WO2013018100A1 - Procédé de préparation de la forme cristalline 1 du n-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide - Google Patents

Procédé de préparation de la forme cristalline 1 du n-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide Download PDF

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Publication number
WO2013018100A1
WO2013018100A1 PCT/IN2011/000503 IN2011000503W WO2013018100A1 WO 2013018100 A1 WO2013018100 A1 WO 2013018100A1 IN 2011000503 W IN2011000503 W IN 2011000503W WO 2013018100 A1 WO2013018100 A1 WO 2013018100A1
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Prior art keywords
crystalline form
ethyl
acetamide
naphthyl
methoxy
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PCT/IN2011/000503
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English (en)
Inventor
Dodda Mohan Rao
Pingili Krishna Reddy
Ambati Anna Reddy
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Symed Labs Limited
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Publication date
Application filed by Symed Labs Limited filed Critical Symed Labs Limited
Priority to PCT/IN2011/000503 priority Critical patent/WO2013018100A1/fr
Publication of WO2013018100A1 publication Critical patent/WO2013018100A1/fr

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    • 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

Definitions

  • the present invention relates to a process for the preparation of N-[2-(7-methoxy-l - naphthyl) ethyl] acetamide crystalline form I. More specifically the present invention relates to cost-effective, reproducible and industrial process for synthesis of the N-[2-(7-methoxy-l - naphthyl) ethyl] acetamide crystalline form I.
  • Agomelatine is an agonist of melatoninergic system receptors and an antagonist of the 5-HT2C receptor. Those properties confer activity in the central nervous system and, more especially, in the treatment of severe depression, seasonal affective disorders, sleep disorders, cardiovascular pathologies, and pathologies of the digestive system, insomnia and fatigue resulting from jetlag, appetite disorders and obesity. Agomelatine is under regulatory review in US and is being approved in EU for the treatment of major depressive disorder. It is marketed under the trade names Valdoxan, Melitor, Thymanax in the form of tablets in dosage strength 25 mg. Agomelatine is chemically described as N-[2-(7-methoxy- l - naphthyl)ethyl]acetamide (herein after referred by generic name agomelatine) and is represented by the structural formula 1
  • U.S.Patent No. 5,225,442 describes agomelatine, a pharmaceutical composition, a method of treatment, and a process for the preparation thereof.
  • US '442 in example 1 also discloses a process for the preparation of agomelatine.
  • agomelatine is obtained by recrystallization from isopropyl ether.
  • No information on the polymorph form obtained therein can be found except the melting point as 109-1 10°C. obtained according to the process described above. It is, in fact, important to be able to obtain a well defined and perfectly reproducible crystalline form.
  • agomelatine is obtained from a biphasic medium of water and chloroform.
  • Bernard Tinant and Jean-Paul Declercq in Acta Cryst. (1994), C50, 907-910 disclose a full crystallographic investigation of the agomelatine produced by Yous et al.
  • the polymorph form of the product obtained by Yous et al. and analyzed by Tinant and Declercq is designated as the polymorph form I of agomelatine.
  • Tinant and Declercq provide the full crystal data of this polymorph form, and regarding the identification of the polymorph form I of agomelatine, it is explicitly referred to Bernard Tinant and Jean-Paul Declercq in Acta Cryst. (1994), C50, 907-910.
  • the crystal data is as follows:
  • EP 23 19827A 1 describes a process for the
  • the known processes for obtaining the polymorphic form I of agomelatine are considered as providing the polymorphic form I of agomelatine not in a sufficiently reproducible and well-defined manner and with only poor filtrability (US 2005/0182276) .
  • the known methods of preparation of polymorph form I of agomelatine use solvents which can be problematic and which should be avoided in medicaments.
  • chloroform that has been used by Yous et al. for the preparation of agomelatine of polymorphic form I, is a class II solvent with a concentration limit of only 60 ppm in pharmaceutical products. It is very difficult to remove the hazardous solvent to the required extent from the agomelatine.
  • a polymorph form of agomelatine for use in a medicament should have excellent properties, such as crystallinity, polymorphic stability, chemical stability and process ability to pharmaceutical compositions.
  • the process for making crystalline Form I of present invention is simple, eco-friendly, cost effective, reproducible, and robust and feasible on an industrial scale.
  • the present invention relates to process for the preparation of " N-[2-(7-methoxy-l - naphthyl) ethyl] acetamide crystalline form I. More specifically the present invention relates to cost-effective, reproducible process for synthesis of the N-[2-(7-methoxy-l -naphthyl) ethyl] acetamide crystalline form I.
  • the present invention provides a cost-effective, reproducible and industrial process for the preparation of N-[2-(7-methoxy-l-naphthyl) ethyl] acetamide crystalline form I comprising:
