WO2011050742A1 - Nouvelles formes cristallines de l'agomélatine et leurs procédés de préparation - Google Patents

Nouvelles formes cristallines de l'agomélatine et leurs procédés de préparation Download PDF

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WO2011050742A1
WO2011050742A1 PCT/CN2010/078228 CN2010078228W WO2011050742A1 WO 2011050742 A1 WO2011050742 A1 WO 2011050742A1 CN 2010078228 W CN2010078228 W CN 2010078228W WO 2011050742 A1 WO2011050742 A1 WO 2011050742A1
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agomelatine
solvent
ether
organic solvent
mixture
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Chinese (zh)
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林蒙
罗君来
罗斌
蒋勇
罗杰
叶文润
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重庆医药工业研究院有限责任公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to the field of organic chemistry and medicine, in particular to three new crystal forms of agomelatine and a preparation method thereof, a pharmaceutical composition containing the three new crystal forms, and the three new crystal forms are used in Manufacture of applications for a variety of indications.
  • Agomelatine chemical name: N-[2-(7-methoxy- 1 -naphthyl)ethyl]acetamide, having the structure shown in Formula I, as disclosed in EP0447285 The method is prepared.
  • Agomelatine is a melatonin 1, 2 ( MT1 , MT2 ) receptor agonist and a serotonin 2c ( 5HT2C ) receptor antagonist that binds directly to the 5HT2C receptor of the synaptic membrane. Its antidepressant effect does not increase the 5HT concentration between the synapses, and thus has no common side effects of serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors.
  • Another unique target of this drug is the MT receptor, through agonism of MT1 and MT2 receptors, such as stress, fatigue, sleep disorders and anxiety, major depression, seasonal affective disorder, cardiovascular disease , digestive diseases, insomnia and fatigue caused by jet lag, schizophrenia, panic attacks, depression, appetite disorders, obesity, insomnia, pain, mental disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, and normal Or various disorders associated with pathological aging, migraine, memory loss, Alzheimer's disease, and cerebral circulation disorders have improved or therapeutic effects. It is also useful in the treatment of sexual dysfunction in another field of activity, has the properties of ovulation inhibition and immunomodulation, and can also be used to treat cancer.
  • Agomelatine is a poorly water-soluble compound and is generally used in solid form in preparations, so the study of its crystal form is of great significance.
  • Agomelatine has a polymorphism, such as Form II disclosed in the patent US7498465, which has a 2-value of 6.30 in the X-ray powder diffraction pattern of the CuKa source. 9.26. , 10.50. 12.65. 13.29. 15.34. , 15.81. 17.15. , 18.03. 18.60. , 19.01°, 20.09. , 20.44.
  • Characteristic absorption peak at 20.97 and 21.18°; US7498466 discloses a type II crystal having an absorption peak at an X-ray powder diffraction pattern of 2.26, 10.50, 15.34, 17.15, and a crystal form III disclosed in Patent CN1907957,
  • the X ⁇ value in the X-ray powder diffraction pattern of the CuKa source was 10.52. 12.92. 16.15. 19.20. , 23.33. 25.07. It has a characteristic peak; the crystal form IV disclosed in the patent CN1907957, which has a value of 5.04 in the X-ray powder diffraction pattern of the CuKa source. 10.16. , 17.41. , 18.03. 18.81. 24.27.
  • the characteristic has a characteristic peak; the crystal form V disclosed in the patent CN1907958, which has a value of 9.84°, 17.95°, 18.88°, 20.99°, 23.07°, 24.28°, etc. in the X-ray powder diffraction pattern of the CuKa source. Characteristic peaks; Form VI disclosed in the patent US20090069434, which has a value of 5.73°, 10.22°, 20.10°, 23.69°, 29.48 in the X-ray powder diffraction pattern of the CuKa source. There are characteristic peaks.
  • agomelatine In the course of the research on the crystal form of agomelatine, the present inventors have surprisingly prepared three new crystal forms of agomelatine, which have obvious X-ray powder diffraction patterns different from the existing crystal forms. It has the characteristics of simple preparation method and excellent chemical stability, and is suitable for use in various preparations.
