KR20160035598A - Novel forms of co-crystals of agomelatine and p-toluenesulphonic acid, method for preparing same and the pharmaceutical compositions containing same - Google Patents

Abstract

The present invention relates to a novel form of co-crystallization of agomelatine and p -toluenesulfonic acid, a process for preparing the same and a pharmaceutical composition containing the same. The co-crystals according to the invention have a better solubility than agomelatine and are thus more suitable for the development of pharmaceutical compositions. They have higher levels of stability and purity and are obtained by a simple method that does not involve difficult steps.

Description

FIELD OF THE INVENTION The present invention relates to a novel form of co-crystallization of agomelatine and P-toluenesulfonic acid, a process for preparing the same, and a pharmaceutical composition containing the same. BACKGROUND OF THE INVENTION PHARMACEUTICAL COMPOSITIONS CONTAINING SAME}

The present invention relates to a novel form of co-crystallization of agomelatine and p -toluenesulfonic acid, a process for the preparation thereof, and a pharmaceutical composition containing the same.

Agomelatine or N - [2- (7-methoxy-1-naphthyl) ethyl] acetamide has the structure of formula (II)

Agomelatine is marketed by Servier of France under the tradename Valdoxan® or Thymanax® as agonists of melatonin receptors and antagonists of 5-HT _2C receptors. It is the first antidepressant of the melatonin type for use in the treatment of major depression, sleep and improving sexual function.

Agomelatine, its preparation and its use in therapy are described in EP 0 447 285 and EP 1 564 202.

In view of its pharmaceutical value, it is important to be able to produce agomelatins or complexes thereof with improved purity, solubility and reproducibility.

A method for the preparation of agomelatine / p -toluenesulfonic acid co-crystals has been reported in patent application CN102702041, where the structure of the co-crystal was confirmed by ¹ H-NMR and the product obtained is amorphous.

Amorphous forms have a number of disadvantages as pharmaceutical products, for example, adherence to the walls, poor flow characteristics, low stability, and therefore it is still of value to have the widely available crystal form of the chemical material available.

It is an object of the present invention to prepare novel crystalline forms of co-crystals of agomelatine and p -toluenesulfonic acid with excellent properties in terms of solubility, stability and purity, Making it possible to foresee its use in manufacture.

The present invention relates to crystalline forms of co-crystals of agomelatine and p -toluenesulfonic acid having the structure of formula (I)

In the above formula, n is 0 or 1.

Preferred compounds according to the invention are the co-crystals of the following agomelatine and p -toluenesulfonic acid:

- Agomelatin / p -toluenesulfonic acid (1/1) monohydrate co-crystals,

- Agomelatin / p -toluenesulfonic acid (1/1) co-crystals.

The agomelatine / p -toluenesulfonic acid (1/1) monohydrate co-crystals are characterized by its X-ray powder diffraction diagram as shown in FIG. 1, which is a Panalytical Xpert Pro MPD diffractometer (copper anticathode, ). The alignment is represented by the interlayer distance d, the Bragg's angle 2 theta (expressed in ° ± 0.2), and the relative intensity (expressed as a percentage of the strongest line), listed in Table 1:

Table 1: Table of diffraction peaks of agomelatine / p -toluenesulfonic acid (1/1) monohydrate co-crystals

When the co-crystals of the present invention are characterized by X-ray diffraction measurements, there may be a measurement error in the identified peaks that can often be attributed to the apparatus or condition used. More particularly, the theta value may have an error of about ± 0.2 and sometimes an error of about ± 0.1 even when a sophisticated device is used. The measurement error should therefore take into account the case of confirming the structure of the co-decision.

The crystal structure of the agomelatine / p -toluenesulfonic acid (1/1) monohydrate co-crystals was determined and the following parameters were confirmed:

- Space group: P 21 21 21 (19)

- lattice parameter: a = 13.7359 (3) A, b = 25.3716 (6) A, c = 6.4487 (1) A; α = 90 °, β = 90 (2) °, γ = 90 °

- Volume of the lattice: V _{unit cell} = 2247.4 Å ³

The agomelatine / p -toluenesulfonic acid (1/1) monohydrate co-crystals are also characterized by DSC (differential scanning calorimetry) in the spectrum shown in Figure 2, at a temperature of about 78 ° C And a broad endotherm corresponding to the melting of the co-crystal in its melting point.

