WO2011113362A1 - Agomelatine hydrochloride hydrate and preparation thereof - Google Patents
Agomelatine hydrochloride hydrate and preparation thereof Download PDFInfo
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- WO2011113362A1 WO2011113362A1 PCT/CN2011/071910 CN2011071910W WO2011113362A1 WO 2011113362 A1 WO2011113362 A1 WO 2011113362A1 CN 2011071910 W CN2011071910 W CN 2011071910W WO 2011113362 A1 WO2011113362 A1 WO 2011113362A1
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- Prior art keywords
- agomelatine
- hydrochloride hydrate
- preparation
- agomelatine hydrochloride
- hydrate according
- Prior art date
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- ZJVMEXOLMFNQPX-UHFFFAOYSA-N n-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide;hydrochloride Chemical compound Cl.C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 ZJVMEXOLMFNQPX-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- YJYPHIXNFHFHND-UHFFFAOYSA-N agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229960002629 agomelatine Drugs 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 32
- 239000013078 crystal Substances 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 208000019901 Anxiety disease Diseases 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 208000019888 Circadian rhythm sleep disease Diseases 0.000 claims description 2
- 208000001456 Jet Lag Syndrome Diseases 0.000 claims description 2
- 206010034912 Phobia Diseases 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 230000036506 anxiety Effects 0.000 claims description 2
- 208000010643 digestive system disease Diseases 0.000 claims description 2
- 206010016256 fatigue Diseases 0.000 claims description 2
- 206010022437 insomnia Diseases 0.000 claims description 2
- 208000033915 jet lag type circadian rhythm sleep disease Diseases 0.000 claims description 2
- 208000024714 major depressive disease Diseases 0.000 claims description 2
- 230000001193 melatoninergic effect Effects 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 208000019899 phobic disease Diseases 0.000 claims description 2
- 201000000980 schizophrenia Diseases 0.000 claims description 2
- 208000012672 seasonal affective disease Diseases 0.000 claims description 2
- 208000019116 sleep disease Diseases 0.000 claims description 2
- 230000035882 stress Effects 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 235000011149 sulphuric acid Nutrition 0.000 description 3
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 2
- 229960003987 melatonin Drugs 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 description 1
- 108010072553 5-HT2C Serotonin Receptor Proteins 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate 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)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010813 internal standard method Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000004457 water analysis Methods 0.000 description 1
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- 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
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/22—Anxiolytics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
Definitions
- the present invention relates to an agomelatine hydrochloride hydrate, preparation and use thereof, and to pharmaceutical composition containing it.
- Agomelatine or N-[2-(7-methoxy-l-naphthyl)ethyl]-acetamide, has the structure of formula II. It is marketed under the trade name of Valdoxan by the French company Servier as a melatonin agonist and antagonist of 5HT2C receptor. It is the first melatonin type anti-depressant, indicated for depression, improving sleep and sexual function.
- the object of the present invention is to provide an agomelatine hydrochloride hydrate featuring excellent solubility, stability and purity, making it favourable for use in the manufacture of pharmaceutical formulations containing agomelatine.
- agomelatine can form a physically and chemically stable agomelatine hydrochloride hydrate when mixed with hydrocholoric acid (HC1).
- Said agomelatine hydrochloride hydrate is suitable for the manufacture of pharmaceutical formulations.
- other conventional inorganic acids such as sulphuric acid, phosphoric acid, perchloric acid
- organic acids such as acetic acid, oxalic acid, tartaric acid, fumaric acid
- the present invention provides an agomelatine hydrochloride hydrate with the following structure of formula I:
- the present invention further provides a method for the preparation of said agomelatine
- agomelatine can be dissolved in aqueous organic solvent before HC1 gas is bubbled through and the precipitated crystal is rinsed and dried; or agomelatine can be added to a solution containing HQ and then the precipitated crystal is rinsed and dried.
- agomelatine can be added to a solution containing HQ and then the precipitated crystal is rinsed and dried.
- agomelatine can also be added to an aqueous organic solvent before a solvent containing HC1 is added dropwise, and the precipitated crystal is rinsed and dried.
- agomelatine is dissolved in organic solvent before aqueous HC1 solution is added dropwise, and the precipitated crystal is rinsed and dried.