  • the agomelastine crystal form A of the present invention has an X-ray powder diffraction pattern characterized by a value of about 12.0 at 2 ⁇ . 17.6. 18.4. 18.7. 19.7. , 19.9. 20.6.
  • the positions of 21.9°, 22.7°, 23.1°, 27.2°, and 25.5° correspond to characteristic diffraction peaks.
  • the agomelatine crystal form A of the present invention has an X-ray powder diffraction pattern substantially as shown in Fig. 1.
  • the agomelatine crystalline form B of the present invention has an X-ray powder diffraction pattern characterized by a ⁇ value of about 6.5. , 9.4. , 12.7. 13.4. 17.2. 18.7. 19.1. 20.1. 22.2. 24.3. 25.5. 26.0. The position corresponds to a characteristic diffraction peak.
  • the agomelatine crystal form B of the present invention has an X-ray powder diffraction pattern substantially as shown in Fig. 2.
  • the agomelatine crystalline form C of the present invention has an X-ray powder diffraction pattern characterized by a value of about 9.3 at 2 ⁇ . 10.6. 11.3. , 12.7. 15.3. , 15.8, 17.1. 18.6. , 19.0. , 20.0. 20.4. 22.1. 23.5. 23.8. 24.1. 25.2. 25.9. The position corresponds to a characteristic diffraction peak.
  • the agomelatine Form C of the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the agmelatin crystalline form A, crystalline form B and crystalline form C provided by the present invention generally have a content (mass content) of greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
  • “Environmental temperature” is generally 0 to 40 ° C;
  • “ambient humidity” is generally 30% to 80% relative humidity.
  • the X-ray powder diffraction patterns of agomelatine crystal forms A, B and C provided by the present invention are shown in the accompanying drawings.
  • the crystal form has an X-ray powder diffraction pattern means that the crystal form substantially has an overall morphology as shown by the X-ray powder diffraction pattern; it will be understood by those skilled in the art that during the test, The peak position or peak of the X-ray powder diffraction pattern measured by the same crystal form is affected by various factors (such as the particle size of the test sample, the sample processing method at the time of the test, the instrument, the test parameters, the test operation, etc.). There will be some difference in strength. Therefore, the diffraction peak 2 ⁇ value in the X-ray powder diffraction pattern in this paper should take into account the experimental error of ⁇ 0.2°.
  • insoluble solvent or “insoluble hydrocarbon solvent” refers to a solvent in which agomelatine is poorly soluble or poorly soluble.
  • the invention provides a preparation method of the above three crystal forms of agomelatine.
  • the invention provides a preparation method of agomelatine crystal form A, which comprises dissolving agomelatine in a liquid aqueous organic solvent, and then crystallization at below 10 ° C, wherein the organic solvent is Gomellatine has good solubility and a volume ratio to water of greater than or equal to 1:5.
  • the method specifically includes the following steps:
  • the agomelatine is dissolved in a liquid aqueous organic solvent to obtain a agomelatine solution, wherein the volume ratio of the organic solvent to water is greater than or equal to 1:5;
  • the separated crystals are dried.
  • the organic solvent of step 1) has good solubility to agomelatine, including alcohols, ketones, esters, nitriles, carboxylic acids, amides, sulfone solvents or a mixture thereof, wherein the alcohol is preferably a lower monohydric alcohol, including methanol, ethanol or isopropanol; the ketones include acetone or 2-butanone; the esters include ethyl acetate, methyl acetate; the nitriles include acetonitrile or Succinic acid; carboxylic acids are preferably lower monocarboxylic acids, including formic acid or acetic acid; amides include N,N-dimethylformamide or N,N-dimethylacetamide; and sulfones include dimethyl sulfoxide.
  • the alcohol is preferably a lower monohydric alcohol, including methanol, ethanol or isopropanol
  • the ketones include acetone or 2-butanone
  • the esters include eth
  • the volume ratio of the organic solvent to water is preferably greater than or equal to 1:2, more preferably greater than or equal to 1:1, and most preferably greater than or equal to 1:0.5, but the volume ratio is preferably no greater than 200:1.
