NZ600479B - New co-crystals of agomelatine, a process for their preparation and pharmaceutical compositions containing them - Google Patents
New co-crystals of agomelatine, a process for their preparation and pharmaceutical compositions containing them Download PDFInfo
- Publication number
- NZ600479B NZ600479B NZ600479A NZ60047912A NZ600479B NZ 600479 B NZ600479 B NZ 600479B NZ 600479 A NZ600479 A NZ 600479A NZ 60047912 A NZ60047912 A NZ 60047912A NZ 600479 B NZ600479 B NZ 600479B
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- Prior art keywords
- acid
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- agomelatine
- crystal
- crystals
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- YJYPHIXNFHFHND-UHFFFAOYSA-N Agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 title claims abstract description 62
- 229960002629 agomelatine Drugs 0.000 title claims abstract description 47
- 238000000034 method Methods 0.000 title abstract description 18
- 238000002360 preparation method Methods 0.000 title description 8
- 239000008194 pharmaceutical composition Substances 0.000 title description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 25
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 24
- LNTHITQWFMADLM-UHFFFAOYSA-N Gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 claims abstract description 16
- JFCQEDHGNNZCLN-UHFFFAOYSA-N Glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 claims abstract description 16
- AEMRFAOFKBGASW-UHFFFAOYSA-N glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims abstract description 16
- OFOBLEOULBTSOW-UHFFFAOYSA-N malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 16
- 150000007524 organic acids Chemical class 0.000 claims abstract description 12
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-Hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 10
- 229940074391 Gallic acid Drugs 0.000 claims abstract description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000004515 gallic acid Nutrition 0.000 claims abstract description 8
- 239000011976 maleic acid Substances 0.000 claims abstract description 8
- 235000006408 oxalic acid Nutrition 0.000 claims abstract description 8
- 239000007787 solid Substances 0.000 claims abstract description 8
- KPGXRSRHYNQIFN-UHFFFAOYSA-N α-Ketoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960004106 citric acid Drugs 0.000 claims abstract description 7
- 235000015165 citric acid Nutrition 0.000 claims abstract description 5
- 229940116315 Oxalic Acid Drugs 0.000 claims abstract description 4
- 229940098895 maleic acid Drugs 0.000 claims abstract description 4
- 238000004090 dissolution Methods 0.000 claims description 30
- 239000004480 active ingredient Substances 0.000 claims description 12
- 230000001264 neutralization Effects 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- 230000004048 modification Effects 0.000 claims 1
- 238000006011 modification reaction Methods 0.000 claims 1
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- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 10
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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- WSVLPVUVIUVCRA-RJMJUYIDSA-N (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol;hydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-RJMJUYIDSA-N 0.000 description 2
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- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
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- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
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- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/06—Oxalic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/08—Malonic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/12—Glutaric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/145—Maleic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/265—Citric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
Abstract
ABSTRACT - 600479 The disclosure relates to a co-crystal of agomelatine, characterised in that it is composed of: (i) agomelatine, or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide of formula (I), and (ii) an organic acid which is in a solid state at ambient temperature chosen from parahydroxybenzoic acid, citric acid, oxalic acid, gallic acid, maleic acid, malonic acid, glutaric acid, glycolic acid or ketoglutaric acid. Also disclosed is a process for obtaining said co-crystal comprising the following steps wherein: (i) the two constituents are mixed in an organic solvent in the desired proportions (1 equivalent of agomelatine per 0.25 to 4 molar equivalents of organic acid), preferably the two constituents are co-ground; (ii) the solution obtained is stirred and optionally heated at a temperature not greater than the boiling point of the selected solvent; (iii) the mixture is cooled, with stirring, and the co-crystal precipitates naturally or precipitates after taking up in a second solvent; (iv) the precipitate obtained is filtered and dried. These co-crystals are suitable 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. c acid, citric acid, oxalic acid, gallic acid, maleic acid, malonic acid, glutaric acid, glycolic acid or ketoglutaric acid. Also disclosed is a process for obtaining said co-crystal comprising the following steps wherein: (i) the two constituents are mixed in an organic solvent in the desired proportions (1 equivalent of agomelatine per 0.25 to 4 molar equivalents of organic acid), preferably the two constituents are co-ground; (ii) the solution obtained is stirred and optionally heated at a temperature not greater than the boiling point of the selected solvent; (iii) the mixture is cooled, with stirring, and the co-crystal precipitates naturally or precipitates after taking up in a second solvent; (iv) the precipitate obtained is filtered and dried. These co-crystals are suitable 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.