- the reaction temperature in the present invention can be conventional temperatures for such reactions in the art as long as it is lower than the boiling point of the solvent.
- room temperature or below is preferred, a temperature below the room temperature is more preferred, and 0-20°C is most preferred.
- the organic solvent is not specifically limited so long as it can dissolve the starting materials agomelatine and HC1 and meanwhile allows said agomelatine hydrochloride hydrate to be precipitated.
- Suitable solvent can be used includes ethyl acetate, methyl acetate, n-butyl acetate, acetone, acetonitrile and the like, and ethyl acetate is preferred.
- Organic solvents with higher polarity such as alcohols (ethanol and methanol etc.), DMF, DMSO are less preferred.
- the present invention is advantageous in that the inventors found that among so many conventional acids, agomelatine can react with HC1 to form a stable agomelatine hydrochloride hydrate, the physical properties of which, such as stability, solubility, and hygroscopicity, are better than those products of agomelatine with any other conventional acid.
- the process is also less complicated than if other acid is used.
- the agomelatine hydrochloride hydrate produced according to the present method has significant increased solubility than agomelatine per se, and therefore is more suitable for manufacturing pharmaceutical formulations.
- the product enjoys higher stability, purity and solubility.
- product with high purity can be obtained through a simple process, free of any complicated steps.
- Pharmacological tests of the agomelatine hydrochloride hydrate demonstrated that it can be used for the treatment of melatoninergic system disorders, sleep disorders, stress, anxiety, seasonal affective disorder, major depression, cardiovascular diseases, digestive system diseases, insomnia and fatigue caused by jet lag, schizophrenia, phobia or depression disorders.
- the present invention further provides a pharmaceutical composition, comprising an agomelatine hydrochloride hydrate of the invention in associated with pharmaceutically acceptable adjuvants or excipients.
- the pharmaceutical composition can be formulated for various routes of administration, especially for oral administration or for injection.
- 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 and may be administrated in a single dose or in several divided doses.
- Fig. 1 shows the TGA thermogram of the product of Example 1 in the present invention.
- Fig. 2 shows the X-ray powder diffraction pattern of the product of Example 7 in the present invention.
- agomelatine 1 g was dissolved in 10 ml of EtOAc under stirring, and concentrated H2SO4 was added dropwise at -10°C. No solid precipitated during the entire process.
- Example 6 1 g of agomelatine was dissolved in 10 ml of EtOAc under stirring, and fumaric acid was added dropwise at -10°C. No solid precipitated during the entire process.
- Agomelatine used in the above examples is commercially available or can be prepared according to methods known in the art.
- Example 1 Some of the product of Example 1 was placed in an incubator at 40°C for 30 days to determine its stability with HPLC. The results are shown in the following table 1. Table 1
- Example 2 Using external standard method, the product of Example 1 was tested with HPLC, compared with agomelatine crystalline form II. The results are shown in the following table 2.
- the agomelatine hydrochloride hydrate of the present invention has better solubility than agomelatine per se in water, in 0.1N HC1, which is similar to human gastric fluid, or in pH 7.0 buffer. This means the former enjoys the potential of higher bioavailability than the latter.
- Example 1 The product of Example 1 was analyzed according to said Fischer's method and water content was found to be 6.15 wt%.
- Example 7 The product of Example 7 was analyzed according to said Fischer's method and water content was found to be 6.10 wt%.
- Example 1 The product of Example 1 was analyzed according to said TGA method and water loss was found to be 6.67 wt%, meaning crystal water content in the product is 6.67 wt%.
- Fig 1 shows TGA thermogram.
- the measurement condition for TGA method is as follows:
- the measurement condition for the X-ray powder diffraction pattern of the product of Example 7 in the present invention is as follows:
- the X-ray powder diffraction pattern of agomelatine hydrochloride hydrate is characterized by Bragg 2 ⁇ angle, interplanar spacing d and relative intensity (1%) as follows:
- 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.