  • the crystalline form I obtained by the process of present invention is characterized by XRPD with characteristic peaks at about 10.8, 1 1.2, 1 1.9, 13.8, 14.6, 14.9, 15.4, 15.8, 17.0, 17.5, 18.4, 19.5, 19.8, 20.5, 21.0, 21.3, 21.8, 22.6, 23.0, 24.0, 24.6, 25.4, 26.0, 26.4, 27.1, 27.7, 28.8, 30.1, 31.6, 31.9, 33.0, 33.7, 34.5 and 36.0 ⁇ 0.2 degrees two-theta, which is substantially in accordance with Fig. Land further characterized by differential scanning calorimetry (DSC) with an endotherm curve at about 108.62°C measured at 0.2 °C/min. ramp, and is substantially in accordance with Fig. 2.
  • DSC differential scanning calorimetry
  • the present invention encompasses a pharmaceutical composition comprising therapeutically effective amount of highly pure agomelatine crystalline Form I obtained by the process of present invention and atleast a pharmaceutically acceptable carrier.
  • Fig. 1 is an X-ray powder diffraction pattern of agomelatine crystalline Form-I.
  • Fig. 2 is a Differential Scanning Calorimetry endotherm of agomelatine crystalline
  • the present invention is directed to a process for the preparation of N-[2-(7-methoxy-l - naphthyl) ethyl] acetamide crystalline form I.
  • the crystalline form I obtained by the process of present invention is characterized by XRPD with characteristic peaks at about 10.8, 1 1.2, 1 1.9, 13.8, 14.6, 14.9, 15.4, 15.8, 17.0, 17.5, 18.4, 19.5, 19.8, 20.5, 21.0, 21.3, 21.8, 22.6, 23.0, 24.0, 24.6, 25.4, 26.0, 26.4, 27.1 , 27.7, 28.8, 30.1, 31.6, 31.9, 33.0, 33.7, 34.5 and 36.0 ⁇ 0.2 degrees two-theta, which is substantially in accordance with Fig. Land further characterized by differential scanning calorimetry (DSC) with an endotherm curve at about 108.62°C measured at 0.2 °C/min. ramp, and is substantially in accordance with Fig. 2.
  • DSC differential scanning calorimetry
  • the solvents that can be used for solubilizing or dissolving the agomelatine in step (a) above include but are not limited to water, alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, isobutyl alcohol, tertiary butyl alcohol and the like ketonic solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-butanone and the like; aprotic polar solvents such as ⁇ , ⁇ -dimethyl formamaide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide, N-methyl pyrrolidone ( MP), acetonitrile and the like; hydrocarbons such as toluene, xylene, cyclohexane, n-hexane and the like; ethers such as 1 ,4-dioxane, tetrahydrofuran, diisopropylether as
  • a mixture of solvents refers to a composition comprising more than one solvent.
  • the volume of the solvent may be from about 5 to about 150 volumes.
  • the volume of the suitable organic solvent may be from about 50 to about 130 volumes.
  • the volume of the suitable organic solvent may be from about 80 to about 120 volumes.
  • the mixture may be heated to a temperature sufficient to obtain partial dissolution.
  • the mixture may be heated to a temperature sufficient to obtain complete dissolution.
  • the broad range of solvent/water ratios from 1 : 100 up to 100: 1 (v/v), preferably at ratios from 1 :20 up to 20: 1 (v/v), more preferably at ratios from 1 :2 to 2: 1 (v/v) at a temperature of 25°C.
  • the solvent/water ratio in process step b) of the process of the present invention is at least 1 :2, more preferably at least 1 :3 and most preferably at least 1 :4.
  • the amount of water can be significantly higher than the amount of solvent for agomelatine, but for practical reasons it is generally sufficient, if the solvent/water ratio is 1 : 10 or less or 1 :8 or less or 1 :6 or less.
  • preferred solvent/water ratios are in the range from 1 :2 to 1 : 10, preferably 1 :3 to 1 :8 and most preferred from 1 :4 to 1 :6.
  • the temperature for obtaining a clear and homogenous solution can range from about 25°C to about 100°C or the boiling point of the solvent/s used, preferably from about 50°C to about boiling point of the solvent/s used.
  • the solution obtained is optionally filtered through celite or diatomaceous earth to separate the extraneous matter present or formed in the solution by using conventional filtration techniques known in the art.
  • Evaporation or removal of solvent(s) is accomplished by, for example, substantially complete evaporation of the solvent, concentrating the solution, cooling to obtain crystalline form and filtering the solid under inert atmosphere.
  • the solvent may also be removed by evaporation. Evaporation can be achieved at sub-zero temperatures by the lyophilisation or freeze-drying technique.
  • the solution may also be completely evaporated in, for example, a pilot plant rota vapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720 mm Hg by flash evaporation techniques by using an agitated thin film dryer (ATFD), or evaporated by spray drying to obtain a dry amorphous powder.
  • the methods for evaporation or removal of solvents are distillation under reduced pressure.
  • Crystal growth may be promoted by cooling the solution to a temperature between about 0°C to about 50°C. Crystal growth may be promoted by cooling the solution to a temperature between about 0°C to about 30°C. Crystal growth may be promoted by cooling the solution to a temperature between about 0°C to about 15°C.
  • the cooling of the solution in step (b) can be from about -10 to about 25°C, preferably from about -5°C to about 5°C.