Description
NEW ZEALAND
PATENTS ACT, 1953
COMPLETE SPECIFICATION
NEW CO-CRYSTALS OF AGOMELATINE, A PROCESS FOR THEIR
PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
We, LES LABORATOIRES SERVIER, a French body corporate of 35, rue de Verdun
92284, Suresnes Cedex, France, do hereby declare the invention for which we pray that a
patent may be granted to us, and the method by which it is to be performed, to be
particularly described in and by the following statement:
The present invention relates to new co-crystals of agomelatine, or N-[2-(7-methoxy
naphthyl)ethyl]acetamide of formula (I):
NHCOMe
(I),
to a process for their preparation and to pharmaceutical compositions containing them.
Specifically, the invention provides a co-crystal of agomelatine, characterised in that it is
composed of: agomelatine, or N-[2-(7-methoxynaphthyl)ethyl]acetamide of formula (I)
NHCOMe
(I),
and an organic acid which is in a solid state at ambient temperature chosen from para-
hydroxybenzoic acid, citric acid, oxalic acid, gallic acid, maleic acid, malonic acid, glutaric
acid, glycolic acid or ketoglutaric acid.
Agomelatine, or N-[2-(7-methoxynaphthyl)ethyl]acetamide, has valuable
pharmacological properties.
In fact, it has the double characteristic of being, on the one hand, an agonist of receptors of
the melatoninergic system and, on the other hand, an antagonist of the 5-HT receptor.
These properties provide it with activity in the central nervous system and, more
especially, in the treatment of major depression, seasonal affective disorder, sleep
disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and
fatigue due to jet-lag, appetite disorders and obesity.
Agomelatine, its preparation and its use in therapeutics have been described in European
Patent Specification EP 0 447 285.
In view of the pharmaceutical value of this compound, a great deal of research work has
been carried out, making it possible to isolate different polymorphic forms having various
advantages, especially regarding purity, stability, reproducibility and formulation
characteristics etc., allowing storage for an extended period without particular conditions
regarding temperature, light, humidity or oxygen levels.
Furthermore, as with any active ingredient intended for administration to humans, it is very
important to be able to control its dissolution rate so as to promote rapid or, on the
contrary, slow diffusion.
The Applicant has now developed new co-crystals of agomelatine which make it possible
to modify the dissolution rate of the active ingredient. The co-crystals according to the
invention have a dissolution rate that is accelerated or delayed compared to the form
available on the market which is described in patent specification EP 1 564 202 and
marketed under the trade mark Valdoxan. These new co-crystals having a modified
dissolution profile accordingly make it possible to consider new formulations matched to
the desired use.
A co-crystal is a crystal complex composed of at least two neutral molecules bound
together in a crystal lattice by non-covalent interactions. The main difference between
solvates and co-crystals is related to the physical state of the pure components: if one of the
constituents is liquid at ambient temperature, the molecular complex is then a solvate; if all
the components are solid at ambient temperature, the complex is then designated by the
term "co-crystal". The major difference between a solvate and a co-crystal is the much
greater stability of the co-crystal compared to the solvate. A co-crystal is characterised by
the method by which it is obtained and by an ordered three-dimensional structure which is
demonstrated, for example, by X-ray diffraction diagrams. It is not possible to know a
priori whether two given constituents will be able to form a co-crystal having a particular
three-dimensional structure or will simply give rise to a juxtaposition of the two powders.
This particular three-dimensional structure bears a direct relationship to the dissolution rate
of the entity thereby formed.
The invention relates more specifically to new co-crystals formed of agomelatine, on the
one hand, and an organic acid, on the other hand. The co-crystals according to the
invention comprise organic acids which are in a solid state at ambient temperature.
The organic acids according to the invention are linear or branched acids containing from
2 to 10 carbon atoms. They have one or more COOH acid function(s) and, more
preferably, one, two or three acid function(s). They may also have, in addition to their acid
function(s), one or more ketone function(s), one or more hydroxy function(s) and/or one or
more unsaturated bond(s).
The organic acids that are constituents of the co-crystals according to the invention are
chosen from para-hydroxybenzoic acid, citric acid, oxalic acid, gallic acid, maleic acid,
malonic acid, glutaric acid, glycolic acid and ketoglutaric acid.
The proportion of organic acid used in relation to the agomelatine varies from 0.25 to
4 molar equivalents, preferably from 0.5 to 2 molar equivalents.
More especially, the invention relates to the following co-crystals: agomelatine/para-
hydroxybenzoic acid (2/1) and (1/2); agomelatine/citric acid (1/1); agomelatine/oxalic acid
(2/1); agomelatine/gallic acid (2/1); agomelatine/maleic acid (1/1); agomelatine/malonic
acid (1/1); agomelatine/glutaric acid (1/1); agomelatine/glycolic acid (1/1);
agomelatine/ketoglutaric acid (1/1).