The present invention also relates to an agomelatine / p -toluenesulfonic acid (1/1) hole catalyst characterized by the X-ray powder diffraction diagram shown in FIG. 3, measured using a Panalytical Xpert Pro MPD diffractometer Decision. The alignment is represented by the interlayer distance d, the Bragg angle 2 theta (expressed in ° ± 0.2), and the relative intensity (expressed as a percentage of the strongest line) and is listed in Table 2:

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

When the co-crystals of the present invention are characterized by X-ray diffraction measurements, there may be a measurement error in the identified peaks that can often be attributed to the apparatus or condition used. More particularly, the theta value may have an error of about ± 0.2 and sometimes an error of about ± 0.1 even when a sophisticated device is used. The measurement error should therefore take into account the case of confirming the structure of the co-decision.

The crystal structure of the agomelatine / p -toluenesulfonic acid (1/1) co-crystals was determined and the following parameters were confirmed:

- Space group: P 2 ₁ 2 ₁ 2 ₁ (19)

Lattice parameter: a = 8.6683 (3) A, b = 30.360 (1) A, c = 8.0982 (4) A; α = 90 °, β = 90 °, γ = 90 °

- Volume of the lattice: V _{unit cell} = 2131.2 Å ³

The agomelatine / p -toluenesulfonic acid (1/1) co-crystal is also characterized by DSC (differential scanning calorimetry) in the spectrum shown in FIG. 4, which corresponds to the melting of the complex at a temperature of about 105 ° C. Endotherm.

The present invention relates to a method for obtaining co-crystallization of agomelatine and p -toluenesulfonic acid,

- agomelatine and p -toluenesulfonic acid monohydrate are mixed in an organic or aqueous-organic solvent in the desired ratio;

The obtained solution is stirred and heated at a temperature no higher than the boiling point of the optionally selected solvent;

The mixture is cooled with stirring, the complex is precipitated naturally or precipitated after taking in a second solvent;

The obtained precipitate is filtered and dried;

- Optionally, the precipitate is dried by heating.

In the process according to the invention, the solvent used is preferably an ether, e.g., diisopropyl ether, tetrahydrofuran, dioxane, or methyl tert-butyl ether; Or aromatic hydrocarbons, such as toluene. When a second solvent is used to promote precipitation of the complex, the selected solvent is an alcohol such as methanol, ethanol or tert -butanol; Alkanes, such as n-hexane or n-heptane; Or benzonitrile.

An alternative method involves co-milling the two components of the co-crystal. The co-milling is preferably carried out in a steel barrel. Modifications of the method include adding an organic solvent during milling, in which case the obtained co-crystals are then dried. Among the solvents used, ethers such as diisopropyl ether, or methyl tert-butyl ether has to be more specifically mentioned. Alcohols, such as methanol or tert-butanol, may also be used. The grinding is advantageously carried out using a ball which is not oxidizable. The pulverization is carried out using vibration, preferably vibration having a frequency in the range of 20 to 30 Hz. The vibration is applied for a period that can range from 5 minutes to 3 hours.

Another alternative method involves mixing the two solutions containing each of the components, rapidly freezing the obtained mixture at a very low temperature, and then drying the coalescence obtained by the same at the same low temperature. The two components are advantageously mixed in an organic or aqueous-organic solvent. The freezing and drying is preferably performed at -40 캜 to -60 캜, more preferably -40 캜.

Another advantageous method according to the invention is to mix the agomelatine and acid powders in a mixer and then to extrude the mixture by twin-screw extrusion without a die to obtain solid particles directly at the outlet of the extruder . The screw profile used is preferably a high shear profile in which a kneader component is used together which optionally allows the contact surface between the components to be improved. The L / D parameter of the screw may vary from 10 to 40, and the rotational speed may vary from 10 to 200 rpm. The temperature used varies from 40 to 100 占 폚.

The co-crystals of agomelatine and p -toluenesulfonic acid that are obtained have a significantly increased solubility relative to agomelatine itself, which makes them more suitable for the manufacture of pharmaceutical formulations. The co-crystals of agomelatine and p -toluenesulfonic acid according to the invention further exhibit advantageous properties of stability, purity and solubility. In addition, they are obtained by a simple method that does not involve any difficult steps.

