WO2015013865A1 - Agomelatine sulfonic acids complexes and preparation thereof - Google Patents

Agomelatine sulfonic acids complexes and preparation thereof Download PDF

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Publication number
WO2015013865A1
WO2015013865A1 PCT/CN2013/080337 CN2013080337W WO2015013865A1 WO 2015013865 A1 WO2015013865 A1 WO 2015013865A1 CN 2013080337 W CN2013080337 W CN 2013080337W WO 2015013865 A1 WO2015013865 A1 WO 2015013865A1
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Prior art keywords
agomelatine
disorders
formula
sulfonic acids
complex
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PCT/CN2013/080337
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French (fr)
Inventor
Hanbin Shan
Yuhui SHEN
Ying Luo
Philippe Letellier
Michael Lynch
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Les Laboratoires Servier
Shanghai Institute Of Pharmaceutical Industry
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Application filed by Les Laboratoires Servier, Shanghai Institute Of Pharmaceutical Industry filed Critical Les Laboratoires Servier
Priority to PCT/CN2013/080337 priority Critical patent/WO2015013865A1/en
Priority to MX2016001219A priority patent/MX369303B/en
Priority to MEP-2020-125A priority patent/ME03741B/en
Priority to SG11201600006RA priority patent/SG11201600006RA/en
Priority to CA2919601A priority patent/CA2919601C/en
Priority to US14/907,670 priority patent/US9573891B2/en
Priority to RU2016106958A priority patent/RU2673080C2/en
Priority to PL14758162T priority patent/PL3027588T3/en
Priority to EA201600142A priority patent/EA031237B1/en
Priority to EP14758162.3A priority patent/EP3027588B1/en
Priority to AU2014298304A priority patent/AU2014298304B2/en
Priority to LTEP14758162.3T priority patent/LT3027588T/en
Priority to ES14758162T priority patent/ES2792248T3/en
Priority to HUE14758162A priority patent/HUE049928T2/en
Priority to RS20200720A priority patent/RS60440B1/en
Priority to DK14758162.3T priority patent/DK3027588T3/en
Priority to PCT/FR2014/051944 priority patent/WO2015015102A2/en
Priority to PT147581623T priority patent/PT3027588T/en
Priority to SI201431601T priority patent/SI3027588T1/en
Priority to CN201480042633.7A priority patent/CN105473547B/en
Priority to NZ716151A priority patent/NZ716151A/en
Priority to JP2016530580A priority patent/JP6595990B2/en
Priority to UAA201601715A priority patent/UA116811C2/en
Publication of WO2015013865A1 publication Critical patent/WO2015013865A1/en
Priority to ZA2016/00448A priority patent/ZA201600448B/en
Priority to HK16106760.7A priority patent/HK1218745A1/en
Priority to HK16111309.5A priority patent/HK1223088A1/en
Priority to HRP20200927TT priority patent/HRP20200927T1/en
Priority to CY20201100565T priority patent/CY1123214T1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/33—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems
    • C07C309/34—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems formed by two rings
    • C07C309/35—Naphthalene sulfonic acids

Definitions

  • the present invention relates to agomelatine sulfonic acids complexes, their preparation and uses thereof, and to pharmaceutical composition containing them.
  • the object of the present invention is to provide agomelatine sulfonic acids complexes having the specific stoichiometry of 2 molar equivalents of agomelatine for 1 molar equivalent of sulfonic acids.
  • Those complexes show excellent solubility, stability and purity, making them favourable for use in the manufacture of pharmaceutical formulations containing agomelatine.
  • the specific stoichiometry of the complexes of the present invention gives a weight advantage in favour of the active part of the complex i.e. agomelatine, allowing the elaboration of pharmaceutical formulation with smaller quantities of complex.
  • the present invention provides agomelatine sulfonic acids complexes having the following structure of formula (I):
  • x 0 or 1
  • RSO3H represents 1 ,5-naphthalene disulfonic acid or benzene sulfonic acid.
