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US20080227771A1 - Delta d-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it - Google Patents

Delta d-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it Download PDF

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Publication number
US20080227771A1
US20080227771A1 US12/151,545 US15154508A US2008227771A1 US 20080227771 A1 US20080227771 A1 US 20080227771A1 US 15154508 A US15154508 A US 15154508A US 2008227771 A1 US2008227771 A1 US 2008227771A1
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Prior art keywords
crystalline form
ivabradine hydrochloride
ivabradine
hydrochloride
rhythm disturbances
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US12/151,545
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Stephane Horvath
Marie-Noelle Auguste
Gerard Damien
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Les Laboratoires Servier SAS
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Les Laboratoires Servier SAS
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Priority to US12/151,545 priority Critical patent/US20080227771A1/en
Publication of US20080227771A1 publication Critical patent/US20080227771A1/en
Priority to US12/583,914 priority patent/US7879841B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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 present invention relates to the ⁇ d-crystalline form of ivabradine hydrochloride of formula (I)
  • Ivabradine, and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischaemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.
  • the present invention relates to the ⁇ d-crystalline form of ivabradine hydrochloride, characterised by the following powder X-ray diffraction diagram, measured using a PANalytical X′Pert Pro diffractometer together with an X′Celerator detector and expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees), line height (expressed in counts), line area (expressed in counts ⁇ degrees), line width at half-height (“FWHM”, expressed in degrees) and interplanar distance d (expressed in ⁇ ):
  • the invention relates also to a process for the preparation of the ⁇ d-crystalline form of ivabradine hydrochloride, which process is characterised in that acetonitrile or a mixture of acetonitrile and water is preheated, ivabradine hydrochloride is added, the solution obtained is allowed to cool at room temperature, held at room temperature until crystallisation is complete, and the crystals formed are dehydrated.
  • the invention relates also to pharmaceutical compositions comprising as active ingredient the ⁇ d-crystalline form of ivabradine hydrochloride together with one or more appropriate, inert and non-toxic excipients.
  • pharmaceutical compositions according to the invention there may be mentioned, more especially, those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragées, sublingual tablets, capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations and drinkable suspensions.
  • the useful dosage can be varied according to the nature and severity of the disorder, the administration route and the age and weight of the patient.
  • the dosage varies from 1 to 500 mg per day in one or more administrations.
  • acetonitrile 160 ml of acetonitrile are preheated to 70° C. and then 2 g of ivabradine hydrochloride obtained according to the process described in patent specification EP 0 534 859 are added, in portions, with stirring until dissolution is complete.
  • the solution is then stored at ambient temperature for 2 days.
  • the crystals are removed by filtration in vacuo and are spread out onto a crystallisation plate.
  • the crystals are then heated to a temperature of 85° C. at a rate of 10° C./min and held at 85° C. for 4 hours.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

A δd-crystalline form of ivabradine hydrochloride of formula (I):
Figure US20080227771A1-20080918-C00001
characterised by its powder X-ray diffraction data.
Medicinal products containing the same which are useful as bradycardics.

