EP2705021A2 - Rasagiline et ses sels pharmaceutiquement acceptables - Google Patents

Rasagiline et ses sels pharmaceutiquement acceptables

Info

Publication number
EP2705021A2
EP2705021A2 EP12766333.4A EP12766333A EP2705021A2 EP 2705021 A2 EP2705021 A2 EP 2705021A2 EP 12766333 A EP12766333 A EP 12766333A EP 2705021 A2 EP2705021 A2 EP 2705021A2
Authority
EP
European Patent Office
Prior art keywords
rasagiline
microns
besylate
particle size
crystalline
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP12766333.4A
Other languages
German (de)
English (en)
Inventor
Shriprakash Dhar Dwivedi
Ashok Prasad
Mayur Ramnikbhai Patel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zydus Lifesciences Ltd
Original Assignee
Cadila Healthcare 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 Cadila Healthcare Ltd filed Critical Cadila Healthcare Ltd
Publication of EP2705021A2 publication Critical patent/EP2705021A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/33—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems
    • C07C309/34—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems formed by two rings
    • C07C309/35—Naphthalene sulfonic acids
    • 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

  • Rasagiline mesylate is an active pharmaceutical substance with an empirical formula of Ci2H 13 NCH 4 0 3 S and a molecular weight of 267.34. Rasagiline mesylate is the international common accepted name for R-(+)-N-propargyl-l-aminoindan mesylate (or (lR)-N-prop-2-yn-l-ylindan-l -amine mesylate or (lR)-2,3-dihydro-N-2- propynyl-lH-inden-l-amine mesylate), which is represented in Formula la.
  • EP 0812190 Bl discloses preparation of rasagiline hydrochloride and mesylate salts. It also discloses comparative stability and solubility of rasagiline mesylate with other salts like tartrate, maleate, sulphate, hydrochloride, tosylate, fumarate, phosphate, esylate, tannate and acetate.
  • U.S. Patent Application No. 2010/0010098 A 1 discloses three crystalline forms of rasagiline hydrochloride i.e., Form-I, Form-II and Form-Ill.
  • Different salt forms of the same pharmaceutically active moiety differ in their physical properties such as melting point, solubility, chemical reactivity, stability etc. These properties may appreciably influence pharmaceutical properties such as dissolution rate and bioavailablility.
  • Polymorphism is very common among pharmaceutical substances. It is commonly defined as the ability of any substance to exist in two or more crystalline phases that have a different arrangement and/or conformation of the molecules in the crystal lattice.
  • particle size distributions have a beneficial effect on the uniformity of the solid pharmaceutical composition of rasagiline.
  • the larger particle size i.e. coarser particle size still provide the better uniformity, flowability and suitable for pharmaceutical formulations.
  • FIG.13 illustrates representative PSD histogram of rasagiline hydrobromide Form-I having larger particle size.
  • the crystalline Form-I of rasagiline besylate may also be characterized by IR spectra 3226, 2985, 2812, 2360, 1479, 1444, 1213, 1182, 1124, 1068, 1053, 1016, 997, 756, 729, 692, 648, 613 and 567 cm "1 . It may also be characterized by IR spectra substantially as depicted in FIG. 2.
  • the crystalline Form-I of rasagiline besylate may also be characterized by DSC having endothermic peak at about 79.40°C. It may also be characterized by DSC endotherm substantially as depicted in FIG. 3.
  • the embodiments of the process comprises treating rasagiline free base in one or more esters solvents with benzene sulfonic acid at about 25°C to 80°C, for example, at about 10°C to about 35°C.
  • a process for the preparation of rasagiline acid addition salts comprising reacting racemic 1-aminoindane with propargyl chloride in presence of atleast two bases in one or more of suitable organic solvent to obtain rasagiline base and converting rasagiline base to rasagiline acid addition salts.
  • the crystalline rasagiline hydrobromide may be further characterized by X-ray powder diffraction (PXRD) pattern with peaks at about 9.3°, 11.6°, 16.8°, 20.3°, 23.5°, 23.7° and 25.1° (2 ⁇ ).
  • the crystalline rasagiline hydrobromide may be characterized by a PXRD pattern substantially as depicted in FIG. 5. 3219, 2347, 2123, 1840, 1564, 1477, 1460, 1435, 1313, 1091, 1024, 894 and 765 cm "1 . It may also be characterized by IR spectra substantially as depicted in FIG. 6.
  • the present invention provides amorphous form of rasagiline hydrobromide characterized by X-ray powder diffraction substantially as depicted in FIG.8 rasagiline hydrobromide, the process comprising:
  • the process includes spray drying a solution of rasagiline; hydrobromide (feed stock), which can be prepared by any of the methods known in the ' art or by methods as discussed below, wherein crystalline rasagiline hydrobromide may be used.
  • feedstock may be dozed into the spray-drying instrument JISL Mini Spray-drier LSD-48 and spray drying may be carried out under the following parameters.
  • the suitable solvents comprise one or more of Q-C5 alcohol solvents, water and mixtures thereof.
  • the C ⁇ -Cs alcohol solvent is isopropanol.
  • An anti- solvent can be optionally added.
  • the suitable anti-solvent can be selected from one or more of aliphatic ethers like methyl tert-butyl ether, diisopropyl ether, and the like, hydrocarbons like cyclohexane, hexane, heptane, toluene, xylene, and the like.
  • the amount of rasagiline besylate contained in a pharmaceutical composition for treating Parkinson's disease, Alzheimer disease and various types of dementia should be sufficient to treat, ameliorate, or reduce the symptoms associated with it.
  • rasagiline may be present in an amount of about 1 % to about 60% by weight of the dose.
  • compositions containing the rasagiline salts of the invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.
  • diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.
  • modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • Wetting agents may include, but are not limited to, glycerin, starch, and the like.
  • Adsorbing agents used include, but are not limited to, starch, lactose, kaolin, bentonite, colloidal silicic acid, and the like.
  • Lubricants used include, but are not limited to, purified talc, stearates, boric acid powder, polyethylene glycol, and the like.
  • the reaction mixture was further cooled to about 10°C and stirred for 2 hours.
  • the product was filtered and washed with ethyl acetate.
  • the wet-cake was dried at 40°C to 45°C for 6 to 8 hours.
  • the product was sieved with 60 Mesh to obtain the crystalline Form-I of rasagiline besylate with larger particle size.
  • PSD particle size distribution
  • the particle size distribution (PSD) was measured by the following method.
  • the product was characterized by XRD (FIG.l), IR (FIG.2) and DSC (FIG.3).
  • the mother liquor obtained after filtration was used for recovery of rasagiline besylate.
  • the product was sieved through a 60 Mesh. Malvern Laser diffraction, using the Malvern Mastersizer 2000 instrument.
  • the Particle Size distribution provided in FIG.4 is a representative histogram provided herein as reference.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des sels d'addition d'acide de rasagiline ayant une taille de particule D(90) supérieure à 250 microns et D(50) supérieure à 100 microns, à condition que le sel d'addition d'acide ne soit pas un mésylate. L'invention concerne en outre un procédé pour la préparation de tels sels d'addition d'acide de rasagiline.
EP12766333.4A 2011-05-04 2012-05-04 Rasagiline et ses sels pharmaceutiquement acceptables Withdrawn EP2705021A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IN1382MU2011 2011-05-04
IN3169MU2011 2011-11-09
PCT/IN2012/000329 WO2012153349A2 (fr) 2011-05-04 2012-05-04 Rasagiline et ses sels pharmaceutiquement acceptables