  • the preferred embodiments of the invention are the agomelatine sulfonic acids complexes as follows:
  • agomelatine/benzenesulfonic acid (2/1 ) complex
  • Agomelatine/1 5-naphthalene disulfonic acid (2/1) complex 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/1 , 5-naphthalene disulfonic acid (2/1) complex
  • the crystal of the present invention 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 2 ⁇ 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.
  • V uni , cel , 1901.51 100A 3
  • This agomelatine/l ,5-naphthalene disulfonic acid (2/1) complex is further characterized by its differential scanning calorimetry (DSC) thermogram shown in Figure 2, which exhibits an endothermic event corresponding to a melt with an onset temperature of approximately 237°C.
  • DSC differential scanning calorimetry
  • the invention also relates to agomelatine/l ,5-naphthalene disulfonic acid (2/1) monohydrate complex.
  • Agomelatine/l ,5-naphthaIene disulfonic acid (2/1) monohydrate complex 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/l ,5-naphthalene disulfonic acid (2/1 )
  • the crystal of the present invention 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 2 ⁇ 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.
  • This agomelatine/l ,5-naphthalene disulfonic acid (2/1) monohydrate complex is further characterized by its differential scanning calorimetry (DSC) thermogram shown in Figure 4, which exhibits two endothermic events: one at about U 6°C corresponding to the dehydration, and the other about 238°C corresponding to the complex.
  • DSC differential scanning calorimetry
  • the invention also relates to agomelatine/benzene sulfonic acid (2/1) complex.
  • Agomelatine/benzene sulfonic acid (2/1) complex has been characterized by the main-ray powder diffraction diagram given in Figure 5, 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 3:
  • Table 3 Table of diffraction peaks for agomelatine/benzene sulfonic acid (2/1 ) complex
  • the crystal of the present invention 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 2 ⁇ 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.
  • This agomelatine/benzene sulfonic acid (2/1) complex is further characterized by its differential scanning calorimetry (DSC) thermogram shown in Figure 6, which exhibits one endothermic events at about 1 16°C.
  • the present invention further provides a method for the preparation of said agomelatine sulfonic acids complexes, wherein:
  • agomelatine and the sulfonic acid are mixed in an organic solvent 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 selected solvent;
  • the mixture is cooled, with stirring, and the co-crystal precipitates naturally or precipitates after taking up in a second solvent;
  • the solvent used is preferably a ketone such as, for example acetone, an ether such as, for example, diisopropyl ether, tetrahydrofuran or methyl tert- butyl ether, or an aromatic hydrocarbon such as, for example, toluene.
  • 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.
  • the solvents used there may be mentioned, more especially, ketones such as for example acetone, or ethers such as for example diisopropyl ether or methyl tert-butyl ether.
  • an alcohol such as, for example methanol, ethanol 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 sulfonic acids 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.
  • 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 ⁇ 0 to 40 and the speed of rotation from 10 to 200 rpm.
  • the temperature used varies from 40 to 100°C.
  • the agomelatine sulfonic acids complexes produced according to the present method have significant increased solubility than agomelatine per se, and therefore are more suitable for manufacturing pharmaceutical formulations.
  • the agomelatine sulfonic acids complexes of the invention furthermore present very good stability, purity and solubility. In addition, they can be obtained through a simple process, free of any complicated steps.
  • Pharmacological tests of the agomelatine sulfonic acids complexes 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 agomelatine sulfonic acids complexes of the invention in association with pharmaceutically acceptable adjuvants or excipients.
  • 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.
  • Fig. 1 shows the X-ray powder diffraction pattern of agomelatine/1 ,5-naphthalene disulfonic acid (2/1 ) complex of Example 1.
  • Fig. 2 shows the DSC thermogram of agomelatine/1, 5-naphthalene disulfonic acid (2/1) complex of Example 1 .
  • Fig. 3 shows the X-ray powder diffraction pattern of agomelatine/l ,5-naphthalene disulfonic acid (2/1 ) monohydrate complex of Example 2.