Description

  • The present invention relates to the δd-crystalline form of ivabradine hydrochloride of formula (I)
  • Figure US20080227771A1-20080918-C00002
  • to a process for its preparation and to pharmaceutical compositions containing it.
  • Ivabradine, and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischaemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.
  • The preparation and therapeutic use of ivabradine and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have been described in the European patent specification EP 0 534 859.
  • In view of the pharmaceutical value of this compound, it has been of prime importance to obtain it with excellent purity. It has also been important to be able to synthesise it by means of a process that can readily be converted to the industrial scale, especially in a form that allows rapid filtration and drying. Finally, that form had to be perfectly reproducible, easily formulated and sufficiently stable to allow its storage for long periods without particular requirements for temperature, light or oxygen level.
  • The patent specification EP 0 534 859 describes a synthesis process for ivabradine and its hydrochloride. However, that document does not specify the conditions for obtaining ivabradine in a form that exhibits those characteristics in a reproducible manner.
  • The Applicant has now found that a particular salt of ivabradine, the hydrochloride, can be obtained in a well defined crystalline form that exhibits valuable characteristics for stability and processability.
  • More specifically, the present invention relates to the δd-crystalline form of ivabradine hydrochloride, characterised by the following powder X-ray diffraction diagram, measured using a PANalytical X′Pert Pro diffractometer together with an X′Celerator detector and expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees), line height (expressed in counts), line area (expressed in counts×degrees), line width at half-height (“FWHM”, expressed in degrees) and interplanar distance d (expressed in Å):
  • Angle 2 theta Area FWHM Interplanar
    Line no. (degrees) Height (counts) (counts × degrees) (degrees) distance (Å)
    1 4.1 414 41 0.1004 21.672
    2 6.8 176 139 0.8029 13.078
    3 8.6 1020 101 0.1004 10.305
    4 9.1 323 43 0.1338 9.687
    5 10.9 224 30 0.1338 8.100
    6 11.7 354 47 0.1338 7.592
    7 14.6 2774 458 0.1673 6.074
    8 15.3 1805 328 0.184 5.800
    9 16.6 986 163 0.1673 5.345
    10 17.2 3821 946 0.2509 5.153
    11 18.1 2290 378 0.1673 4.898
    12 19.1 440 73 0.1673 4.649
    13 19.6 289 38 0.1338 4.526
    14 20.1 650 86 0.1338 4.408
    15 20.9 887 146 0.1673 4.252
    16 21.4 3112 565 0.184 4.147
    17 22.1 1708 254 0.1506 4.027
    18 22.5 1191 275 0.2342 3.945
    19 23.4 619 102 0.1673 3.800
    20 23.9 1343 222 0.1673 3.728
    21 24.7 256 34 0.1338 3.604
    22 25.6 309 41 0.1338 3.482
    23 26.2 1899 313 0.1673 3.397
    24 26.9 1588 183 0.1171 3.310
    25 27.6 1357 224 0.1673 3.231
    26 29.1 140 37 0.2676 3.069
    27 29.5 145 29 0.2007 3.023
  • The invention relates also to a process for the preparation of the δd-crystalline form of ivabradine hydrochloride, which process is characterised in that acetonitrile or a mixture of acetonitrile and water is preheated, ivabradine hydrochloride is added, the solution obtained is allowed to cool at room temperature, held at room temperature until crystallisation is complete, and the crystals formed are dehydrated.
      • In the crystallisation process according to the invention it is possible to use ivabradine hydrochloride obtained by any process, for example ivabradine hydrochloride obtained by the preparation process described in patent specification EP 0.534 859.
      • The solution may advantageously be seeded during the cooling step.
      • The acetonitrile or mixture of acetonitrile and water is preferably preheated to a temperature between 60° C. and reflux, more preferably between 65 and 75° C.
      • The dilution is preferably more than 15 ml/g, more preferably between 50 and 100 ml/g.
      • The dehydration is preferably performed by heating.
  • The invention relates also to pharmaceutical compositions comprising as active ingredient the δd-crystalline form of ivabradine hydrochloride together with one or more appropriate, inert and non-toxic excipients. Among the pharmaceutical compositions according to the invention there may be mentioned, more especially, those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragées, sublingual tablets, capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations and drinkable suspensions.
  • The useful dosage can be varied according to the nature and severity of the disorder, the administration route and the age and weight of the patient. The dosage varies from 1 to 500 mg per day in one or more administrations.
  • The Examples that follow illustrate the invention.
  • The X-ray powder diffraction spectrum was measured under the following experimental conditions:
      • PANalytical X′Pert Pro diffractometer, X′Celerator detector, temperature-regulated chamber,
      • voltage 45 kV, intensity 40 mA,
      • mounting θ-θ,
      • nickel (Kβ) filter,
      • incident-beam and diffracted-beam Soller slit: 0.04 rad,
      • automatic divergence slits: irradiated length of 10 mm,
      • mask: 10 mm,
      • antiscatter slit: ½°,
      • measurement mode: continuous from 30 to 300, in increments of 0.017°,
      • measurement time per step: 19.7 s,
      • total time: 4 min 32 s,
      • measurement speed: 0.108°/s.
    EXAMPLE 1 δd-Crystalline Form of Ivabradine Hydrochloride
  • 160 ml of acetonitrile are preheated to 70° C. and then 2 g of ivabradine hydrochloride obtained according to the process described in patent specification EP 0 534 859 are added, in portions, with stirring until dissolution is complete. The solution is then stored at ambient temperature for 2 days. The crystals are removed by filtration in vacuo and are spread out onto a crystallisation plate. The crystals are then heated to a temperature of 85° C. at a rate of 10° C./min and held at 85° C. for 4 hours.
    • Powder X-Ray Diffraction Diagram:
  • The powder X-ray diffraction profile (diffraction angles) of the δd-form of ivabradine hydrochloride is given by the significant lines collated in the following table:
  • Angle 2 theta Area FWHM Interplanar
    Line no. (degrees) Height (counts) (counts × degrees) (degrees) distance (Å)
    1 4.1 414 41 0.1004 21.672
    2 6.8 176 139 0.8029 13.078
    3 8.6 1020 101 0.1004 10.305
    4 9.1 323 43 0.1338 9.687
    5 10.9 224 30 0.1338 8.100
    6 11.7 354 47 0.1338 7.592
    7 14.6 2774 458 0.1673 6.074
    8 15.3 1805 328 0.184 5.800
    9 16.6 986 163 0.1673 5.345
    10 17.2 3821 946 0.2509 5.153
    11 18.1 2290 378 0.1673 4.898
    12 19.1 440 73 0.1673 4.649
    13 19.6 289 38 0.1338 4.526
    14 20.1 650 86 0.1338 4.408
    15 20.9 887 146 0.1673 4.252
    16 21.4 3112 565 0.184 4.147
    17 22.1 1708 254 0.1506 4.027
    18 22.5 1191 275 0.2342 3.945
    19 23.4 619 102 0.1673 3.800
    20 23.9 1343 222 0.1673 3.728
    21 24.7 256 34 0.1338 3.604
    22 25.6 309 41 0.1338 3.482
    23 26.2 1899 313 0.1673 3.397
    24 26.9 1588 183 0.1171 3.310
    25 27.6 1357 224 0.1673 3.231
    26 29.1 140 37 0.2676 3.069
    27 29.5 145 29 0.2007 3.023
    • EXAMPLE 2 Pharmaceutical Composition
  • Formula for the preparation of 1000 tablets each containing 5 mg of ivabradine base:
  •
    Compound of Example 1 5.39 g  
    Maize starch 20 g
    Anhydrous colloidal silica 0.2 g 
    Mannitol 63.91 g  
    PVP 10 g
    Magnesium stearate 0.5 g 