The invention relates also to a process for obtaining co-crystals of agomelatine and organic
acids, wherein:
- the two constituents are mixed in an organic solvent in the desired proportions
(1 equivalent of agomelatine per 0.25 to 4 molar equivalents of organic acid);
- 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 an alcohol such as,
for example, methanol or tert-butanol; an ether such as, for example, diisopropyl ether 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, benzonitrile is
advantageously selected.
An alternative process comprises co-grinding the two constituents of the co-crystal. 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 obtained is then
dried. Among the solvents used, there may be mentioned, more especially, alcohols such as
for example, ethanol or ethers such as, for example, diisopropyl ether.
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 15 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 of the acid in question 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.
In the processes for preparation of the co-crystals according to the invention there may be
used a compound of formula (I) that has been obtained by any process, especially by the
process described in EP 1 564 202.
The co-crystals according to the invention exhibit properties that are highly valuable in
terms of stability and dissolution - two essential parameters in the pharmaceutical industry.
The dissolution of active ingredients is an important characteristic which may determine
the rate of their adsorption in the human body. It is an important step in the release process,
which has a major impact on the activity of a medicament. In fact, in order to cross
biological membranes or in order to be absorbed, the active ingredient has to be dispersed
in the molecular state in aqueous media (that is to say, dissolved) at the absorption site.
The dissolution rate of the active ingredient is governed by its physico-chemical
characteristics and also by the conditions of the absorption medium. It is accordingly
important to have at one's disposal forms having a modified active ingredient dissolution
rate, making it possible to obtain more, or less, rapid dissolution of the active ingredient
matched to the desired use: a form having improved dissolution for use in immediate-
release formulations, and a form having less rapid dissolution for use in retard or delayed-
release formulations.
The co-crystals according to the invention meet this requirement, because it is possible to
modify the dissolution rate of agomelatine and to promote or reduce its dissolution by a
factor of up to 2 relative to the form currently marketed in the pharmaceutical product
Valdoxan. More particularly, the co-crystals according to the invention make it possible
to modify the active ingredient dissolution rate compared to the dissolution rate of the form
currently marketed in the pharmaceutical product Valdoxan by at least 25% under neutral
(pH 6.8) or acid (0.01N HCl) conditions. It is accordingly possible to use the co-crystals
according to the invention in developing immediate-release pharmaceutical forms in which
the dissolution rate is improved relative to the form currently available on the market and
also delayed-release forms in which the dissolution rate is retarded.
The pharmaceutical forms comprising the co-crystals according to the invention will be
used for their activity in respect of the central nervous system and microcirculation, 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. In another field of activity, it will be possible to use the co-crystals
according to the invention in sexual dysfunctions, as ovulation inhibitors and
immunomodulators and in the treatment of cancers.
The co-crystals according to the invention will preferably be used in treatments for major
depression, seasonal affective disorder, sleep disorders, anxiety disorders, mood disorders,
cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due
to jet-lag, appetite disorders and obesity.
The invention relates also to pharmaceutical compositions comprising as active ingredient
a co-crystal according to the invention together with one or more appropriate, inert, non-
toxic 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 dragées, granules, sublingual tablets,
capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations,
drinkable suspensions and chewing gums.
The useful dosage can be varied according to the nature and severity of the disorder, the
administration route and the age and weight of the patient. The dosage varies from 0.1 mg
to 1 g of agomelatine per day in one or more administrations.
The term “comprising” as used in this specification and claims means “consisting at least
in part of”. When interpreting statements in this specification and claims which include
the term “comprising”, other features besides the features prefaced by this term in each
statement can also be present. Related terms such as “comprise” and “comprised” are to be
interpreted in similar manner.
In this specification where reference has been made to patent specifications, other external
documents, or other sources of information, this is generally for the purpose of providing a
context for discussing the features of the invention. Unless specifically stated otherwise,
reference to such external documents is not to be construed as an admission that such
documents, or such sources of information, in any jurisdiction, are prior art, or form part of
the common general knowledge in the art.
In the description in this specification reference may be made to subject matter that is not
within the scope of the claims of the current application. That subject matter should be
readily identifiable by a person skilled in the art and may assist in putting into practice the
invention as defined in the claims of this application.
The Examples hereinbelow illustrate the invention but do not limit it in any way.