  • Fig. 4 shows the DSC thermogram of agomelatine/ 1 ,5 -naphthalene disulfonic acid (2/1) monohydrate complex of Example 2.
  • Fig. 5 shows the X-ray powder diffraction pattern of agomelatine/benzene sulfonic acid (2/1) complex of Example 3.
  • Fig. 6 shows the DSC thermogram of agomelatine/benzene sulfonic acid (2/1) complex of Example 3.
  • Example 1 Agomelatine / 1,5-naphthalene disulfonic acid (2/1) complex
  • Agomelatine used in the above examples is commercially available or can be prepared according to methods known in the art.
  • Agomelatine (0.500g) and 1 ,5-naphthalene disulfonic acid tetrahydrate (0.370g) are introduced into a 50ml non-oxidisable jar. Two stainless steel balls of 12 mm diameter are added and jar is closed. Vibrations with a frequency of 30 Hz are applied for 15 minutes to yield, after drying overnight at room temperature, 0.805g solid was got.
  • Agomelatine (0.500g) and 1 ,5-naphthalene disulfonic acid tetrahydrate (0.370g) are introduced into a 50ml non-oxidisable jar. Two stainless steel balls of 12 mm diameter are added and jar is closed. ⁇ ⁇ 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, 0.803g solid was got.
  • Agomelatine used in the above example is commercially available or can be prepared according to methods known in the art.
  • Melting point: 116°C Agomelatine used in the above example is commercially available or can be prepared according to methods known in the art.
  • Example 4 Pharmaceutical Compositions: Capsules containing 25 mg agom
  • Example 5 Pharmaceutical Compositions: Tablets containing 25 mg agomelatine Formula for the preparation of 1000 tablets each containing 25 mg of agomelatine:
  • H relative Humidity
  • OB Open Bottle
  • CB Close Bottle
  • agomelatine sulfonic acids complexes of the present invention exhibit 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.
  • the measurement condition for the X-ray powder diffraction pattern of the products of Examples 1, 2 and 3 in the present invention is as follows:
  • K-A2 / K-A1 Ratio 0.50000 Scan type continuous from 3° to 55° (Bragg angle 2 theta)

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Abstract

Disclosed are agomelatine sulfonic acids complexes having the specific stoichiometry of 2 molar equivalents of agomelatine for 1 molar equivalent of sulfonic acids. Those complexes show excellent solubility, stability and purity, making them favourable for use in the manufacture of pharmaceutical formulations containing agomelatine.

Description

AGOMELATINE SULFONIC ACIDS COMPLEXES AND PREPARATION THEREOF
Technical Field
The present invention relates to agomelatine sulfonic acids complexes, 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):
Figure imgf000002_0001
It is marketed under the trade name of Valdoxan® or Thymanax® by the French company Servier as a melatonin agonist and antagonist of 5-HT2c receptor. It is the first melatonin type antidepressant, 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.
Summary of the Invention
The object of the present invention is to provide agomelatine sulfonic acids complexes having the specific stoichiometry of 2 molar equivalents of agomelatine for 1 molar equivalent of sulfonic acids. Those complexes show excellent solubility, stability and purity, making them favourable for use in the manufacture of pharmaceutical formulations containing agomelatine. Furthermore, the specific stoichiometry of the complexes of the present invention gives a weight advantage in favour of the active part of the complex i.e. agomelatine, allowing the elaboration of pharmaceutical formulation with smaller quantities of complex.
The present invention provides agomelatine sulfonic acids complexes having the following structure of formula (I):
Figure imgf000002_0002
wherein x represents 0 or 1 , and RSO3H represents 1 ,5-naphthalene disulfonic acid or benzene sulfonic acid. The preferred embodiments of the invention are the agomelatine sulfonic acids complexes as follows:
agomelatine/l ,5-naphthalene disulfonic acid (2/1) complex,
- agomelatine/1 ,5-naphtha!ene disulfonic acid (2/1) monohydrate complex,
agomelatine/benzenesulfonic acid (2/1 ) complex.