  • Particularly preferred organic solvents include methanol, ethanol, isopropanol, acetone, acetonitrile or a mixed solvent thereof, wherein the volume ratio of methanol, ethanol, isopropanol, acetone, acetonitrile or a mixture thereof to water is greater than or equal to 1:1. Preferably, it is greater than or equal to 1:0.5.
  • Step 2) The crystallization may be carried out under standing or stirring conditions, and the crystallization temperature is preferably -20 to 10 ° C, more preferably -10 to 10 ° C.
  • Step 3) drying the drying temperature is generally 20 to 100 ° C, preferably 40 to 80 ° C; can be dried under normal pressure, or can be dried under reduced pressure, the vacuum is generally 300 ⁇ 760 mmHg, preferably 600. ⁇ 760mmHg.
  • the agomelatine Form A of the present invention can also be prepared as follows:
  • the method comprises dissolving agomelatine in a non-hydrocarbon liquid organic solvent capable of being sufficiently dissolved at ambient temperature, and then forming the formed
  • the solution is mixed with a reverse-soluble solvent, and crystallized below 10 ° C, and when the non-hydrocarbon liquid organic solvent is acetic acid, the reverse-soluble solvent does not include water.
  • the volume ratio of the reverse soluble solvent to the non-hydrocarbon liquid organic solvent is less than 20:1.
  • the method includes the following steps:
  • the separated crystals are dried.
  • the non-hydrocarbon liquid organic solvent capable of sufficiently dissolving agomelatine at ambient temperature in the step 1) includes ketones, esters, ethers, alcohols, nitriles, halogenated alkanes, Solvents such as carboxylic acids, amides, sulfones, such as acetone, 2-butanone, ethyl acetate, methyl acetate, tetrahydrofuran, dioxane, ethanol, methanol, isopropanol, ethylene glycol, acetonitrile, two Methyl chloride, chloroform, tetrachloromethane, formic acid, acetic acid, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, or a mixture thereof.
  • Solvents such as carboxylic acids, amides, sulfones, such as acetone, 2-butanone, ethyl a
  • the anti-solvent solvent described in the step 2) as described above refers to a solvent in which agomelatine is poorly soluble or poorly soluble, including water, diethyl ether, ethylene glycol dimethyl ether, and diisopropyl ether. , methyl tert-butyl ether, etc. or a mixture thereof.
  • the non-hydrocarbon liquid organic solvent is acetic acid
  • the reversely soluble solvent is not water.
  • the volume ratio of the reverse soluble solvent to the non-hydrocarbon liquid organic solvent is preferably between less than 20:1 and 0.5:1, more preferably between 15:1 and 3:1.
  • the crystallization may be carried out under standing or stirring conditions, and the crystallization temperature is preferably -20 to 10 ° C, more preferably -10 to 10 ° C.
  • Step 3) drying the drying temperature is generally 20 ⁇ 100 ° C, preferably 40 ⁇ 80 ° C; can be dried under normal pressure, or can be dried under reduced pressure, the vacuum degree under reduced pressure is generally 300 ⁇ 760 mmHg, preferably 600 ⁇ 760mmHg.
  • the hydrocarbons described herein refer to hydrocarbons containing only carbon and hydrogen.
  • the invention also provides a preparation method of agomelatine crystal form B, which comprises dissolving agomelatine in a hydrocarbon solvent and mixing with a reversely soluble hydrocarbon solvent,
  • the method specifically includes the following steps:
  • the agomelatine is dissolved in a hydrocarbon solvent, the dissolution temperature is generally 20 ⁇ 60 ° C, and the agomelatine solution is obtained;
  • the crystallization temperature is generally 10 to 50 ° C, preferably 15 to 35;
  • the precipitated crystal is separated by filtration or centrifugation; 4) Optionally, the separated crystal is dried.