- Affecting factors test (in open container for 10 days): high temperature (60 °C), photostability under strong light (45001x), high humidity (92.5%RH at 25 ° C)
- agomelatine hydrochloride hydrate is stable under other conditions, particularly in accelerated test and long-term test, which is favourable for use in pharmaceutical formulations.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Anesthesiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
An agomelatine hydrochloride hydrate of formula (I), preparation, use, and pharmaceutical composition thereof are provided. Said hydrate obtained through the present method has significant increased solubi1ity than agomelatine, and therefore is more suitable for manufacturing pharmaceutical formulations. Using the present method, high purity can be obtained through a simple process, free of any complicated steps. Wherein X is Cl.
Description
AGOMELATINE HYDROCHLORIDE HYDRATE AND PREPARATION THEREOF Technical Field
The present invention relates to an agomelatine hydrochloride hydrate, preparation and use thereof, and to pharmaceutical composition containing it.
Technical Background
Agomelatine, or N-[2-(7-methoxy-l-naphthyl)ethyl]-acetamide, has the structure of formula II. It is marketed under the trade name of Valdoxan by the French company Servier as a melatonin agonist and antagonist of 5HT2C receptor. It is the first melatonin type anti-depressant, indicated for depression, improving sleep and sexual function.
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 an agomelatine hydrochloride hydrate featuring excellent solubility, stability and purity, making it favourable for use in the manufacture of pharmaceutical formulations containing agomelatine.
When the present inventors attempted to purify agomelatine product, we surprisingly found that agomelatine can form a physically and chemically stable agomelatine hydrochloride hydrate when mixed with hydrocholoric acid (HC1). Said agomelatine hydrochloride hydrate is suitable for the manufacture of pharmaceutical formulations. When other conventional inorganic acids (such as sulphuric acid, phosphoric acid, perchloric acid) or organic acids (such as acetic acid, oxalic acid, tartaric acid, fumaric acid) were used, it was not easy to produce a hydrate or hydrates with unstable physical and chemical properties were obtained.
The present invention provides an agomelatine hydrochloride hydrate with the following structure of formula I:
(I ) wherein X is CI.
The present invention further provides a method for the preparation of said agomelatine
hydrochloride hydrate, wherein agomelatine is reacted with HC1 in any form to produce the agomelatine hydrochloride hydrate. There can be two processes: agomelatine can be dissolved in
aqueous organic solvent before HC1 gas is bubbled through and the precipitated crystal is rinsed and dried; or agomelatine can be added to a solution containing HQ and then the precipitated crystal is rinsed and dried. The results from repeated experiments show that in the first method, the oversupply of HC1 only results in lower yield, while in the second method, it is easier to control the amount of HC1 in the solvent. Therefore, the second method is preferred.
Specifically, agomelatine can also be added to an aqueous organic solvent before a solvent containing HC1 is added dropwise, and the precipitated crystal is rinsed and dried.
Alternatively, agomelatine is dissolved in organic solvent before aqueous HC1 solution is added dropwise, and the precipitated crystal is rinsed and dried.
The reaction temperature in the present invention can be conventional temperatures for such reactions in the art as long as it is lower than the boiling point of the solvent. In order to increase yield, room temperature or below is preferred, a temperature below the room temperature is more preferred, and 0-20°C is most preferred.
In the above-mentioned preparation method for said agomelatine hydrochloride hydrate, the organic solvent is not specifically limited so long as it can dissolve the starting materials agomelatine and HC1 and meanwhile allows said agomelatine hydrochloride hydrate to be precipitated. Suitable solvent can be used includes ethyl acetate, methyl acetate, n-butyl acetate, acetone, acetonitrile and the like, and ethyl acetate is preferred. Organic solvents with higher polarity such as alcohols (ethanol and methanol etc.), DMF, DMSO are less preferred.
The present invention is advantageous in that the inventors found that among so many conventional acids, agomelatine can react with HC1 to form a stable agomelatine hydrochloride hydrate, the physical properties of which, such as stability, solubility, and hygroscopicity, are better than those products of agomelatine with any other conventional acid. The process is also less complicated than if other acid is used.
The agomelatine hydrochloride hydrate produced according to the present method has significant increased solubility than agomelatine per se, and therefore is more suitable for manufacturing pharmaceutical formulations. The product enjoys higher stability, purity and solubility. In addition, product with high purity can be obtained through a simple process, free of any complicated steps.