Agomelatine/1 , 5-naphthalene disulfonic acid (2/1) complex 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/1 , 5-naphthalene disulfonic acid (2/1) complex
Figure imgf000003_0001
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 crystal structure of agomelatine/1 , 5-naphthalene disulfonic acid (2/1) complex was determined as having the following parameters:
- Space group : P 1 21/c 1 (14)
- Lattice parameters: a = 8.4970(3)A, b = 8.0873(3)A, c = 27.7107(9)A; a = 90°, β =
93.059(2)°, γ = 90° - Unit cell volume : Vuni, cel, = 1901.51 100A3
This agomelatine/l ,5-naphthalene disulfonic acid (2/1) complex is further characterized by its differential scanning calorimetry (DSC) thermogram shown in Figure 2, which exhibits an endothermic event corresponding to a melt with an onset temperature of approximately 237°C.
The invention also relates to agomelatine/l ,5-naphthalene disulfonic acid (2/1) monohydrate complex. Agomelatine/l ,5-naphthaIene disulfonic acid (2/1) monohydrate complex 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/l ,5-naphthalene disulfonic acid (2/1 )
Figure imgf000004_0001
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 crystal structure of agomelatine/l ,5-naphthalene disulfonic acid (2/1) monohydrate complex was determined as having the following parameters: Space group : P -1 (2)
- Lattice parameters: a = 9.5673(3) A, b = 9.7223(3) A, c = 1 1.4632(3) A; a = 76.967(2)°, β = 75.339(1)°, γ = 78.675(2)°
- Unit cell volume : Vunit ceii = 993.93800 A3
This agomelatine/l ,5-naphthalene disulfonic acid (2/1) monohydrate complex is further characterized by its differential scanning calorimetry (DSC) thermogram shown in Figure 4, which exhibits two endothermic events: one at about U 6°C corresponding to the dehydration, and the other about 238°C corresponding to the complex.
The invention also relates to agomelatine/benzene sulfonic acid (2/1) complex. Agomelatine/benzene sulfonic acid (2/1) complex has been characterized by the main-ray powder diffraction diagram given in Figure 5, 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 3:
Table 3 : Table of diffraction peaks for agomelatine/benzene sulfonic acid (2/1 ) complex
Figure imgf000005_0001
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 crystal structure of agomelatine/benzene sulfonic acid (2/1) complex was determined as having the following parameters:
Space group : P -1 (2)
- Lattice parameters: a = 15.5878(8) A, b = 15.7088(6) A, c = 7.2091 (3) A; a = 100.445(2)°, β = 99.470(2)°, γ = 89.054(3)°
- Unit cell volume : VUnit ceii = 1712.18900 A3
This agomelatine/benzene sulfonic acid (2/1) complex is further characterized by its differential scanning calorimetry (DSC) thermogram shown in Figure 6, which exhibits one endothermic events at about 1 16°C.
The present invention further provides a method for the preparation of said agomelatine sulfonic acids complexes, wherein:
agomelatine and the sulfonic acid are mixed in an organic solvent 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 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.
In the process according to the invention, the solvent used is preferably a ketone such as, for example acetone, an ether such as, for example, diisopropyl ether, tetrahydrofuran 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, ketones such as for example acetone, or ethers such as for example diisopropyl ether or methyl tert-butyl ether. Alternatively an alcohol such as, for example methanol, ethanol 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 sulfonic acids 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 } 0 to 40 and the speed of rotation from 10 to 200 rpm. The temperature used varies from 40 to 100°C.
The agomelatine sulfonic acids complexes produced according to the present method have significant increased solubility than agomelatine per se, and therefore are more suitable for manufacturing pharmaceutical formulations. The agomelatine sulfonic acids complexes of the invention furthermore present very good stability, purity and solubility. In addition, they can be obtained through a simple process, free of any complicated steps.