Example 1: Co-crystal of agomelatine/citric acid (1/1)
Procedure A
3 g of N-[2-(7-methoxynaphthyl)ethyl]acetamide and 2.6 g of citric acid are introduced
into a 100-ml flask. 30 ml of MeOH are added and the solution is stirred for 20 hours at
ambient temperature. After evaporation to dryness, the white gum obtained is taken up in
ml of benzonitrile added in portions of 3 ml. The suspension obtained is stirred until
conversion of the gum into crystals is complete. After filtering, and washing with 20 ml of
benzonitrile, the solid obtained is dried in vacuo at ambient temperature. It is characterised
by its melting point and by the following X-ray powder diffraction diagram, measured
using a Panalytical Xpert Pro MPD diffractometer (copper anticathode) and 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):
2-Theta (°) exp. d (Å) exp. Intensity (%)
.2156 16.94412 68.95
.4436 8.47079 6.74
11.6034 7.62656 14.07
12.2434 7.2293 30.56
12.4588 7.10477 10.78
13.7638 6.43394 15.73
.4174 5.74741 16.17
.5925 5.68326 19.78
17.0703 5.19444 100
17.7473 4.99777 16.62
19.3834 4.57946 94.32
19.7762 4.48938 17.46
.6894 4.29325 36.51
.9759 4.23524 16.96
21.8985 4.05886 28.16
22.8106 3.89859 41.15
23.1664 3.83951 10.48
24.0776 3.69623 18.91
24.2435 3.6713 7.06
24.7742 3.59385 13.06
.0152 3.55977 6.18
.2672 3.52484 13.34
.581 3.48231 5.37
26.3081 3.38769 16.92
26.5266 3.36028 17.15
27.0632 3.29486 6.91
27.2996 3.26687 30.63
27.8968 3.19827 8.39
28.7066 3.10986 7.1
29.6523 3.0128 9.86
31.4888 2.84116 17.44
34.4996 2.59979 5.96
.0074 2.56324 5.71
Bragg's angles 2 theta (expressed in °+0.2) characteristic of the X-ray powder diffraction
diagram: 5.21°, 12.24°, 17.07°, 19.38°, 20.69°, 21.90°, 22.81°, 27.30°.
Melting point: 126-129°C
Procedure B
316.59 g of agomelatine and 250 g of citric acid monohydrate are mixed in a mixer of
Turbula type for 10 minutes. The mixture is then extruded by twin screw extrusion without
a die in order to obtain a solid granular product directly at the extruder outlet. A high-shear
screw profile is used together with mixing elements in order to improve the surface contact
between the two constituents. The L/D parameter of the screw used is 19. The rotation
speed of the screws is 50 rpm for a feed rate measured at 300 g/h. The extrusion
temperature is 55°C. The co-crystal obtained is characterised by its X-ray powder
diffraction diagram, which is the same as that obtained by Procedure A.
Example 2: Co-crystal of agomelatine/gallic acid (2/1)
A solution of 300.6 mg of N-[2-(7-methoxynaphthyl)ethyl]acetamide in 15 ml of tert-
butanol is slowly added to a solution of 106 mg of gallic acid in 35 ml of water in a 250-ml
flask. The mixture is stirred for 10 minutes and then the solution is frozen to -40°C and
dried at that same temperature for 2 days in order to yield the title product, which is
characterised by its melting point and by the following X-ray powder diffraction diagram,
measured using a Panalytical Xpert Pro MPD diffractometer (copper anticathode) and
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):
2-Theta (°) exp. d (Å) exp. Intensity (%)
7.4888 11.8051 13.8
9.9347 8.90352 14.42
12.456 7.10638 9.11
12.7479 6.9443 14.08
14.0965 6.28286 5.63
14.4701 6.12146 20.24
16.7302 5.29926 14.01
16.829 5.26837 13.25
17.6782 5.01714 100
19.8178 4.48005 27.73
21.2441 4.18238 14.42
21.8521 4.06737 7.02
22.3357 3.98038 39.37
23.2889 3.81958 10.11
23.9313 3.71848 64.55
24.3882 3.64985 17.32
.1812 3.53668 5.33
27.5931 3.23278 5.39
29.6861 3.00945 7.02
.7722 2.90566 7.71
Bragg's angles 2 theta (expressed in °+0.2) characteristic of the X-ray powder diffraction
diagram: 14.47°, 17.68°, 19.82°, 22.33°, 23.93°.