Pharmacological tests of the agomelatine hydrochloride hydrate demonstrated that it can be used for the treatment of melatoninergic system disorders, sleep disorders, stress, anxiety, seasonal affective disorder, major depression, cardiovascular diseases, digestive system diseases, insomnia and fatigue caused by jet lag, schizophrenia, phobia or depression disorders.
The present invention further provides a pharmaceutical composition, comprising an agomelatine hydrochloride hydrate of the invention in associated with pharmaceutically acceptable adjuvants or excipients.
The pharmaceutical composition can be formulated for various routes of administration, especially for oral administration or for injection.
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 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 TGA thermogram of the product of Example 1 in the present invention.
Fig. 2 shows the X-ray powder diffraction pattern of the product of Example 7 in the present invention.
Examples
Example 1
1 g of agomelatine was added to 20 ml of EtOAc, 0.5 g aqueous HC1 solution (36%) was added dropwise at 10 °C. The mixture was stirred for lh, and then filtered, and the solid was rinsed twice with 2 ml of EtOAc and dried at 40 °C to afford 1 g of white solid (purity: 99.9%; yield: 81.7%). Elemental analysis for CI:
Calculated: Cl% (11.91 wt%)
Found: Cl% (1 1.88 wt%)
Mp: 88-90°C
Example 2
10 g of agomelatine was added to 100 ml of EtOAc, and 4.6 g of aqueous HC1 solution (36%) was added dropwise at 10 °C. The mixture was stirred for lh, and then filtered, and the solid was rinsed twice with 10 ml of EtOAc and dried at 40 °C to afford 10.2 g of white solid (purity: 99.8%; yield: 88.7%).
Elemental analysis for CI:
Calculated: Cl% (11.91 wt%)
Found: Cl% (1 1.86 wt%)
Mp: 88-90 °C
Example 3
1 g of agomelatine was dissolved in 10 ml of EtOAc under stirring, and concentrated H2SO4 was added dropwise at room temperature. No solid precipitated during the entire process.
Example 4
1 g of agomelatine was dissolved in 10 ml of EtOAc under stirring, and concentrated H2SO4 was added dropwise at -10°C. No solid precipitated during the entire process.
Example 5
1 g of agomelatine was dissolved in 10 ml of EtOAc under stirring, and glacial acetic acid was added dropwise at -10°C. No solid precipitated during the entire process.
Example 6
1 g of agomelatine was dissolved in 10 ml of EtOAc under stirring, and fumaric acid was added dropwise at -10°C. No solid precipitated during the entire process.
Example 7
100 g of agomelatine was added to 1 L of EtOAc, and 50 g of aqueous HC1 solution (36%) was added dropwise at 10 °C. The mixture was stirred for lh, and then filtered, and the solid was rinsed twice with 100 ml of EtOAc and dried at 40 °C to afford 101 g of white solid (purity: 99.7%; yield: 82.5%).
Elemental analysis for CI:
Calculated: Cl% (1 1.91 wt%)
Found: Cl% (1 1.86 wt%)
Mp: 87-89°C
Agomelatine used in the above examples is commercially available or can be prepared according to methods known in the art.
Example 8: Pharmaceutical Composition
Formulation for the preparation of 1000 capsules each containing a dose of 25 mg (agomelatine)
Compound of Example 7 30.5 g
Lactose (Spherolac 100) 85.2 g
Starch 1500 25.5 g
CMS-Na 8.5 g
Ac-Di-Sol ® (FMC) 17 g
Stearic Acid 3.4 g
Detection Methods and Results
1. Purity of Samples
Chromatographic conditions: C I 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 products of Examples 1 and 2.
Solutions of the products at 1 mg/mL were prepared with the mobile phase . 10 iL of each solution was injected into the liquid chromatograph system and chromatograms were recorded. The results of the purity are shown in Examples 1 and 2.
2. Stability Test
Some of the product of Example 1 was placed in an incubator at 40°C for 30 days to determine its stability with HPLC. The results are shown in the following table 1.
Table 1
AG = Agomelatine C15H17 O2
3. Water Solubility
Using external standard method, the product of Example 1 was tested with HPLC, compared with agomelatine crystalline form II. The results are shown in the following table 2.
Table 2
As can be seen, the agomelatine hydrochloride hydrate of the present invention has better solubility than agomelatine per se in water, in 0.1N HC1, which is similar to human gastric fluid, or in pH 7.0 buffer. This means the former enjoys the potential of higher bioavailability than the latter.