Pharmacological tests of the agomelatine sulfonic acids complexes 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 agomelatine sulfonic acids complexes 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 agomelatine/1 ,5-naphthalene disulfonic acid (2/1 ) complex of Example 1.
Fig. 2 shows the DSC thermogram of agomelatine/1, 5-naphthalene disulfonic acid (2/1) complex of Example 1 . Fig. 3 shows the X-ray powder diffraction pattern of agomelatine/l ,5-naphthalene disulfonic acid (2/1 ) monohydrate complex of Example 2.
Fig. 4 shows the DSC thermogram of agomelatine/ 1 ,5 -naphthalene disulfonic acid (2/1) monohydrate complex of Example 2.
Fig. 5 shows the X-ray powder diffraction pattern of agomelatine/benzene sulfonic acid (2/1) complex of Example 3. Fig. 6 shows the DSC thermogram of agomelatine/benzene sulfonic acid (2/1) complex of Example 3.
Examples Example 1 : Agomelatine / 1,5-naphthalene disulfonic acid (2/1) complex
Process 1
Agomelatine (5.00g, 2 eq) and 1 ,5-naphthalene disulfonic acid anhydrous (2,96g, 1 eq) were added into a reactor. 20ml of acetone was then added. The suspension was stirred at reflux for lhr, filtered immediately. The filter cake was washed by acetone twice, and then dried for lhour. 25g white solid corresponding to the compound of the title was obtained.
Yield: 78.5%.
Melting point: 237°C
Process 2
Agomelatine (2.98g, 2 eq) and 1,5-naphthalene disulfonic acid tetrahydrate (2.18g, 1 eq) were introduced in a 250 mL round bottom flask. 100 mL of acetone were added and the reaction mixture was then refluxed for 3 hours (crystallization occurred after about 1 hour). The suspension was cooled to room temperature and stirred for 1 hour. 4.03g white solid corresponding to the title product was isolated by filtration and dried under vacuum (10 mbars) at 40°C for 15 hours.
Yield : 85.0%
Melting point: 237 °C
Process 3
Agomelatine (5.00g, 2 eq) and 1,5-naphthalene disulfonic acid anhydrous (2.96g, 1 eq) were added into a reactor. 40ml of methyl tert-butyl ether was then added. The suspension was stirred at reflux for 3hr, filtered immediately. The filter cake was washed by methyl tert-butyl ether twice, and then dried for lhour. 5.28g white solid corresponding to the compound of the title was obtained.
Yield: 66.3%.
Melting point: 237°C
Agomelatine used in the above examples is commercially available or can be prepared according to methods known in the art.
Example 2 : Agomelatine / 1,5-naphthalene disulfonic acid (2/1) monohydrate complex Process 1
Agomelatine (5.00g, l .Oeq) and 1 ,5-naphthalene disulfonic acid anhydrous (5.92g, l .Oeq) were added into a reactor. 10ml ethanol and 20ml water were then added. The suspension was stirred at reflux for 0.5hr to reach clear. After natural cooling to room temperature and stirring 0.5 hour, the suspension was filtered. The filter cake was washed by ethanol and water, and then dried for 1 hour. 5.15g white solid was isolated.
Yield: 63.2%
Melting point: 1 16°C(dehydration endotherm), 238°C Processs 2
Agomelatine (5.00g, l .Oeq) and 1,5-naphthalene disulfonic acid tetrahydrate (7.40g, l .Oeq) were added into a reactor. 10ml ethanol and 20ml water were then added. The suspension was stirred at reflux for 0.5hr to reach clear. After natural cooling to room temperature and stirring 0.5 hour, the suspension was filtered. The filter cake was washed by ethanol and water, and then dried for 1 hour. 4.90g white solid was isolated.
Yield : 60.2%
Melting point: 1 16°C (dehydration endotherm), 238°C Process 3
Agomelatine (0.500g) and 1 ,5-naphthalene disulfonic acid tetrahydrate (0.370g) are introduced into a 50ml non-oxidisable jar. Two stainless steel balls of 12 mm diameter are added and jar is closed. Vibrations with a frequency of 30 Hz are applied for 15 minutes to yield, after drying overnight at room temperature, 0.805g solid was got.