The pharmacological studies of the co-crystals according to the present invention show that they are useful for the treatment of disorders of the melatonin system, more particularly for the treatment of stress, sleep disorders, anxiety disorders and in particular generalized anxiety disorders, obsessive disorders, mood disorders and especially bipolar disorders, Insomnia, obesity, insomnia, pain, psychiatric disorders, epilepsy, diabetes, Parkinson ' s disease, senile dementia, schizophrenia, panic attacks, melancholia, Can be used in the treatment of various disorders associated with general or pathological aging, migraine, amnesia, treatment of Alzheimer's disease, and also in the treatment of cerebral circulatory disorders. In another active field, it will be possible to use the crystals according to the invention as ovulation inhibitors and immunomodulators in sexual dysfunction and in the treatment of cancer.

The present invention also relates to a pharmaceutical composition comprising the co-crystals of agomelatine and p -toluenesulfonic acid according to the invention as active ingredient together with one or more adjuvants or excipients.

Among the pharmaceutical compositions according to the present invention, pharmaceutical compositions suitable for oral, parenteral (intravenous or subcutaneous) or intranasal administration, tablets or dragees, granules, sublingual tablets, capsules, lozenges, suppositories, , Skin gels, injectable preparations, soluble suspensions and chewing gums may be mentioned more particularly.

The useful dose may vary depending on the nature and severity of the disorder, the route of administration and the age and weight of the patient. The dosage varies from 0.1 mg to 1 g of agomelatine per day with one or more doses.

Representative examples of the invention are illustrated in the accompanying drawings to better appreciate the subject matter, features and advantages of the invention.

Figure 1: X-ray powder diffraction diagram of agomelatine / p -toluenesulfonic acid (1/1) monohydrate co-crystals.

Figure 2: DSC thermogram of agomelatine / p -toluenesulfonic acid (1/1) monohydrate co-crystals.

Figure 3: X-ray powder diffraction diagram of agomelatine / p -toluenesulfonic acid (1/1) co-crystals.

Figure 4: DSC thermogram of agomelatine / p -toluenesulfonic acid (1/1) co-crystals.

Example  One : Agomel Latin / p - Toluene sulfonic acid  (1/1) Monohydrate Ball decision

Procedure 1

Agomelatin (5.00 g, 1 eq.) And p -toluenesulfonic acid monohydrate (3.92 g, 1 eq.) Were placed in the reactor. 40 ml of tetrahydrofuran and 20 ml of hexane were added. The suspension was stirred at reflux for 0.5 hour (until no more cloudy, additional tetrahydrofuran was added until cloudy) until cloudy. The solution was spontaneously cooled to 5 < 0 > C and stirred for 0.5 h, then the suspension was filtered. The cake was dried under vacuum for 1 hour. 8.53 g of a white solid were obtained.

Yield: 95.8%

Melting point: 78 캜

Procedure 2

Agomelatin (5.00 g, 1 eq.) And p -toluenesulfonic acid monohydrate (3.952 g, 1 eq.) Were introduced into the reactor. 40 ml of acetone and 10 ml of hexane were added. The suspension was stirred under reflux for 0.5 h (until no more cloudy, additional acetone was added until cloudy) until cloudy. The solution was spontaneously cooled to 5 < 0 > C and stirred for 0.5 h, then the suspension was filtered. The cake was dried under vacuum for 1 hour. 8.06 g of a white solid were obtained.

Yield: 90.4%

Melting point: 78 캜

Procedure 3

Agomelatine (0.5 g) and p -toluenesulfonic acid monohydrate (0.392) were placed in a 50-ml non-oxidizable vessel. Two stainless steel balls of 12 mm diameter were added and the pail closed. A vibration with a frequency of 30 Hz was applied for 15 minutes, resulting in 0.881 g of solid after drying overnight at ambient temperature.

Melting point: 78 캜

Procedure 4

Agomelatine (0.5 g) and p -toluenesulfonic acid monohydrate (0.392) were placed in a 50-ml non-oxidizable vessel. Two stainless steel balls of 12 mm diameter were added and the pail closed. 100 ㎕ of methyl tert-butyl ether was added. A vibration with a frequency of 30 Hz was applied for 30 minutes to produce 0.883 g of solid after drying overnight at ambient temperature.