4. Crystal Water Analysis
Calculated water content in Ci5Hi7N02-HCl-H20 is 6.06 wt%.
4.1 Fischer's Method (Appendix VIII M, Chinese Pharmacopoeia, 2010)
The product of Example 1 was analyzed according to said Fischer's method and water content was found to be 6.15 wt%.
The product of Example 7 was analyzed according to said Fischer's method and water content was found to be 6.10 wt%.
4.2 Thermal Gravity Analysis (Appendix VIII Q, Chinese Pharmacopoeia, 2010)
The product of Example 1 was analyzed according to said TGA method and water loss was found to be 6.67 wt%, meaning crystal water content in the product is 6.67 wt%. Fig 1 shows TGA thermogram.
The measurement condition for TGA method is as follows:
Type of Instrument: NETZSCH TG 209F1
Type of Crucible: AI2O3
Flushing gas: N2 20 ml/min
Protective gas: N2 10 ml/min
Temperature range: Room temperature -300 °C
Heat rate: 10°C/min
5. Crystal Structure Analysis
The measurement condition for the X-ray powder diffraction pattern of the product of Example 7 in the present invention is as follows:
XRD parameters
Instrument Bruker D8 ADVANCE X-Ray Diffractometer
Detector LynxEye detector
X-Ray CuKa 40 kV/40 mA
Scanning Mode Theta/Theta
Monochromater Ni-filter
DivSlit 1 deg.
DivH.L.Slit 1.0 mm
Scanning Continous Scanning from 3° to 45° with 0.02°/step
Scaning time 5 min
Scaning speed 8.0°/min
Scaning temp Room temperature
The X-ray powder diffraction pattern of agomelatine hydrochloride hydrate is characterized by Bragg 2Θ angle, interplanar spacing d and relative intensity (1%) as follows:
Table 3
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.
6. Stability Test of the Agomelatine Hydrochloride Hydrate
The method for stability test as described in Chinese Pharmacopoeia was used in this test.
1) Affecting factors test (in open container for 10 days): high temperature (60 °C), photostability under strong light (45001x), high humidity (92.5%RH at 25 °C)
2) Accelerated test (in closed container for 6 months): at 40 °C, humidity: 75%RH
3) Long-term test (in closed container for 9 months): at 25 °C , humidity: 60%RH
The results are shown in the following table 4.
Table 4
Therefore, except that water content and CI content of agomelatine hydrochloride hydrate are decreased under a very severe condition, agomelatine hydrochloride hydrate is stable under other conditions, particularly in accelerated test and long-term test, which is favourable for use in pharmaceutical formulations.
Claims
1. An agomelatine hydrochloride hydrate of formula I:
2. An agomelatine hydrochloride hydrate of formula I according to claim 1 in the form of crystalline form, characterized by Bragg 2Θ angle, interplanar spacing d and relative intensity as follows:
and which also includes crystals whose peak diffraction angles match within an error of ±0.2°.
3. A method for the preparation of the agomelatine hydrochloride hydrate according to claim 1 or 2, wherein agomelatine is reacted with HCl to produce the agomelatine hydrochloride hydrate.
4. The method for the preparation of the agomelatine hydrochloride hydrate according to claim 3, wherein agomelatine is reacted with HCl in an aqueous organic solvent to produce the agomelatine hydrochloride hydrate.
5. The method for the preparation of the agomelatine hydrochloride hydrate according to claim 4, wherein agomelatine is dissolved in organic solvent before aqueous HCl solution is added to precipitate the crystal of the product.
6. The method for the preparation of the agomelatine hydrochloride hydrate according to claim 5, wherein said aqueous HCl solution is added dropwise.
7. The method for the preparation of the agomelatine hydrochloride hydrate according to claim 4, wherein agomelatine is added to an aqueous organic solvent containing HCl to precipitate the crystal of the product.
8. The method for the preparation of the agomelatine hydrochloride hydrate according to claim 5 or 7, which further includes rinsing and drying the solid after crystallisation.
9. The method for the preparation of the agomelatine hydrochloride hydrate according to claim 5 or 7, wherein the reaction temperature is 0-20°C.