Melting point: 1 16°C (dehydration endotherm), 238 °C Process 4
Agomelatine (0.500g) and 1 ,5-naphthalene disulfonic acid tetrahydrate (0.370g) are introduced into a 50ml non-oxidisable jar. Two stainless steel balls of 12 mm diameter are added and jar is closed. Ι ΟΟμΙ 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, 0.803g solid was got.
Melting point: 1 16°C (dehydration endotherm), 238°C
Agomelatine used in the above example is commercially available or can be prepared according to methods known in the art.
Example 3 : Agomelatine / benzene sulfonic acid (2/1) complex
Agomelatine (5.00g, 2.0eq) and benzene sulfonic acid (1.62g, l .Oeq) were added into a reactor. l Oml of ethanol and 15ml (10ml + 5ml) of toluene were then added. The suspension was stirred at reflux for 0.5hr to reach clear (if it cannot get clear, adding ethanol until clear). After natural cooling to 5°C and stirring 0.5hour, the suspension was filtered. The filter cake was dried for 1 hour. 4.3 l g title compound was obtained as a white solid.
Yield: 65.2%
Melting point: 116°C Agomelatine used in the above example is commercially available or can be prepared according to methods known in the art.
Example 4: Pharmaceutical Compositions: Capsules containing 25 mg agom
Pharmaceutical composition containing compound of Example 1
Formulation for the preparation of 1000 capsules
each containing a dose of 25 mg agomelatine
Compound of Example 1 39.8 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
Pharmaceutical composition containing compound of Example 2
Formulation for the preparation of 1000 capsules
each containing a dose of 25 mg agomelatine
Compound of Example 2 40.7 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
Pharmaceutical composition containing compound of Example 3
Formulation for the preparation of 1000 capsules
each containing a dose of 25 mg agomelatine
Compound of Example 3 33.1 g
Lactose (Spherolac 100) 85.2 g
Starch 1500 25.5 g
CMS-Na 8.5 g
Ac-Di-Sol ® (FMC) Π g
Stearic Acid 3.4 g
Example 5: Pharmaceutical Compositions: Tablets containing 25 mg agomelatine Formula for the preparation of 1000 tablets each containing 25 mg of agomelatine:
Compound of Example 1 39.8 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
Formula for the preparation of 1000 tablets each containing 25 mg of agomelatine:
Compound of Example 2 40.7 g
Lactose monohydrate 1 15 g
Magnesium stearate 2 g
Maize starch 33 g
Maltodextrins 15 g
Anhydrous colloidal silica l g
Pregelatinised maize starch, Type A 9 g
Formula for the preparation of 1000 tablets each containing 25 mg of agomelatine:
Compound of Example 3 33.1 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 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 Example 1.
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.
Compounds of the invention all exhibit purities superior or equal to 99%.
2. Stability Test
Some of the product of Examples 1 , 2 and 3 were placed into incubators under denaturing conditions and stability was determined using DSC measures over 2 months. The results are shown in the following Table 4.
Figure imgf000011_0001
Product of Example 3 stable stable stable
H = relative Humidity; OB = Open Bottle; CB = Close Bottle
Compounds of the invention are stable under strong denaturing conditions, which is favourable for use in pharmaceutical formulations.
3. Water Solubility
Using external standard method, the products of Examples 1, 2 and 3 were tested with HPLC, compared with agomelatine crystalline form II. The results are shown in the following Table 5 as % of solubility improvement compared to agomelatine form II solubility:
Table 5
Figure imgf000012_0001
As can be seen, the agomelatine sulfonic acids complexes of the present invention exhibit 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. Differential Scanning Calorimetry (DSC) Analysis
Approximately, 5-10 mg of the compounds of Examples 1 , 2 and 3 were 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 for compounds of Example 1 , 2 and 3 are shown in Figures 2, 4 and 6.