Melting point: 108-110°C
Example 3: Co-crystal of agomelatine/maleic acid (1/1)
1 g of N-[2-(7-methoxynaphthyl)ethyl]acetamide and 482 mg of maleic acid are
introduced into a 25-ml non-oxidisable jar. Two stainless steel balls of 12 mm diameter are
added and the jar is closed. Vibrations with a frequency of 30 Hz are applied for 60
minutes to yield the title product, which is characterised by its melting point and by the
following X-ray powder diffraction diagram, measured using a Panalytical Xpert Pro MPD
diffractometer (copper anticathode) and 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):
2-Theta (°) exp. d (Å) exp. Intensity (%)
8.5443 10.34036 13.27
11.3006 7.82375 41.61
.4031 5.74794 37.77
.5752 5.68481 5.97
17.1135 5.17711 17.72
17.2840 5.12642 21.02
17.5446 5.05086 5.98
17.9818 4.92905 13.71
18.7041 4.74029 17.45
21.7442 4.08392 11.17
22.8692 3.88551 10.99
23.9084 3.71893 19.53
24.2950 3.66062 100
.4494 3.49712 19.43
26.1055 3.4107 5.75
26.2070 3.39772 17.23
26.4841 3.36279 5.79
27.2254 3.27288 9.35
.0238 2.9739 6.06
.2591 2.95131 8.82
Bragg's angles 2 theta (expressed in °+0.2) characteristic of the X-ray powder diffraction
diagram: 11.30°, 15.40°, 17.28°, 24.29°.
Melting point: 73-75°C
Example 4: Co-crystal of agomelatine/malonic acid (1/1)
A solution of 300 mg of N-[2-(7-methoxynaphthyl)ethyl]acetamide in 15 ml of tert-
butanol is slowly added to a solution of 129 mg of malonic acid in 35 ml of water in a
250-ml flask. The mixture is stirred for 30 minutes and then the solution is frozen to -40°C
and dried at that same temperature for 2 days in order to yield the title product, which is
characterised by its melting point and by the following X-ray powder diffraction diagram,
measured using a Panalytical Xpert Pro MPD diffractometer (copper anticathode) and
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):
2-Theta (°) exp. d (Å) exp. Intensity (%)
7.8661 11.23971 16.84
.4713 8.44846 46.94
11.9502 7.406 45.62
12.7824 6.92563 9.99
14.7848 5.99187 21.65
.3432 5.77504 19.95
16.0487 5.52273 100
16.7983 5.27793 11.99
16.9715 5.22445 13.9
17.1267 5.17745 9.19
21.0784 4.21489 9.77
22.3247 3.98233 23.32
24.0567 3.69939 6.29
24.5022 3.63313 56.82
.0477 3.55523 23.07
.2424 3.52825 40.38
.7892 3.45467 10.44
26.7244 3.33585 7.17
27.3793 3.25753 20.44
27.9097 3.19682 26.63
29.4500 3.03304 10.41
34.0469 2.63332 5.16
Bragg's angles 2 theta (expressed in °+0.2) characteristic of the X-ray powder diffraction
diagram: 10.47°, 11.95°, 14.78°, 16.05°, 22.32°, 24.50°, 25.05°, 25.24°, 27.38°, 27.91°.
Melting point: 67-68°C
Example 5: Co-crystal of agomelatine/para-hydroxybenzoic acid (2/1)
1 g of N-[2-(7-methoxynaphthyl)ethyl]acetamide and 283.8 mg of para-hydroxybenzoic
acid are introduced into a 25-ml non-oxidisable jar. Two stainless steel balls of 12 mm
diameter are added and the jar is closed. 200 µl of isopropyl ether are added. Vibrations
with a frequency of 30 Hz are applied for 60 minutes to yield the title product, which is
characterised by its melting point and by the following X-ray powder diffraction diagram,
measured using a Panalytical Xpert Pro MPD diffractometer (copper anticathode) and
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):
2-Theta (°) exp. d (Å) exp. Intensity (%)
.6835 8.28111 11.39
11.9471 7.40793 8.16
12.0698 7.33288 12.04
13.1596 6.72799 22.29
14.6189 6.05948 6.29
14.7754 5.99567 11.14
14.907 5.94301 43.41
.1499 5.84827 14.08
16.7697 5.28686 7.17
17.08 5.19149 8.17
17.2378 5.14433 10.12
17.3731 5.10456 20.24
17.5783 5.04543 16.57
18.3905 4.82442 24.81
18.7565 4.73108 11.19
18.9282 4.68855 23.85
19.0366 4.6621 21.45
19.4137 4.57238 8.15
19.6471 4.5186 20.4
19.9637 4.44765 20.12
.1044 4.41683 19.09
.2539 4.38456 20.62
.9205 4.24635 10.62
21.491 4.13489 100
21.7733 4.08191 91.9
22.2831 3.98966 7.75
23.7997 3.73875 12.32
23.9912 3.70935 8.36
24.2112 3.67614 6,78
24.6151 3.61672 17.26
24.9976 3.56224 22.13
26.5573 3.35646 4.98
26.7447 3.33337 5.85
27.5321 3.2398 12.36
29.4497 3.03306 12.87
Bragg's angles 2 theta (expressed in °+0.2) characteristic of the X-ray powder diffraction
diagram: 13.16°, 14.91°, 17.37°, 18.39°, 18.93°, 19.04°, 19.65°, 19.96°, 20.25°, 21.49°,
.00°.