Melting point: 78 캜

Procedure 5

Agomelatin (5 g) and p -toluenesulfonic acid monohydrate (3.92 g) were placed in a 100-ml non-oxidizable vessel. Two stainless steel balls of 12 mm diameter were added and the pail closed. 100 ㎕ of methyl tert-butyl ether was added. Vibration with a frequency of 30 Hz was applied for 30 minutes to yield 8.83 g of solid after drying overnight at ambient temperature.

Melting point: 78 캜

Example  2 : Agomel Latin / p - Toluene sulfonic acid  (1/1) Ball decision

2 g of the agomelatin / p -toluenesulfonic acid (1/1) monohydrate co-crystals obtained in Example 1 were heated at 85 DEG C for 4 hours. A white solid was obtained.

Yield: 100%

Melting point: 105 DEG C

In the following examples, it is possible to use commercially available agomelatine or agomelatine prepared by one of the methods described in the prior art.

Example  3 : Pharmaceutical composition: 25 mg of Agomelatin  Capsule containing dose

Example  4 : Pharmaceutical composition: 25 mg of Agomelatin  Tablets containing each dose

≪ RTI ID = 0.0 > 25 mg < / RTI > agomelatin,

The compound of Example 1 44.5 g

Lactose monohydrate 115 g

Magnesium stearate 2 g

Corn starch 33 g

Maltodextrin 15 g

Anhydrous colloidal silica 1 g

All pregelatinized corn starch, Type A 9 g

≪ RTI ID = 0.0 > 25 mg < / RTI > agomelatin,

The compound of Example 2 42.7 g

Lactose monohydrate 115 g

Magnesium stearate 2 g

Corn starch 33 g

Maltodextrin 15 g

Anhydrous colloidal silica 1 g

All pregelatinized corn starch, Type A 9 g

Detection method and result

1. Purity of the sample

Chromatographic conditions: C18 column; Mobile phase: phosphate buffer 10 mmol / L (adjusted to pH 7.0 with NaOH): acetonitrile 2: 7 (v / v); Temperature of column: 40 캜; Detection wavelength: 220 nm; The internal standard method used with the compounds of Examples 1 and 2.

A 1 mg / ml solution of the compound of the present invention was prepared using mobile phase. 10 [mu] l of each solution was injected into the liquid chromatography system and the chromatogram was recorded.

The compounds of Examples 1 and 2 have a purity of at least 99%.

2. Stability

Samples of the compounds of Examples 1 and 2 were placed in an incubator at 40 < 0 > C for 30 days to determine their stability by HPLC. The results are shown in Table 3:

Table 3

3. Solubility in water

By the external standard method, the compounds of Examples 1 and 2 were 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 agomelat in Form II:

Table 4

The results indicate that the co-crystals of agomelatine and p -toluenesulfonic acid of the present invention have greater solubility in water, 0.1N HCl analogous to human gastric juice, or a buffer of pH 6.8 than agomelatin form II itself. These results indicate that the co-crystals have a much better potential for bioavailability than agomelatine of type II.

4. DSC analysis

About 5-10 mg of the compounds of Examples 1 and 2 were weighed into an aluminum crucible closed with a perforated (unsealed) aluminum lid, unless otherwise specified. The sample was introduced into a TA Q 1000 instrument (equipped with a condenser), cooled and maintained at 25 ° C. After thermal stabilization, the samples and the references were heated from 200 DEG C to 250 DEG C at a rate of 10 DEG C / min and the response to heat flow was recorded. Nitrogen was used as a purge gas at a flow rate of 100 cm ³ / min.

DSC thermograms obtained with the compounds of Examples 1 and 2 are shown in Figures 2 and 4.

5. Analysis of crystal structure

The measurement conditions of the X-ray powder diffraction diagram of the products of Examples 1 and 2 are as follows:

About 50 mg of the compounds of Examples 1 and 2 were placed between two Kapton (R) films and fixed on a sample support. The sample was then placed in a PANALYTICAL XPERT-PRO MPD diffractometer in the delivery mode under the following conditions:

Generator Parameters: 45 kV / 40 mA

Form theta / theta

Anode: Cu

K-alpha 1 [A] 1.54060

K-alpha 2 [A] 1.54443

K-beta [A] 1.39225

K-A2 / K-A1 ratio 0.50000

Scanning mode: Continuous from 3 ° to 55 ° (Bragg 2 theta)

