding an organic solvent during the grinding; in this case, the co-crystal form obtained is dried. Among the solvents used, there may be mentioned, more especially ethers such as for example diisopropyl ether or methyl tert-butyl ether. Alternatively, an alcohol such as, for example, methanol or tert-butanol can be used. The grinding is advantageously carried out using non-oxidisable balls. The grinding is carried out using vibrations, preferably vibrations having a frequency ranging from 20 to 30 Hz. The vibrations are applied for a period which may range from 5 minutes to 3 hours. Another alternative process comprises mixing two solutions containing each of the constituents and rapidly freezing the mixture obtained at a very low temperature, and then at that same low temperature drying the co-crystal thereby obtained. The two constituents are advantageously mixed in an organic or aqueous-organic solvent. The freezing and drying are carried out preferably between -40°C and -60°C, and more preferably at -40°C. Another advantageous process according to the invention comprises mixing powders of agomelatine and 7-toluenesulfonic acid in a mixer and then extruding by twin screw extrusion without a die in order to obtain a solid granular product directly at the extruder outlet. Preferably, the screw profile used is a high-shear profile, optionally using mixing elements making it possible to improve the surface contact between the two constituents. The L/D parameter of the screw may vary from 10 to 40 and the speed of rotation from 10 to 200 rpm. The temperature used varies from 40 to 100°C.

The /?-toluenesulfonic acid co-crystals of agomelatine produced according to the present method has significant increased solubility than agomelatine per se, and therefore is more suitable for manufacturing pharmaceutical formulations. The product enjoys higher stability, purity and solubility. In addition, product with high purity can be obtained through a simple process, free of any complicated steps.

Pharmacological tests of the / toluenesulfonic acid co-crystals of agomelatine of the invention demonstrated that it can be used for the treatment of melatoninergic system disorders, and more especially in the treatment of stress, sleep disorders, anxiety disorders and especially generalised anxiety disorder, obsessive-compulsive disorders, mood disorders and especially bipolar disorders, major depression, seasonal affective disorder, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet-lag, 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 in cerebral circulation disorders, and also in sexual dysfunctions, and as ovulation inhibitors and immunomodulators and in the treatment of cancers.

The present invention further provides a pharmaceutical composition, comprising a p- toluenesulfonic acid co-crystal of agomelatine of the invention in association with pharmaceutically acceptable adjuvants or excipients.

Among the pharmaceutical compositions according to the invention there may be mentioned, more especially, those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragees, granules, sublingual tablets, capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions and chewing gums. The useful dosage can be adjusted depending on the nature and severity of the diseases to be treated, the mode of administration, and age and weight of the patients. The daily dosage varies from 0.1 mg to 1 g of agomelatine and may be administrated in a single dose or in several divided doses.

Brief Description of Drawings Representative examples of the present invention are illustrated with the drawings in order to better convey the objects, features, and advantages of the present invention.

Fig. 1 shows the X-ray powder diffraction pattern of the agomelatine/p-toluenesulfonic acid (1/1) monohydrate co-crystal

Fig. 2 shows the DSC thermogram of the agomelatine/p-toluenesulfonic acid (1/1) monohydrate co- crystal

Fig. 3 shows the X-ray powder diffraction pattern of the agomelatine/p-toluenesulfonic acid (1/1) co-crystal

Fig. 4 shows the DSC thermogram of the agomelatine/p-toluenesulfonic acid (1/1) co-crystal Examples

Example 1: agomelatine/ >-toluenesulfonic acid (1/1) monohydrate co-crystal Process 1

Agomelatine (5.00g, l.Oeq) and jc-toluenesulfonic acid monohydrate (3.92g, l .Oeq) were added into a reactor. 40 ml tretrahydrofuran and 20 ml hexane were then added. The suspension was stirred at reflux for 0.5 hour to reach clear (if it cannot get clear, adding tretrahydrofuran until it clear). After natural cooling to 5^°C and stirring 0.5 hour, the suspension was filtered. The filter cake was dried for 1 hour under vacuum. 8.53g white solid was got.