Melting point: 93-95°C
Example 6: Co-crystal of agomelatine/para-hydroxybenzoic acid (1/2)
1 g of N-[2-(7-methoxynaphthyl)ethyl]acetamide and 1.14 g of para-hydroxybenzoic
acid are introduced into a 25-ml non-oxidisable jar together with 250 µl of diisopropyl
ether. Two stainless steel balls of 12 mm diameter are added and the jar is closed.
Vibrations with a frequency of 30 Hz are applied for 120 minutes to yield the title product,
which is characterised by its melting point and by the following X-ray powder diffraction
diagram, measured using a Panalytical Xpert Pro MPD diffractometer (copper anticathode)
and 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):
2-Theta (°) exp. d (Å) exp. Intensity (%)
6.9836 12.65784 17.63
8.4549 10.45823 6.16
9.4969 9.31293 34.61
12.2797 7.208 38.63
12.9651 6.82845 14.3
13.1503 6.7327 7.88
13.7866 6.42337 7.33
13.9951 6.32814 27.1
.7604 5.62307 52.5
16.1791 5.4785 32.32
16.6241 5.33282 51.26
17.5572 5.05145 39.19
18.1485 4.8882 54.91
18.3819 4.82664 17.31
19.3253 4.5931 17.44
19.4415 4.56592 17.76
19.7593 4.49317 51.9
19.959 4.44867 42.09
21.0028 4.22989 45.52
21.2989 4.17175 20.42
22.0032 4.03979 60.83
22.6859 3.91973 11.33
22.9715 3.87164 20.19
23.5476 3.77821 39.55
23.7609 3.74477 93.42
24.4422 3.64191 32.21
.3271 3.51664 19.07
.5471 3.48685 14.62
26.0938 3.41502 100
26.8242 3.32367 21.88
26.9813 3.30467 16.4
27.9183 3.19586 6.85
28.4188 3.1407 27.49
28.7129 3.1092 30.36
29.276 3.05067 5.22
29.8536 2.99295 28.73
.7825 2.90472 6.33
34.5702 2.59464 5.06
Bragg's angles 2 theta (expressed in °+0.2) characteristic of the X-ray powder diffraction
diagram: 9.50°, 12.28°, 14.00°, 15.76°, 16.18°, 16.62°, 17.56°, 18.15°, 19.96°, 21.00°,
21.30°, 22.00°, 22.97°, 23.55°, 23.76°, 24.44°, 26.09°, 26.82°, 28.42°, 28.71°, 29.85°.
Melting point: 116-118°C
Example 7: Co-crystal of agomelatine/oxalic acid (2/1)
1 g of N-[2-(7-methoxynaphthyl)ethyl]acetamide and 185.5 mg of oxalic acid are
introduced into a 25-ml non-oxidisable jar. Two stainless steel balls of 12 mm diameter are
added and the jar is closed. Vibrations with a frequency of 30 Hz are applied for
minutes to yield the title product, which is characterised by its melting point and by the
following X-ray powder diffraction diagram, measured using a Panalytical Xpert Pro MPD
diffractometer (copper anticathode) and 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):
2-Theta (°) exp. d (Å) exp. Intensity (%)
8.7632 10.09092 8.8
12.4791 7.09329 100
13.8057 6.41451 28.18
14.0254 6.31452 63.44
14.2244 6.22663 31.66
.302 5.79047 61.34
.4283 5.74335 27.34
17.6112 5.03608 83.89
17.8165 4.97852 55.54
19.6373 4.52082 57.35
19.7701 4.49075 45.05
21.533 4.12692 37.04
21.7182 4.08876 64.35
21.7902 4.07878 58.69
21.9725 4.04535 62.54
24.2928 3.66397 16.29
24.9548 3.56825 55.55
.3868 3.50851 45.81
26.4367 3.3715 11.92
26.7285 3.33536 6.99
27.3623 3.25682 24.66
27.4684 3.24718 36.5
27.8038 3.20876 12.84
29.2866 3.04959 26.14
29.768 3.00136 26.04
.8738 2.89633 5.28
31.2434 2.86291 8.55
31.853 2.8095 5.8
Bragg's angles 2 theta (expressed in °+0.2) characteristic of the X-ray powder diffraction
diagram: 12.48°, 13.80°, 14.02°, 14.22°, 15.30°, 15.43°, 17.61°, 17.82°, 19.64°, 19.77°,
21.53°, 21.72°, 21.79°, 21.97°, 24.95°, 25.39°, 27.36°, 27.47°, 29.29°, 29.77°.