  • the crystalline Form 1 obtained by the process of present invention is stable with good flow properties, which make them well suitable for formulating agomelatine in any dosage form.
  • Recovery of agomelatine crystalline Form I obtained can be achieved by any conventional methods known in the art, for example filtration.
  • the agomelatine substantially in crystalline form I obtained by the above process may be further dried in, for example, vacuum tray dryer, rotocon vacuum dryer, vacuum paddle dryer or pilot plant rotavapor, to further lower residual solvents.
  • the preferred instrument is a vacuum tray dryer.
  • the crystalline form I of agomelatine obtained by the process of present invention can be optionally dried at a temperature range from about 30°C to about 75°C, preferably from about 35°C to about 55°C.
  • Polymorphs of a molecule can be obtained by a number of methods known in the art. Such methods include, but are not limited to, recrystallization, melt recrystallization, melt cooling, solvent recrystallization (including using single or multiple solvents), precipitation, anti-solvent precipitation, evaporation, rapid evaporation, slurrying, slurry ripening, suspension equilibration, desolvation, dehydration, vapor diffusion, liquid-liquid diffusion, sublimation, grinding, milling, crystallization from the melt, heat induced transformations, desolvation of solvates, salting out, pH change, lyophilization, distillation, drying, rapid cooling, slow cooling, and combinations thereof.
  • Polymorphs can be detected, identified, classified and characterized using well-known techniques such as, but not limited to, differential scanning calorimetry (DSC), thermogravimetry (TGA), powder X-ray diffractometry (PXRD), single crystal X-ray diffractometry, vibrational spectroscopy, solution calorimetry, solid state nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, Raman spectroscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography, quantitative analysis, solubility, and rate of dissolution.
  • DSC differential scanning calorimetry
  • TGA thermogravimetry
  • PXRD powder X-ray diffractometry
  • vibrational spectroscopy vibrational spectroscopy
  • solution calorimetry solid state nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, Raman spectroscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography, quantitative analysis, solubility, and
  • the crystalline form I of agomelatine obtained by the process of present invention was characterized by using Diffractometer Make Bruker AXS, Model D8 FOCUS Goniometer Type : Theta-2Theta
  • sample Approximately 1 g of sample was gently flattened on a sample holder and scanned from 2 to 50° two theta, at 0.03° two theta per step and a step time of 0.4 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30rpm at a voltage 40 KV and current 35 mA.
  • compositions comprising at least a therapeutically effective amount of highly pure agomelatine crystalline Form 1 obtained by the process of present invention and atleast a pharmaceutically acceptable excepient.
  • Such pharmaceutical compositions may be administered to a mammalian patient for the treatment or prevention of major depressive episodes in adults in a dosage form, e.g., solid, liquid, powder, elixir, aerosol, syrups, injectable solution, etc.
  • Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration.
  • Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, lozenges, elixirs and the like.
  • the highly pure agomelatine or a pharmaceutically acceptable salt thereof substantially free of hydrazine impurity may also be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes.
  • Tablets and powders may also be coated with an enteric coating.
  • the enteric-coated powder forms may have .coatings containing at least phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, the coating agents may be employed with suitable plasticizers and/or extending agents.
  • a coated capsule or tablet may have a coating on the surface thereof or may be a capsule or tablet comprising a powder or granules with an enteric-coating.
  • the process for the preparation of agomelatine crystalline form I of the present invention is simple, eco-friendly, robust, reproducible, cost effective and well amenable on industrial scale.
  • Example -2 Preparation of agomelatine crystalline form I using isopropyl alcohol 3 gr of N-[2-(7-(-methoxy -1 -naphthyl)ethyl)] acetamide and 10 ml of isopropyl alcohol were charged into a clean and dry 4 neck R.B.Flask followed by heating to about 50° C . The resultant solution was allowed to reach about 30 °C and seeded with 0.2 gr of pure crystalline form-I of N-[2-(7-(-methoxy -l-naphthyl)ethyl)] acetamide. The solution was further cooled to about 5°C for about 15 min. The solid separated was filtered and the solid obtained was dried to obtain pure crystalline form I. Yield: 1.5 gr.
  • Example -4 Preparation of agomelatine crystalline form I using toluene
  • Example -6 Preparation of agomelatine crystalline form I using methyl isobutyl ketone
  • Example -7 Preparation of agomelatine crystalline form I using DMF and water mixture
  • Example-9 Preparation of agomelatine crystalline form I using water and ethanol
  • Example-11 Preparation of agomelatine crystalline form I using water and DMF