10. The method for the preparation of the agomelatine hydrochloride hydrate according to claim 5 or 7, wherein said organic solvent is ethyl acetate, methyl acetate, n-butyl acetate, acetone or acetonitrile.
1 1. The method for the preparation of the agomelatine hydrochloride hydrate according to claim 10, wherein said organic solvent is ethyl acetate.
12. A pharmaceutical composition, comprising an agomelatine hydrochloride hydrate according to claim 1 or 2 in associated with pharmaceutically acceptable adjuvants or excipients.
13. Use of an agomelatine hydrochloride hydrate according to claim 1 or 2 for the treatment of melatoninergic system disorders, sleep disorders, stress, anxiety, seasonal affective disorder, major depression, cardiovascular diseases, digestive system diseases, insomnia and fatigue caused by jet lag, schizophrenia, phobia or depression disorders.
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| DK11755679.5T DK2547649T3 (en) | 2010-03-17 | 2011-03-17 | Agomelatine Hydrochloride Hydrate and its Preparation |
| UAA201211720A UA105425C2 (en) | 2010-03-17 | 2011-03-17 | Crystal form of agomelatine hydrobromide hydrate and process for the preparation thereof |
| AU2011229618A AU2011229618B2 (en) | 2010-03-17 | 2011-03-17 | Agomelatine hydrochloride hydrate and preparation thereof |
| EA201201294A EA022067B1 (en) | 2010-03-17 | 2011-03-17 | Agomelatine hydrochloride hydrate and preparation thereof |
| ES11755679T ES2530772T3 (en) | 2010-03-17 | 2011-03-17 | Agomelatine Hydrochloride Hydrate and Preparation |
| CA2792417A CA2792417C (en) | 2010-03-17 | 2011-03-17 | Agomelatine hydrochloride hydrate and preparation thereof |
| EP11755679.5A EP2547649B1 (en) | 2010-03-17 | 2011-03-17 | Agomelatine hydrochloride hydrate and preparation thereof |
| RS20150041A RS53815B1 (en) | 2010-03-17 | 2011-03-17 | Agomelatine hydrochloride hydrate and preparation thereof |
| CN201180024357.8A CN102958911B (en) | 2010-03-17 | 2011-03-17 | Agomelatine hydrogen chloride hydrate and preparation method thereof |
| MEP-2015-23A ME02054B (en) | 2010-03-17 | 2011-03-17 | Agomelatine hydrochloride hydrate and preparation thereof |
| US13/635,063 US8729131B2 (en) | 2010-03-17 | 2011-03-17 | Agomelatine hydrochloride hydrate and preparation thereof |
| SI201130403T SI2547649T1 (en) | 2010-03-17 | 2011-03-17 | Agomelatine hydrochloride hydrate and preparation thereof |
| NZ602450A NZ602450A (en) | 2010-03-17 | 2011-03-17 | Agomelatine hydrochloride hydrate and preparation thereof |
| MX2012010541A MX2012010541A (en) | 2010-03-17 | 2011-03-17 | Agomelatine hydrochloride hydrate and preparation thereof. |
| MA35192A MA34055B1 (en) | 2010-03-17 | 2011-03-17 | AGOMELATIN HYDRATE HYDROCHLORIDE AND ITS PREPARATION |
| PL11755679T PL2547649T3 (en) | 2010-03-17 | 2011-03-17 | Agomelatine hydrochloride hydrate and preparation thereof |
| JP2012557392A JP5634532B2 (en) | 2010-03-17 | 2011-03-17 | Agomelatine hydrochloride hydrate and its production |
| BR112012023317-3A BR112012023317B1 (en) | 2010-03-17 | 2011-03-17 | agomelatine hydrochloride hydrate and its preparation |
| AP2012006492A AP2012006492A0 (en) | 2010-03-17 | 2011-03-17 | Agomelatine hydrochloride hydrate and preparation thereof |
| KR1020127026895A KR101406727B1 (en) | 2010-03-17 | 2011-03-17 | Agomelatine hydrochloride hydrate and preparation thereof |
| SG2012065009A SG183868A1 (en) | 2010-03-17 | 2011-03-17 | Agomelatine hydrochloride hydrate and preparation thereof |