  • the hydrocarbon solvent described in the step 1) is preferably an aromatic hydrocarbon, including benzene, toluene, xylene, ethylbenzene, polyethylbenzene, propylbenzene, cumene, mixed benzene, etc. or a mixture thereof. More preferred are benzene, toluene and mixtures thereof.
  • the reversely soluble hydrocarbon solvent described in the step 2) is preferably an aliphatic hydrocarbon including n-hexane, cyclohexane, cyclopentane, 2-methylpentane, 3-methylpentane, n-heptane, octane. Etc.
  • the volume ratio of the inversely soluble hydrocarbon solvent to the hydrocarbon solvent is less than 20:1, preferably less than 20:1 to 0.5:1, more preferably 15:1 to 3:1. between.
  • the crystallization can be carried out under standing or stirring conditions. Drying as described in step 4), the drying temperature is generally 20 to 100 ° C, preferably 30 to 70 ° C; it can be dried at normal pressure or under reduced pressure, and the vacuum is generally 300 to 760 mmHg under reduced pressure. 600 ⁇ 760mmHg.
  • the present invention also provides a process for preparing agomelatine crystal form C, which comprises melting agomelatine and adding it to a solvent to dissolve it.
  • the method specifically includes the following steps:
  • the melting temperature is generally 100 ⁇ 150 ° C, preferably 110 ⁇ 120 ° C;
  • the molten agomelatine is added to the insoluble solvent for crystallization, the crystallization temperature is generally 10 ⁇ 50 ° C;
  • the separated crystals are dried.
  • the anti-solvent solvent described in the step 2) includes water, an ether such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, or an aliphatic hydrocarbon such as n-hexane. Cyclohexane, cyclopentane, n-heptane, and the like, or a mixture thereof, among which, water, diethyl ether, diisopropyl ether, methyl tert-butyl ether, n-hexane, cyclohexane are preferred.
  • the crystallization can be carried out under standing or stirring conditions. Drying as described in step 4), the drying temperature is generally 20 to 100 ° C, preferably 30-70 °C; It can be dried at normal pressure or under reduced pressure. The vacuum is generally under reduced pressure.
  • agomelatine crystal forms A, B and C of the present invention have stable physicochemical properties, are suitable for long-term storage and are used in the manufacture of formulations.
  • One of the objects of the present invention is also to provide a pharmaceutical composition comprising agomelatine crystal form A, B or C.
  • the pharmaceutical composition of the present invention comprises a therapeutically effective amount of agomelatine Form A, B or C and a pharmaceutical excipient, and can be prepared in a manner well known in the pharmaceutical art, generally effective in treating
  • the amount of agomelatine Form A, B or C is mixed or contacted with one or more pharmaceutical excipients to form the desired dosage form.
  • a further object of the present invention is to provide the use of agomelatine Form A, B or C for the manufacture of a medicament for the treatment of diseases of the central nervous system and microcirculation diseases.
  • the central nervous system and shield ring diseases include stress, fatigue, sleep disorders and anxiety, severe depression, seasonal affective disorder, cardiovascular disease, digestive system disease, insomnia and fatigue caused by jet lag, schizophrenia , panic attacks, depression, appetite disorders, obesity, insomnia, pain, mental disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders associated with normal or pathological aging, migraine, memory loss, Alzheimer's disease and cerebral circulation disorder; on the other hand, it can also be used for the treatment of sexual dysfunction, has the properties of ovulation inhibition and immunomodulation, and can also be used for the treatment of cancer; among them, sleep disorder and anxiety, severe depression, season are preferred Sexual affective disorder, depression.
  • agomelatine Form 8, B or C is used in the manufacture of a medicament for the treatment of diseases of the central nervous system.
  • the pharmaceutical composition or preparation containing agomelatine crystal form A, B or C comprises: a tablet, a dragee, a granule, a sublingual tablet, a capsule, a lozenge, a cream, Ointments, dermatological gels, injectable preparations, drinkable suspensions, and disintegrable pastes are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration.
  • the applicable dose of the above composition or formulation is adjusted depending on the nature and severity of the disorder, the route of administration, and the age, weight, etc. of the patient, varying between 0.1 mg and lg per day, one or more administrations.