Yield : 95.8%

Mp: 78 ^°C

Process 2

Agomelatine (5.00g, l .Oeq) and >-toluenesulfonic acid monohydrate (3.92g, l .Oeq) were added into a reactor. 40 ml acetone and 10 ml hexane were then added. The suspension was stirred at reflux for 0.5 hour to reach clear (if it cannot get clear, adding acetone until it clear). After natural cooling to 5^°C and stirring 0.5 hour, the suspension was filtered. The filter cake was dried for 1 hour under vacuum. 8.06g white solid was got.

Yield : 90.4%

Mp: 78 ^°C

Process 3

Agomelatine (0.500g) and /j-toluenesulfonic acid monohydrate (0.392g) were introduced into a 50 ml non-oxidisable jar. Two stainless steel balls of 12 mm diameter were added and jar was closed. Vibrations with a frequency of 30 Hz were applied for 15 minutes to yield, after drying overnight at room temperature, 0.88 lg solid was got.

Mp: 78 ^°C Process 4

0.500g of agomelatine, 0.392g jc-toluenesulfonic acid monohydrate were introduced into a 50 ml non-oxidisable jar. Two stainless steel balls of 12 mm diameter were added and jar is closed. 100 u 1 of methyl tertbutyl ether were added. Vibrations with a frequency of 30 Hz were applied for 30 minutes to yield, after drying overnight at room temperature, 0.883g solid was got.

Mp: 78 ^°C Process 5

5.0 of agomelatine, 3.92 j9-toluenesulfonic acid monohydrate are introduced into a 100 ml non- oxidisable jar. Two stainless steel balls of 12 mm diameter are added and jar is closed. 100 μ 1 of methyl tertbutyl ether are added. Vibrations with a frequency of 30 Hz are applied for 30 minutes to yield, after drying overnight at room temperature, 0.883g solid was got.

Mp: 78 ^°C

Example 2: agomelatine/ ^7-toluenesulfonic acid co-crystal

2 g of agomelatine/ >-toluenesulfonic acid (1/1) monohydrate co-crystal obtained in Example 1 were heated at 85°C for 4 hours. The white solid isolated.

Yield : 100%

Mp: 105^°C

Agomelatine used in the above examples is commercially available or can be prepared according to methods known in the art.

Example 3: Pharmaceutical Compositions, capsules

Formulation for the preparation of 1000 capsules

each containing a dose of 25 mg 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) IV g

Stearic Acid 3.4 g

Formulation for the preparation of 1000 capsules

each containing a dose of 25 mg ; 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

Formula 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

Compound of Example 2 42.7g

Lactose monohydrate 1 1 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 Samples

Chromatographic conditions: CI 8 column; mobile phase: 10 mmol/L phosphate buffer (adjusted to pH 7.0 with NaOH): acetonitrile = 2 : 7 (v/v); column temperature: 40°C; detection wavelength: 220 nm; internal standard method was used on the product of Examples 1 and 2.

Solutions of the products at 1 mg/mL were prepared with the mobile phase. 10

of each solution was injected into the liquid chromatograph system and chromatograms were recorded.

Purity of compounds of Examples 1 and 2 were superior to 99%.

2. Stability Test

Some of the product of Examples 1, 2 and 3 was placed in an incubator at 40°C for 30 days to determine its stability with HPLC. The results are shown in the following Table 3.

Table 3

3. Water Solubility

Using external standard method, the product of Examples 1, 2 and 3 was tested with HPLC, compared with agomelatine crystalline form II. The results are shown in the following Table 4. Table 5

As can be seen, the j?-toluenesulfonic acid co-crystal of agomelatine and ^-toluenesulfonic acid co- crystal monohydrate of the present invention has better solubility than agomelatine form II per se in water, in 0.1N HC1, which is similar to human gastric fluid, or in pH 6.8 buffer. This means the former enjoys the potential of higher bioavailability than the latter.