| TNP2012000435A TN2012000435A1 (en) | 2010-03-17 | 2012-08-31 | Agomelatine hydrochloride hydrate and preparation thereof |
| IL221782A IL221782A (en) | 2010-03-17 | 2012-09-04 | Agomelatine hydrochloride hydrate and pharmaceutical compositions comprising it |
| CU2012000137A CU20120137A7 (en) | 2010-03-17 | 2012-09-17 | HYDROCHLORIDE HYDROCHLORIDE HYDROCHLORIDE AND PREPARATION OF THIS |
| HK13104588.5A HK1177451A1 (en) | 2010-03-17 | 2013-04-16 | Agomelatine hydrochloride hydrate and preparation thereof |
| HRP20150071AT HRP20150071T1 (en) | 2010-03-17 | 2015-01-20 | Agomelatine hydrochloride hydrate and preparation thereof |
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| CN201010126254XA CN102190594A (en) | 2010-03-17 | 2010-03-17 | Agomelatine hydrogen chloride hydrate and preparation method thereof |
| CN201010126254.X | 2010-03-17 |
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| EP (1) | EP2547649B1 (en) |
| JP (1) | JP5634532B2 (en) |
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| CU (1) | CU20120137A7 (en) |
| CY (1) | CY1116086T1 (en) |
| DK (1) | DK2547649T3 (en) |
| EA (1) | EA022067B1 (en) |
| EC (1) | ECSP12012155A (en) |
| ES (1) | ES2530772T3 (en) |
| GE (1) | GEP20156231B (en) |
| GT (1) | GT201200259A (en) |
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| NI (1) | NI201200140A (en) |
| NZ (1) | NZ602450A (en) |
| PE (1) | PE20130013A1 (en) |
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| SI (1) | SI2547649T1 (en) |
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| EP2551257A1 (en) * | 2011-07-28 | 2013-01-30 | Laboratorios Del. Dr. Esteve, S.A. | Co-crystals of agomelatine with co-crystal-formers |
| EP2556824A1 (en) | 2011-08-10 | 2013-02-13 | Les Laboratoires Servier | Solid pharmaceutical composition for buccal administration of agomelatine |
| WO2014096373A1 (en) | 2012-12-21 | 2014-06-26 | Laboratorios Lesvi, S. L. | Process for prepararing n-(2-(7-methoxy-1-naphthalenyl)ethyl) acetamide and solid forms thereof |
| WO2014122405A1 (en) | 2013-02-08 | 2014-08-14 | Les Laboratoires Servier | Solid pharmaceutical composition for oral delivery of agomelatine |
| WO2015013865A1 (en) * | 2013-07-29 | 2015-02-05 | Les Laboratoires Servier | Agomelatine sulfonic acids complexes and preparation thereof |
| JP2015521179A (en) * | 2012-05-14 | 2015-07-27 | 上海右手医葯科技▲開▼発有限公司 | Agomelatine acid group composite and its production method and use |
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| EP2556824A1 (en) | 2011-08-10 | 2013-02-13 | Les Laboratoires Servier | Solid pharmaceutical composition for buccal administration of agomelatine |
| WO2013021139A1 (en) | 2011-08-10 | 2013-02-14 | Les Laboratoires Servier | Solid pharmaceutical composition for orally delivering agomelatine |
| JP2015521179A (en) * | 2012-05-14 | 2015-07-27 | 上海右手医葯科技▲開▼発有限公司 | Agomelatine acid group composite and its production method and use |
| CN102718675A (en) * | 2012-06-07 | 2012-10-10 | 上海右手医药科技开发有限公司 | Agomelatine methanesulfonic acid complex and preparation method thereof |
| WO2014096373A1 (en) | 2012-12-21 | 2014-06-26 | Laboratorios Lesvi, S. L. | Process for prepararing n-(2-(7-methoxy-1-naphthalenyl)ethyl) acetamide and solid forms thereof |
| WO2014122405A1 (en) | 2013-02-08 | 2014-08-14 | Les Laboratoires Servier | Solid pharmaceutical composition for oral delivery of agomelatine |
| WO2015013865A1 (en) * | 2013-07-29 | 2015-02-05 | Les Laboratoires Servier | Agomelatine sulfonic acids complexes and preparation thereof |
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