WO2017115284A1 - Nouvelles formes co-cristallines d'agomélatine - Google Patents

Nouvelles formes co-cristallines d'agomélatine Download PDF

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Publication number
WO2017115284A1
WO2017115284A1 PCT/IB2016/058030 IB2016058030W WO2017115284A1 WO 2017115284 A1 WO2017115284 A1 WO 2017115284A1 IB 2016058030 W IB2016058030 W IB 2016058030W WO 2017115284 A1 WO2017115284 A1 WO 2017115284A1
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WO
WIPO (PCT)
Prior art keywords
agomelatine
crystal
iii
saccharin
adipic acid
Prior art date
Application number
PCT/IB2016/058030
Other languages
English (en)
Inventor
Chandrashekhar Kocherlakota
Nagaraju Banda
Original Assignee
Leiutis Pharmaceuticals Pvt, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Leiutis Pharmaceuticals Pvt, Ltd. filed Critical Leiutis Pharmaceuticals Pvt, Ltd.
Publication of WO2017115284A1 publication Critical patent/WO2017115284A1/fr

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Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • C07C233/22—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 an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • 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

  • APIs active pharmaceutical ingredients
  • the APIs may be amorphous, may have different crystalline polymorphs, or may exist in different solvation or hydration states.
  • varying the form of an API it is possible to vary the physical properties thereof.
  • Pharmaceutical polymorphs have different solubilities from one another and can also differ in properties such as shelf-life, bioavailability, morphology, vapour pressure, density, colour, and compressibility. Therefore changing the crystalline state of an API is one of many ways to modulate the physical properties thereof.
  • Agomelatine is a melatonin receptor agonist sold as Valdoxan ® .
  • Agomelatine has the chemical name N[2-(7-methoxy-l-naphthyl)ethyl] acetamide and has the following structure.
  • composition comprising noncrystalline form of Agomelatine.
  • the present invention relates to stable novel co-crystal forms of Agomelatine with improved solubility, making it favourable for use in the manufacture of pharmaceutical formulations.
  • the invention provides stable novel co-crystal forms of Agomelatine and pharmaceutical formulations comprising the novel co-crystal forms.
  • the invention also relates to a process of manufacture of Agomelatine co-crystals.
  • the invention further relates to Adipic acid co-crystal of Agomelatine and process of preparation thereof and pharmaceutical formulations comprising the same.
  • the invention also relates to Saccharin co-crystal of Agomelatine and process of preparation thereof and pharmaceutical formulations comprising the same.
  • Fig 1 Depicts powder X-ray diffraction pattern ("Powder XRD” or "PXRD”) of Adipic acid co-crystal of Agomelatine obtained in example 1.
  • Fig 2 Depicts powder X-ray diffraction pattern ("Powder XRD” or “PXRD”) of Saccharin co-crystal of Agomelatine obtained in example 2.
  • Fig 3 Depicts powder X-ray diffraction pattern ("Powder XRD” or “PXRD”) of Saccharin co-crystal of Agomelatine obtained in example 3.
  • Fig 4 Depicts a DSC (Differential Scanning Calorimetry) thermogram of Adipic acid co-crystal of Agomelatine obtained in example 1.
  • Fig 5 Depicts a DSC (Differential Scanning Calorimetry) thermogram of Saccharin co- crystal of Agomelatine obtained in example 2.
  • Fig 6 Depicts Infrared spectrum of Adipic acid co-crystal of Agomelatine obtained in example 1.
  • Fig 7 Depicts Infrared spectrum of Saccharin co-crystal of Agomelatine obtained in example 2.
  • the present invention is related to novel co-crystal forms of Agomelatine, process of preparation and solid oral pharmaceutical formulations containing them.
  • the co-crystal former is selected from Adipic acid and Saccharin.
  • Co-crystal as used herein is defined as a crystalline material comprising two or more compounds of which at least two are held together, wherein at least one of the compounds is a co-crystal former.
  • Co-crystal-former as used herein is defined as a component with which Agomelatine is able to form co-crystals. The co-crystal former is part of the crystal lattice.
  • the "intrinsic dissolution rate” is defined as the dissolution rate of pure substances under the condition of constant surface area.
  • Agomelatine is practically insoluble in purified water ( ⁇ 0.1 mg/mL) but freely soluble (> 100 mg/mL) in various organic solvents (96% ethanol, methanol, methylene chloride). Solubility in water and aqueous media is a desired characteristic of APIs to ensure physiological absorption and bioavailability. Intrinsic dissolution rate is often used as a powerful tool for the evaluation of solubility.
  • the inventors of the present invention have found that the novel co-crystals of Agomelatine produced according to the invention have significantly higher solubility than Agomelatine API.
  • the inventors prepared the co-crystals of Agomelatine using Adipic acid or Saccharin and determined solubility by measuring the intrinsic dissolution rate.
  • the co-crystals of Agomelatine have better solubility than Agomelatine per se in 0.1N HC1 and pH 6.8 buffer.
  • Agomelatine co-crystal forms can be characterized by one or more analytical techniques, like X-ray powder diffraction pattern (XRPD), infrared absorption spectra and differential scanning calorimetry (DSC) curves.
  • analytical techniques like X-ray powder diffraction pattern (XRPD), infrared absorption spectra and differential scanning calorimetry (DSC) curves.
  • one aspect of the invention relates to Adipic acid co-crystal of Agomelatine, comprising of Agomelatine in the form of co-crystal with Adipic acid.
  • the molar ratio of Agomelatine to Adipic acid is preferably 1:1, which resulted in a stable co-crystal form of Agomelatine.
  • thermogram (iii) an endothermic trace comprising an endothermic peak at about 87.7°C in a DSC (Differential Scanning Calorimetry) thermogram
  • Another aspect of the invention relates to Saccharin co-crystal of Agomelatine, comprising of Agomelatine in the form of co-crystal with Saccharin.
  • the molar ratio of Agomelatine to Saccharin is preferably 1:1, which resulted in a stable co-crystal form of Agomelatine.
  • thermogram (ii) an infrared absorption spectrum comprising infrared absorption bands at: 3240, 1717 cm 1 .
  • an endothermic trace comprising an endothermic peak at about 91.0°C in a DSC (Differential Scanning Calorimetry) thermogram
  • Yet another aspect of invention relates to process of preparing the said co-crystal of Agomelatine.
  • the process comprises:
  • Yet another aspect of invention relates to process of preparing the said co-crystal of Agomelatine.
  • the process comprises:
  • step (iv) Addition of solvent to step (iii), followed by evaporating the solvent and collecting the material.
  • Yet another aspect of the invention relates to pharmaceutical formulation of Agomelatine tablets comprising of Adipic acid co-crystal of Agomelatine and other pharmaceutically acceptable excipients.
  • Yet another aspect of the invention relates to pharmaceutical formulation of Agomelatine tablets comprising of Saccharin co-crystal of Agomelatine and other pharmaceutically acceptable excipients.
  • Agomelatine tablet formulations prepared according to the invention can be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Formulations may be presented as coated or uncoated tablet.
  • Pharmaceutically acceptable excipients used in the tablet formulations of Agomelatine include one or more excipients selected from diluents, binders, disintegrants, glidants, lubricants, solvents, film coating materials and the like.
  • excipients that are useful in the present application include, but are not limited to, diluents such as powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, starch, co- processed excipients such as combilac (70% lactose monohydrate, 20% microcrystalline cellulose, 20% maize starch) and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidone, modified cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sugars, starches and the like; disintegrants such as sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium and the like; glidants such as calcium phosphate, calcium silicate, powdered cellulose, magnesium trisilicate, silicon dioxide, talc, colloidal silica, colloidal silica anhydrous
  • Solvents used for granulation can be either aqueous or non-aqueous solvents.
  • Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film-formers, plasticizers, colorants, solvents, lubricants, flavoring agents, sweeteners and the like.
  • Agomelatine tablet formulations of Example No. 4 and 5 were subjected to in-vitro dissolution studies using USP Type II (Paddle) apparatus at 50 RPM at 37°C in various dissolution media. The results are tabulated in table 2 and table 3.
  • Table 2 In vitro dissolution data of Agomelatine Tablets, 25 mg prepared with Adipic acid co-crystal in various dissolution media.
  • Table 3 In vitro dissolution data of Agomelatine Tablets 25 mg prepared with Saccharin co-crystal in various dissolution media.
  • Adipic acid co-crystal of Agomelatine and Saccharin co-crystal of Agomelatine prepared according to the invention were tested for stability under accelerated conditions. The results are tabulated in table 4:
  • Adipic acid co-crystal of Agomelatine and Saccharin co- crystal of Agomelatine were found to be stable even after storing at 60° for 10 days.
  • Agomelatine, lactose monohydrate, sodium starch glycolate, micro crystalline cellulose, povidone were co-sifted and blended.
  • the obtaindd blend was compressed as slugs. Slugs were milled and sifted and lubricated with co-sifted magnesium stearate, colloidal silica anhydrous and stearic acid. The blend was compressed into tablets and coated.
  • Agomelatine, lactose monohydrate, sodium starch glycolate, micro crystalline cellulose, povidone were co-sifted and blended.
  • the obtained blend was compressed as slugs. Slugs were milled and sifted and lubricated with co-sifted magnesium stearate, colloidal silica anhydrous and stearic acid. The blend was compressed into tablets and coated.