  • the pharmaceutical composition of the present invention is a solid oral preparation, it may contain a usual excipient such as a filler, a disintegrant, a binder, a lubricant, etc., and if necessary, the tablet may be coated.
  • a usual excipient such as a filler, a disintegrant, a binder, a lubricant, etc., and if necessary, the tablet may be coated.
  • the filler generally comprises silica, lactose, maltodextrin, pregelatinized starch, mannitol, microcrystalline cellulose, xylitol, sorbitol, glucose, starch, etc., which may be used alone or in combination.
  • silica, lactose, maltodextrin, pregelatinized starch, and mannitol are preferred.
  • the disintegrant generally comprises sodium starch glycolate, starch, crosslinked polyvinylpyrrolidone, polyvinylpyrrolidone, microcrystalline cellulose, low substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, agar, calcium carbonate and Sodium hydrogencarbonate or the like may be used singly or in combination, and among them, starch glycolic acid, starch, crosslinked polyvinylpyrrolidone, and polyvinylpyrrolidone are preferable.
  • the binder generally comprises povidone, microcrystalline cellulose, hydroxypropyl cellulose, starch slurry, hydroxypropyl methylcellulose, polyvinyl alcohol, water, various concentrations of ethanol solution, which can be used alone. It can also be used in combination, and among them, povidone, microcrystalline cellulose, and hydroxypropylmethylcellulose are preferable.
  • the lubricant generally comprises stearic acid, magnesium stearate, calcium stearate, palmitic acid, aluminum silicate, stearamide, talc, solid ethylene glycol, silica. They may be used singly or in combination, and among them, stearic acid, magnesium stearate, and calcium magnesium stearate are preferred.
  • excipients such as sweeteners, coloring agents, taste masking agents, stabilizers and the like may be added to the pharmaceutical composition of the present invention.
  • the pharmaceutical composition of the present invention can be prepared according to any of the conventional methods used in the preparation of an oral solid preparation, such as: wet granulation tableting, powder direct compression, granulation followed by capsule preparation.
  • the pharmaceutical composition can be coated into a film-coated tablet or a sugar-coated tablet using a conventional coating device.
  • the coating base includes celluloses, acrylics, saccharides such as hydroxypropylmethylcellulose, Eudragit L, sucrose.
  • a plasticizer, an anti-adhesive agent, and an opacifier may also be added to the coating base.
  • the solid pharmaceutical composition of the present invention can be subjected to a conventional dosage by sequentially performing a granulation step, an encapsulation step or a tableting step, and a coating step (if necessary).
  • the form is usually in the form of a tablet or a surface coated tablet, a powder, a granule, a surface coated granule or a capsule dosage form.
  • the tablets include conventional tablets, sustained release tablets, buccal tablets, orally disintegrating tablets, chewable tablets, effervescent tablets and the like.
  • the pharmaceutical composition of the present invention can be prepared by conventional techniques of pharmacy. For example, wet granulation tableting and dry powder direct compression can be used for tablets.
  • agomelatine crystal form A, B and C preparations provided by the invention have good stability and activity in preparation and storage.
  • agomelatine crystal forms A, B and C provided by the present invention are distinct from the existing crystal form and are a new crystal form of agomelatine. They have the advantages of simple preparation method, good stability and formulation adaptability, and have industrial applicability.
  • Figure 1 is an X-ray diffraction pattern of agomelatine Form A.
  • Figure 2 is an X-ray diffraction pattern of agomelatine Form B.
  • Figure 3 is an X-ray diffraction pattern of agomelatine Form C.
  • agomelatine was dissolved in 15 ml of ethanol at room temperature, dissolved, cooled to an internal temperature of 0 to 5 ° C, and added to 60 ml of water with stirring.
  • the internal temperature was controlled to 5 to 5 during the addition.
  • °C after the completion of the dropwise addition, the crystallization is continued at -5 to 5 ° C for about 1.5 h; filtration; the filter cake is dried at 50 to 60 ° C to obtain agomelatine crystal form A.