Publications (1)

Publication Number Publication Date
EP2705021A2 true EP2705021A2 (fr) 2014-03-12

Family

ID=46939731

Family Applications (1)

Application Number Title Priority Date Filing Date
EP12766333.4A Withdrawn EP2705021A2 (fr) 2011-05-04 2012-05-04 Rasagiline et ses sels pharmaceutiquement acceptables

Country Status (2)

Country Link
EP (1) EP2705021A2 (fr)
WO (1) WO2012153349A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN2013MU01782A (fr) * 2013-05-20 2015-06-26 Cadila Healthcare Ltd

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL92952A (en) 1990-01-03 1994-06-24 Teva Pharma R-enantiomers of n-propargyl-1-aminoindan compounds, their preparation and pharmaceutical compositions containing them
IL111240A (en) 1993-10-18 2001-10-31 Teva Pharma Salts of r(+) - enantiomers of n- propargyl-1-aminoindan and pharmaceutical compositions comprising them
AU2006216696B2 (en) 2005-02-23 2011-08-18 Teva Pharmaceutical Industries, Ltd. Rasagiline formulations of improved content uniformity
EP1892233A1 (fr) 2006-08-18 2008-02-27 Ratiopharm GmbH De nouveaux sels de la substance active rasagiline
ES2375761T3 (es) 2006-12-14 2012-03-06 Teva Pharmaceutical Industries Ltd. Base de rasagilina cristalina sólida.
EP1987816A1 (fr) 2007-04-30 2008-11-05 Ratiopharm GmbH Adsorbate d'un sel de rasagiline en combinaison avec un agent inactive soluble dans l'eau
EP2276722A2 (fr) 2008-03-28 2011-01-26 Medichem, S.A. Forme polymorphe d un dérivé de mésylate d amino-indane
WO2011012140A2 (fr) 2008-07-11 2011-02-03 Synthon Bv Polymorphes de chlorhydrate de rasagiline
AR074637A1 (es) 2008-07-18 2011-02-02 Medichem Sa Formas de sal de adicion acida de r-(+)-n-propargil-1-aminoindano (es decir , base de rasagilina), un compuesto de formula (1), procesos para prepararlos y aislarlos y usos de los mismos
WO2010111264A2 (fr) 2009-03-24 2010-09-30 Dr. Reddy's Laboratories Ltd. Préparations de rasagiline
JP2012532843A (ja) 2009-07-09 2012-12-20 ラティオファーム ゲーエムベーハー ラサギリンの塩およびその製剤
WO2011009873A2 (fr) * 2009-07-20 2011-01-27 Medichem, S.A. Nouvelle forme d'un dérivé de mésylate d'aminoindane
US8741962B2 (en) 2009-11-26 2014-06-03 Usv Limited Process for preparation of Rasagiline and salts thereof
WO2011080589A2 (fr) 2009-12-30 2011-07-07 Actavis Group Ptc Ehf Formes à l'état solide de sels de rasagiline
US20120321896A1 (en) 2010-02-01 2012-12-20 Kuppuswamy Nagarajan Rasagiline mesylate having large particle size and a process for preparation thereof
WO2011095985A2 (fr) 2010-02-02 2011-08-11 Glenmark Generics Limited Sels de rasagiline et procédés de preparation de ces derniers
WO2011121607A2 (fr) 2010-03-29 2011-10-06 Cadila Healthcare Limited Composé de rasagiline et sels pharmaceutiquement acceptables de celui-ci
GB201005626D0 (en) 2010-04-01 2010-05-19 Isis Innovation Biological cell system instability investigation apparatus and method

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2012153349A2 *

Also Published As

Publication number Publication date
WO2012153349A2 (fr) 2012-11-15
WO2012153349A9 (fr) 2014-02-13
WO2012153349A3 (fr) 2013-03-21

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