5. Crystal Structure Analysis
The measurement condition for the X-ray powder diffraction pattern of the products of Examples 1, 2 and 3 in the present invention is as follows:
Approximately, 50 mg of compounds of Examples 1, 2 and 3 were placed between two Kapton® films fixed on the sample holder. The sample was then loaded into a PANALYTICAL XPERT-PRO PD 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-A1 Ratio 0.50000 Scan type : continuous from 3° to 55° (Bragg angle 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 diagram obtained for compounds of Example 1, 2 and 3 are represented Figures 1 , 3 and 5.

Claims

Claims:
1 . Agomelatine sulfonic acids complexes of formula (I):
Figure imgf000014_0001
wherein x represents 0 or 1 , and RSO3H represents 1,5-naphthalene disulfonic acid or benzene sulfonic acid.
2. Agomelatine sulfonic acid complex of formula (I) according to claim 1 that is agomelatine/ 1,5- naphthalene disulfonic acid (2/1) complex.
3. Agomelatine sulfonic acid complex of formula (I) according to claim 2, characterised in its X-ray powder diffraction diagram by the Bragg's angles 2 theta (expressed in °±0.2), interplanar spacing d and relative intensit as follows:
Figure imgf000014_0002
and which also includes crystals whose peak diffraction angles match within an error of ±0.2°. 4. Agomelatine sulfonic acid complex of formula (I) according to claim 1 that is agomelatine/1,5- naphthalene disulfonic acid (2/1) monohydrate complex.
5. Agomelatine sulfonic acid complex of formula (I) according to claim 4, 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:
Figure imgf000015_0001
and which also includes crystals whose peak diffraction angles match within an error of ±0.2°.
6. Agomelatine sulfonic acid complex of formula (I) according to claim 1 that is agomelatine/benzene sulfonic acid (2/1) complex.
7. Agomelatine sulfonic acid complex of formula (I) according to claim 6, 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:
Figure imgf000015_0002
16.1644 5.48344 12.98
17.2360 5.14486 21.06
18.1046 4.89993 36.33
18.6255 4.76406 10.91
18.8009 4.72001 33.43
20.0908 4.41978 30.26
20.4742 4.33788 42.37
20.6921 4.29270 56.78
20.8640 4.25771 26.42
21.7142 4.09289 13.88
23.3683 3.80679 15.16
23.6410 3.76349 100.00
24.9314 3.57154 26.81
25.6543 3.47253 10.71
27.5599 3.23660 14.00 and which also includes crystals whose peak diffraction angles match within an error of +0.2°.
8. Process for obtaining the agomelatine sulfonic acids complexes of formula (I) according to claims I to 7, characterised in that:
- agomelatine and sulfonic acids are mixed in an organic solvent 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 selected solvent;
the mixture is cooied, with stirring, and the co-crystal precipitates naturaiJy or precipitates after taking up in a second solvent;
the precipitate obtained is filtered and dried.
9. Process for obtaining the agomelatine sulfonic acids complexes of formula (I) according to claims 1 to 7, characterised in that the two constituents are co-ground.
10. Process for obtaining the agomelatine sulfonic acids complexes of formula (I) according to claims 1 to 7, 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.
1 1. Process for obtaining the agomelatine sulfonic acids complexes of formula (I) according to claims 1 to 7, characterised in that powders of agomelatine and of the sulfonic acids 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.
12. Pharmaceutical compositions comprising as active ingredient agomelatine sulfonic acids complexes of formula (I) according to claims 1 to 7, in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers.
13. Pharmaceutical compositions according to claim 12 for use in the manufacture of medicaments for treating disorders of the melatoninergic system.
14. Pharmaceutical compositions according to claim 12 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.
15. Agomelatine sulfonic acids complexes of formula (I) according to claims 1 to 7 for the treatment of disorders of the melatoninergic system.
16. Agomelatine sulfonic acids complexes of formula (I) according to claims 1 to 7 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.
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