Melting point: 112.5-114.5°C
Example 8: Co-crystal of agomelatine/glutaric acid (1/1)
1 g of N-[2-(7-methoxynaphthyl)ethyl]acetamide and 555 mg of glutaric acid are
introduced into a 25-ml non-oxidisable jar. Two stainless steel balls of 12 mm diameter are
added and the jar is closed. Vibrations with a frequency of 30 Hz are applied for
60 minutes to yield the title product, which is characterised by its melting point and by the
following X-ray powder diffraction diagram, measured using a Panalytical Xpert Pro MPD
diffractometer (copper anticathode) and 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):
2-Theta (°) exp. d (Å) exp. Intensity (%)
9.5919 9.22091 22.85
.3486 8.5483 28.18
11.9618 7.39882 23.63
13.0927 6.76218 8.08
13.7395 6.44526 5.45
14.7283 6.0147 8.81
16.4376 5.39291 13.05
16.9847 5.2204 10.58
17.493 5.06987 10.05
17.6723 5.01881 6.83
18.6123 4.76741 17.35
18.9534 4.68238 15.44
19.9041 4.46083 16.48
.5662 4.31869 20.46
21.6468 4.10548 38.05
21.9751 4.04488 5.01
22.0881 4.02444 5.94
23.3395 3.81143 100
23.7133 3.75217 6.65
24.0288 3.70362 5.71
24.6109 3.61733 5.25
.0027 3.56152 6.82
.863 3.44497 8.04
27.6684 3.22415 17.51
29.1279 3.06584 4.97
Bragg's angles 2 theta (expressed in °+0.2) characteristic of the X-ray powder diffraction
diagram: 9.59°, 10.35°, 11.96°, 20.57°, 21.65°, 23.34°.
Melting point: 74-75°C
Example 9: Co-crystal of agomelatine/ketoglutaric acid (1/1)
1 g of N-[2-(7-methoxynaphthyl)ethyl]acetamide and 600 mg of ketoglutaric acid are
introduced into a 25-ml non-oxidisable jar together with 500 µl of ethanol. Two stainless
steel balls of 12 mm diameter are added and the jar is closed. Vibrations with a frequency
of 30 Hz are applied for 15 minutes to yield, after drying overnight at 40°C, the title
product, which is characterised by its melting point and by the following X-ray powder
diffraction diagram, measured using a Panalytical Xpert Pro MPD diffractometer (copper
anticathode) and 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):
2-Theta (°) exp. d (Å) exp. Intensity (%)
.2391 16.86816 18.25
6.1796 14.30283 7.39
9.6513 9.16426 12.13
.4827 8.43926 8.6
14.2638 6.20954 5
.3616 5.76815 45.63
16.3452 5.41872 43.96
16.5381 5.35593 59.36
17.0478 5.20123 6.44
18.3191 4.84305 8.1
19.2396 4.61337 21.8
.5617 4.31961 7.64
21.036 4.22329 12.12
21.3726 4.15752 7.66
23.57 3.77466 36.07
23.9026 3.7229 24.64
24.4145 3.64597 100
26.4474 3.37016 6.58
29.1314 3.06548 6.73
37.1969 2.41723 5.98
Bragg's angles 2 theta (expressed in °+0.2) characteristic of the X-ray powder diffraction
diagram: 15.36°, 16.34°, 16.54°, 19.24°, 23.57°, 23.90°, 24.41°.
Melting point: 94-96°C
Example 10: Co-crystal of agomelatine/glycolic acid (1/1)
1 g of N-[2-(7-methoxynaphthyl)ethyl]acetamide and 319 mg of glycolic acid are
introduced into a 25-ml non-oxidisable jar. Two stainless steel balls of 12 mm diameter are
added and the jar is closed. Vibrations with a frequency of 30 Hz are applied for
minutes to yield, after drying overnight at 40°C, the title product, which is characterised
by its melting point and by the following X-ray powder diffraction diagram, measured
using a Panalytical Xpert Pro MPD diffractometer (copper anticathode) and 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):
2-Theta (°) exp. d (Å) exp. Intensity (%)
.2906 8.59638 45.79
13.9365 6.35459 5.32
14.1139 6.27513 31.57
14.2265 6.22572 24.57
14.3625 6.16708 11.84
17.9846 4.93237 90.49
18.617 4.76622 10.66
18.8288 4.71308 89.79
19.19 4.62519 9.61
19.5137 4.54918 30.43
19.941 4.45266 6.52
.6101 4.30959 66.27
.9906 4.23232 8.23
22.8209 3.89685 6.31
23.6248 3.76604 5.61
23.9623 3.71375 26.41
24.2171 3.67524 17.2
24.3906 3.64949 100
26.4458 3.37037 27.5
28.1154 3.1739 29.75
28.4808 3.134 5.71
28.6849 3.11217 6.41
28.9288 3.08648 5.75
29.518 3.02621 29.2
32.2458 2.77386 14.35
Bragg's angles 2 theta (expressed in °+0.2) characteristic of the X-ray powder diffraction
diagram: 10.29°, 14.11°, 14.23°, 17.98°, 18.83°, 19.51°, 20.61°, 23.96°, 24.39°, 26.44°,
28.11°, 29.52°.