Claims (8)

1. A δd-Crystalline form of ivabradine hydrochloride of formula (I):
Figure US20080227771A1-20080918-C00003
2. The δd-Crystalline form of ivabradine hydrochloride of claim 1 having a powder X-ray diffraction diagram exhibiting peaks at 14.6, 15.3, 17.2, 18.1 and 21.4 deg 2 theta.
3. The δd-Crystalline form of ivabradine hydrochloride of claim 1 having a powder X-ray diffraction diagram exhibiting peaks at 8.6, 9.1, 10.9 and 11.7 deg 2 theta.
4. A pharmaceutical composition comprising as active ingredient the δd-crystalline form of ivabradine hydrochloride of claim 1, in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers.
5. A method for treating or preventing a condition requiring a bradycardic, such method comprising the step of administering to a living animal body, including a human, a therapeutically effective amount of the δd-crystalline form of ivabradine hydrochloride of claim 1.
6. A method for treating or preventing clinical situations of myocardial ischaemia and/or a condition involving rhythm disturbances, such method comprising the step of administering to a living animal body, including a human, a therapeutically effective amount of the δd-crystalline form of ivabradine hydrochloride of claim 1.
7. The method of claim 6, wherein the clinical situation of myocardial ischaemia is selected from angina pectoris, myocardial infarct and associated rhythm disturbances.
8. The method of claim 6, wherein the condition involving rhythm disturbances is selected from supraventricular rhythm disturbances and heart failure.
US12/151,545 2005-10-11 2008-05-07 Delta d-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it Abandoned US20080227771A1 (en)

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US12/583,914 US7879841B2 (en) 2005-10-11 2009-08-27 Delta D-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it

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FR05.10354 2005-10-11
FR0510354A FR2891827B1 (en) 2005-10-11 2005-10-11 CRYSTALLINE DELTAD FORM OF IVABRADINE HYDROCHLORIDE, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
US11/545,362 US7384932B2 (en) 2005-10-11 2006-10-10 δd-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it
US12/151,545 US20080227771A1 (en) 2005-10-11 2008-05-07 Delta d-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it

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