Step [° 2Th.] 0.0170

Phase duration [s] 35.5301

Starting angle [° 2Th.] 3.0034

Final angle [° 2Th.] 54.9894

Rotation: Yes

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

Claims (12)

Crystalline forms of the co-crystals of agomelatine and p -toluenesulfonic acid of the formula (I)

In the above formula, n is 0 or 1. 2. A diffractive optical element according to claim 1, characterized by an X-ray powder diffraction diagram expressed by an interlayer distance d, a Bragg's angle 2 theta (expressed in < RTI ID = 0.0 & Crystallization of agomelatine and p -toluenesulfonic acid monohydrate of formula (I) comprising the corresponding form within < RTI ID = 0.0 >

The method of claim 1, wherein the diffraction angle is within ± 0.2 °, characterized by an X-ray powder diffraction diagram expressed by interlayer distance d, Bragg angle 2 theta (expressed in degrees ± 0.2) The crystallization of agomelatine and p -toluenesulfonic acid of formula (I) comprising the corresponding form:

Mixing agomelatine and p -toluenesulfonic acid monohydrate in the desired ratio in an organic or aqueous-organic solvent;
Comprising the steps of stirring and heating, optionally in not greater than the boiling point of the selected solvent, the temperature of the obtained solution;
- cooling the mixture with stirring and, after precipitation to precipitate the complex naturally or stirred in the solvent of the second;
Filtering the obtained precipitate and drying,
Optionally, drying the precipitate by heating.
A process for obtaining a co-crystal of agomelatine and p -toluenesulfonic acid according to any one of claims 1 to 3. Process for the preparation of the co-crystals of agomelatine and p -toluenesulfonic acid according to any one of claims 1 to 3, characterized in that the two components are co-milled. The composition according to any one of claims 1 to 3, characterized in that the two components are mixed in an organic or aqueous-organic solvent, then frozen and dried at a very low temperature, and the agomelatine and p -toluenesulfonic acid ≪ / RTI > Characterized in that the agomelatine and the acid powder are mixed in a mixer and then the mixture is extruded by twin-screw extrusion without a die to obtain solid particles directly at the outlet of the extruder. A process for the preparation of the co-crystals of agomelatine and p -toluenesulfonic acid according to any one of claims 3 to 6. Pharmaceutical compositions comprising one of the co-crystals of agomelatine and p -toluenesulfonic acid according to any one of claims 1 to 3 as an active ingredient in combination with one or more inert non-toxic pharmaceutically acceptable carriers Gt; 9. A pharmaceutical composition according to claim 8 for use in the manufacture of a medicament for the treatment of a disorder of the melatoninergic system. 10. The method of claim 9, further comprising administering an effective amount of at least one compound selected from the group consisting of stress, sleep disorders, anxiety disorders and especially generalized anxiety disorders, obsessive compulsive disorders, mood disorders and especially bipolar disorders, major depression, seasonal affective disorders, cardiovascular pathology, Migraine, amnesia, depression, anxiety, depression and fatigue, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, pain, psychosis, epilepsy, diabetes, Parkinson's disease, senile dementia, Alzheimer ' s disease, and also for the treatment of cerebral circulatory disorders, and also for use in the treatment of cancer, as an ovulation inhibitor and an immunomodulator in sexual dysfunction and in the treatment of cancer. 4. The method according to any one of claims 1 to 3, wherein the co-crystals of agomelatine and p -toluenesulfonic acid of formula (I) for the treatment of disorders of the melatonin system. 4. A method according to any one of claims 1 to 3, for the treatment of stress, sleep disorders, anxiety disorders and in particular generalized anxiety disorders, obsessive compulsive disorders, mood disorders and especially bipolar disorders, major depression, seasonal affective disorders, cardiovascular pathology, Related to aging, generalized or pathological aging, such as diabetes, Parkinson's disease, senile dementia, insomnia and fatigue, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, pain, psychotic disorders, epilepsy, variety of disorders, migraine, memory loss, Alzheimer's disease, and also in the treatment of cardio-cerebral circulation disorders, and also as an ovulation inhibitor, and immunomodulating substances from sexual dysfunction, and agomelatine and p of formula (I) for the treatment of cancer-toluene 0.0 > sulfonic < / RTI >

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