Melting point: 75-77°C
Example 11: Measurement of the dissolution rate of the co-crystals
Measurement of the dissolution rates of the co-crystals obtained is carried out with aid of a
µDISS analytical apparatus (pION) in an acidic and a neutral medium at 37°C using a
stirring speed of 700 rpm. The results obtained are collated in the following tables and are
expressed as percentage increases in the dissolution rate of the co-crystal compared to the
dissolution rate obtained for agomelatine of form II contained in the marketed Valdoxan
form:
(Dissolution rate of co-crystal) - (Dissolution rate of Valdoxan)
x 100
(Dissolution rate of Valdoxan)
0.01N HCl pH 6.8 buffer
Compound of Example 1 +25% +70%
Compound of Example 2 +37% +29%
Compound of Example 5 +97% +89%
Compound of Example 6 +19% +46%
Compound of Example 7 +1.5% +33%
The results obtained show an increase in the dissolution rate of the co-crystals which
ranges from 33% to 97% under at least one of the two, acid or neutral, conditions tested.
0.01N HCl pH 6.8 buffer
Compound of Example 3 -26% -4%
Compound of Example 4 -55% -21%
Compound of Example 8 -42% -29%
Compound of Example 9 -47% -32%
Compound of Example 10 -30% -30%
The results obtained show a reduction in the dissolution rate of the co-crystals which
ranges from 26% to 55% under at least one of the two, acid or neutral, conditions tested.
E Ex xa am mp plle e 1 12 2: : A Ac cc ce elle er ra at te ed d- -r re elle ea as se e p ph ha ar rm ma ac ce eu ut tiic ca all c co om mp po os siit tiio on n
Formula for the preparation of 1000 tablets each containing 25 mg of agomelatine:
Compound of Example 5 ................................................................................................. 50 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
Example 13: Retarded-release pharmaceutical composition
Example 13: Retarded-release pharmaceutical composition
Formula for the preparation of 1000 tablets each containing 25 mg of active ingredient:
Compound of Example 9 ................................................................................................. 50 g
Lactose monohydrate ............................................................................................... 100 g
Magnesium stearate ................................................................................................. 2 g
Povidone .................................................................................................................. 12 g
Anhydrous colloidal silica ....................................................................................... 1 g
Hypromellose .......................................................................................................... 85 g
Claims (4)
1. Co-crystal of agomelatine, characterised in that it is composed of: - agomelatine, or N-[2-(7-methoxynaphthyl)ethyl]acetamide of formula (I) NHCOMe (I), 5 and - an organic acid which is in a solid state at ambient temperature chosen from para- hydroxybenzoic acid, citric acid, oxalic acid, gallic acid, maleic acid, malonic acid, glutaric acid, glycolic acid or ketoglutaric acid.
2. Co-crystal according to claim 1, characterised in that it modifies the active ingredient 10 dissolution rate compared to agomelatine of form II.
3. Co-crystal according to claim 1 or claim 2, characterised in that it brings about a modification of the active ingredient dissolution rate compared to the dissolution rate of agomelatine of form II of at least 25% under neutral (pH 6.8) or acid (0.01N HCl) conditions. 15
4. Co-crystal according to one of claims 1 to 3 which is N-[2-(7-methoxynaphthyl)- ethyl]acetamide/para-hydroxybenzoic acid (
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR11/01766 | 2011-06-09 | ||
FR1101766A FR2976284B1 (en) | 2011-06-09 | 2011-06-09 | NOVEL CO-CRYSTALS OF AGOMELATIN, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
CN201110245039.6 | 2011-08-25 | ||
CN201110245039 | 2011-08-25 |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ600479A NZ600479A (en) | 2013-10-25 |
NZ600479B true NZ600479B (en) | 2014-01-28 |
Family
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