  • the obtained crystal form was subjected to X-ray powder diffraction, and the diffraction pattern thereof is shown in Fig. 1, and its value is as follows (the relative intensity is 10% or more).
  • Example 17 The crystal forms obtained in Examples 9 to 16 were confirmed to be Form A by X powder test.
  • Example 17 The crystal forms obtained in Examples 9 to 16 were confirmed to be Form A by X powder test.
  • agomelatine was dissolved in 15 ml of toluene at room temperature, and it was added dropwise to 45 ml of cyclohexane with stirring, and the inner temperature was maintained at 25 to 35 ° C for about 4 h; filtration; It was dried under reduced pressure at 70 to 80 ° C, and the dried product was confirmed to be agomelatine crystal form B by an X-ray powder diffraction test within an error range.
  • agomelatine crystal form C was X-ray powder diffraction, and its diffraction pattern is shown in Fig. 3. The value of 2 ⁇ is as follows (relative intensity is greater than or equal to 10%).
  • agomelatine crystal form C 3 g of agomelatine was completely melted at 115 ° C, rapidly added to 20 ml of cyclohexane at 20 to 25 ° C for 3 h; separation of solid; 30 ⁇ 40 ° C It was dried under reduced pressure, and the dried product was subjected to X-ray powder diffraction, and it was confirmed to be agomelatine crystal form C within the error range.
  • Example 21
  • agomelatine crystal form C 5 g of agomelatine was completely melted at 113 ° C, rapidly added to 25 ml of methyl tert-butyl ether at 15 to 20 ° C for 3 h; separation of solid; 40 ⁇ 50 The mixture was dried under reduced pressure at ° C, and the dried product was subjected to X-ray powder diffraction, and it was confirmed that it was agmelatin crystal form C within the error range.
  • Agomelatine Form B 25g Pregelatinized Starch 67g Hard Moon Magnesium 1.8g Corn Starch 22g Maltodextrin mixture 8g anhydrous colloidal silica 0.4g

Abstract

L'invention porte sur trois nouvelles formes cristallines de l'agomélatine, sur leurs procédés de préparation et sur les compositions pharmaceutiques les contenant et sur leur utilisation en préparation de médicament utilisé pour guérir les maladies du système nerveux central. Ces trois nouvelles formes cristallines de l'agomélatine, qui présentent l'avantage d'une grande stabilité et d'une préparation facile, sont appropriées afin de préparer une préparation pharmaceutique.
PCT/CN2010/078228 2009-10-29 2010-10-29 Nouvelles formes cristallines de l'agomélatine et leurs procédés de préparation WO2011050742A1 (fr)

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EP2556824A1 (fr) 2011-08-10 2013-02-13 Les Laboratoires Servier Composition pharmaceutique solide pour administration buccale d'agomelatine
WO2014122405A1 (fr) 2013-02-08 2014-08-14 Les Laboratoires Servier Composition pharmaceutique solide pour l'administration buccale d'agomélatine

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CN102050756A (zh) * 2009-11-09 2011-05-11 北京利乐生制药科技有限公司 阿戈美拉汀新晶型及其制备方法
CN102030673B (zh) * 2010-11-24 2014-04-23 威海迪素制药有限公司 一种阿戈美拉汀新晶型及制备方法
CN102557979B (zh) * 2010-12-16 2014-11-26 北大方正集团有限公司 一种阿戈美拉汀的晶型、其制备方法、用途及药物组合物
ITMI20111078A1 (it) 2011-06-15 2012-12-16 Laboratorio Chimico Int Spa Procedimento per la preparazione di forme cristalline dell?agomelatina e nuovo polimorfo
CN103130673B (zh) * 2011-11-28 2017-05-03 重庆医药工业研究院有限责任公司 一种阿戈美拉晶型i的制备方法
CN103360276B (zh) * 2012-03-29 2015-02-18 北大方正集团有限公司 阿戈美拉汀的晶型、制备方法和用途、以及药物组合物
CN104341315A (zh) * 2013-08-08 2015-02-11 上海科胜药物研发有限公司 一种阿戈美拉汀晶型i的制备方法

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