4. Diffential Scanning Calorimetry (DSC) Analysis

Approximately, 5-10 mg of the compounds of Examples 1, 2 and 3 was weighed into an aluminium DSC pan and sealed with a pierced aluminium lid (non-hermetically), unless specified otherwise. The sample pan was then loaded into a TA instruments Q1000 (equipped with a cooler) cooled and held at 25 °C. Once a stable heat-flow response was obtained, the sample and reference were then heated to ca. 200°C to 250°C at scan rate of 10 °C/min and the resulting heat flow response monitored. Nitrogen was used as the purge gas, at a flow rate of 100 cm3/min. The DSC thermograms obtained are shown in Figures 2 and 4. 5. Crystal Structure Analysis

The measurement condition for the X-ray powder diffraction pattern of the products of Example 1 , and 2 in the present invention is as follows:

Approximately, 50 mg of compounds of Example 1 and 2 was placed between two Kapton® films of fixed on the sample holder. The sample was then loaded into a P A ALYTICAL XPERT-PRO MPD diffractometer running in transmission mode and analysed using the following experimental conditions:

Generator Settings: 45 kV / 40 mA,

theta/theta configuration

Anode Material: Cu

K-Alphal [A] 1.54060

K-Alpha2 [A] 1.54443

K-Beta [A] 1.39225

K-A2 / K-Al Ratio 0.50000

Scan type : continuous de 3° a 55° (angle de Bragg 2 theta)

Step Size [°2Th.] 0.0170

Scan Step Time [s] 35.5301

Start Position [°2Th.] 3.0034

End Position [°2Th.] 54.9894

Spinning: Yes

X-ray powder diffraction diagrams obtained for compounds of Examples 1 and 2 are represented in Figures 1 and 3.

Claims

Claims:

1. Crystalline forms of £>-toluenesulfonic acid co-crystals of agomelatine of formula (I):

wherein n represents 0 or 1.

2. A -toluenesulfonic acid/agomelatine (1/1) co-crystal monohydrate of formula (I) according to claim 1, characterised in its X-ray powder diffraction diagram by the Bragg's angles 2 theta (expressed in °±0.2), interplanar spacing d and relative intensity as follows:

and which also includes crystals whose peak diffraction angles match within an error of ±0.2°.

3. An agomelatine/p-toluenesulfonic acid (1/1) co-crystal of formula (I) according to claim 1, characterised in its X-ray powder diffraction diagram by the Bragg's angles 2 theta (expressed in °+0.2), interplanar spacing d and relative intensity as follows:

4. Process for obtaining the -toluenesulfonic acid co-crystals of agomelatine of formula (I) according to claims 1 to 3, characterised in that:

agomelatine and />-toluenesulfonic acid are mixed in an organic solvent in the desired proportions;

- the precipitate obtained is filtered and dried;

optionally, the precipitate is dried under heating.

5. Process for obtaining the />-toluenesulfonic acid co-crystals of agomelatine of formula (I) according to claims 1 to 3, characterised in that the two constituents are co-ground.

6. Process for obtaining the j'-toluenesulfonic acid co-crystals of agomelatine of formula (I) according to claims 1 to 3, characterised in that the two constituents are mixed in an organic or aqueous-organic solvent and then frozen and dried at a very low temperature.

7. Process for obtaining the -toluenesulfonic acid co-crystals of agomelatine of formula (I) according to claims 1 to 3, characterised in that powders of agomelatine and of the acid in question are mixed in a mixer and then the mixture is extruded by twin screw extrusion without a die in order to obtain a solid granular product directly at the extruder outlet.

8. Pharmaceutical compositions comprising as active ingredient the -toluenesulfonic acid co- crystals of agomelatine of fomiula (I) according to claims 1 to 3, in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers.

9. Pharmaceutical compositions according to claim 8 for use in the manufacture of medicaments for treating disorders of the melatoninergic system.

10. Pharmaceutical compositions according to claim 9 for use in the manufacture of medicaments for treating stress, sleep disorders, anxiety disorders and especially generalised anxiety disorder, obsessive-compulsive disorders, mood disorders and especially bipolar disorders, major depression, seasonal affective disorder, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet-lag, 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 in cerebral circulation disorders, and also in sexual dysfunctions, and as ovulation inhibitors and immunomodulators and in the treatment of cancers.

1 1. ?-toluenesulfonic acid co-crystals of agomelatine of formula (I) according to claims 1 to 3 for the treatment of disorders of the melatoninergic system.

12. -toluenesulfonic acid co-crystals of agomelatine of formula (I) according to claims 1 to 3 for treating stress, sleep disorders, anxiety disorders and especially generalised anxiety disorder, obsessive-compulsive disorders, mood disorders and especially bipolar disorders, major depression, seasonal affective disorder, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet-lag, 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 in cerebral circulation disorders, and also in sexual dysfunctions, and as ovulation inhibitors and immunomodulators and in the treatment of cancers.