Abstract

La présente invention concerne de nouvelles formes co-cristallines d'agomélatine, un procédé de préparation, et des formulations pharmaceutiques solides à administration orale les contenant.
PCT/IB2016/058030 2015-12-28 2016-12-28 Nouvelles formes co-cristallines d'agomélatine WO2017115284A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN6988CH2015 2015-12-28
IN6988/CHE/2015 2015-12-28

Publications (1)

Publication Number Publication Date
WO2017115284A1 true WO2017115284A1 (fr) 2017-07-06

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012146371A1 (fr) * 2011-04-28 2012-11-01 Zentiva, K.S. Co-cristaux de n-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide pharmaceutiquement acceptables et leurs procédés de préparation
US20120316245A1 (en) * 2011-06-09 2012-12-13 Les Laboratoires Servier Co-crystals of agomelatine, a process for there preparation and pharmaceutical compositions containing them
WO2015013903A1 (fr) * 2013-07-31 2015-02-05 Les Laboratoires Servier Nouvelles formes de co-cristaux d'agomélatine et d'acide p-toluènesulfonique et leur préparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012146371A1 (fr) * 2011-04-28 2012-11-01 Zentiva, K.S. Co-cristaux de n-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide pharmaceutiquement acceptables et leurs procédés de préparation
US20120316245A1 (en) * 2011-06-09 2012-12-13 Les Laboratoires Servier Co-crystals of agomelatine, a process for there preparation and pharmaceutical compositions containing them
WO2015013903A1 (fr) * 2013-07-31 2015-02-05 Les Laboratoires Servier Nouvelles formes de co-cristaux d'agomélatine et d'acide p-toluènesulfonique et leur préparation

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