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé industriel, reproductible et économique de préparation de la forme cristalline 1 du N-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide, ainsi que des compositions pharmaceutiques à base de ladite forme cristalline 1.
PCT/IN2011/000503 2011-08-01 2011-08-01 Procédé de préparation de la forme cristalline 1 du n-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide WO2013018100A1 (fr)

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PCT/IN2011/000503 WO2013018100A1 (fr) 2011-08-01 2011-08-01 Procédé de préparation de la forme cristalline 1 du n-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide

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PCT/IN2011/000503 WO2013018100A1 (fr) 2011-08-01 2011-08-01 Procédé de préparation de la forme cristalline 1 du n-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103690499A (zh) * 2013-12-23 2014-04-02 天津泰普药品科技发展有限公司 一种稳定的晶i型阿戈美拉汀片剂及其制备方法
EP3466413A1 (fr) 2017-10-09 2019-04-10 KRKA, d.d., Novo mesto Composition pharmaceutique contenant de l'agomelatine et son procédé de préparation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060270877A1 (en) * 2005-03-08 2006-11-30 Les Laboratoires Servier Crystalline form V of agomelatine, a process for its preparation and pharmaceutical compositions containing it
US20070197829A1 (en) * 2004-02-13 2007-08-23 Les Laboratoires Servier Process for the synthesis and crystalline form agomelatine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070197829A1 (en) * 2004-02-13 2007-08-23 Les Laboratoires Servier Process for the synthesis and crystalline form agomelatine
US20060270877A1 (en) * 2005-03-08 2006-11-30 Les Laboratoires Servier Crystalline form V of agomelatine, a process for its preparation and pharmaceutical compositions containing it

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHENG ET AL.: "Structures of Polymorphic Agomelatine and Its Cocrystals with Acetic Acid and Ethylene Glycol.", CRYSTAL GROWTH & DESIGN, vol. 11, 6 January 2011 (2011-01-06), pages 466 - 471, XP002658583, DOI: doi:10.1021/cg101234p *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103690499A (zh) * 2013-12-23 2014-04-02 天津泰普药品科技发展有限公司 一种稳定的晶i型阿戈美拉汀片剂及其制备方法
EP3087977A4 (fr) * 2013-12-23 2017-08-02 Tianjin Taipu Pharmaceutical Science & Technology Development Co., Ltd. Comprimé d'agomélatine stable de type i et son procédé de préparation
EP3466413A1 (fr) 2017-10-09 2019-04-10 KRKA, d.d., Novo mesto Composition pharmaceutique contenant de l'agomelatine et son procédé de préparation
WO2019072866A1 (fr) 2017-10-09 2019-04-18 Krka, D.D., Novo Mesto Composition pharmaceutique contenant de l'agomélatine et procédé de préparation de celle-ci

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