Title of Invention

"PROCESS FOR THE PREPARATION OF THE γD- CRYSTALLINE FORM OF IVABRADINE HYDROCHILORIDE "

Abstract Process for the preparation of the γd-crystalline form of ivabradine hydrochloride, characterized in that a mixture of ivabradine hydrochloride and 2-ethoxyethanol, a mixture of ivabradine hydrochloride, 2-ethoxyethanol and water, or a mixture of ivabradine hydrochloride, ethanol and water is heated until dissolution is complete and is then cooled until crystallization is complete, and the crystals obtained are collected by filtration and dehydrated.
Full Text The present invention relates to process for the preparation of the yd-crystalline form of ivabradine hydrochloride.
The present invention relates to the new yd-crystalline form of ivabradine hydrochloride of formula (I), to a process for its preparation and to pharmaceutical compositions containing it.
(Formula Removed)



Ivabradine, and addition salts thereof with a pharmacentically 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 phamaaceutically 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 crystalline form that is well defined and that exhibits valuable characteristics of stability and processability.
More specifically, the present invention relates to the yd-crystalline form of ivabradine hydrochloride, which is 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 ray position (Bragg's angle 2 theta, expressed in degrees), ray height (expressed in counts), ray area (expressed in counts x degrees), ray width at half-height ("FWHM", expressed in degrees) and interplanar distance d (expressed in A):

(Table Removed)
The invention relates also to a process for the preparation of the yd-crystalline form of ivabradine hydrochloride, which process is characterised in that a mixture of ivabradine hydrochloride and 2-ethoxyethanol, a mixture of ivabradine hydrochloride, 2-ethoxyethanol and water, or a mixture of ivabradine hydrochloride, ethanol and water is heated until dissolution is complete and is then cooled until crystallisation is complete, and the crystals obtained are collected by filtration and 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 invention relates also to pharmaceutical compositions comprising as active ingredient the yd-crystalline form of ivabradine hydrochloride together with one or more appropriate, inert, 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 dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, 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. That dosage varies from 1 to 500 mg per day in one or more administrations.
The following Examples 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 8-0,
- nickel (K(3) filter,
- incident-beam and diffracted-beam Soller slit: 0.04 rad,
- fixed angle of divergence slits : 1/8°,
mask: 10 mm,
- antiscatter slit: 1/4°,
- measurement mode : continuous from 3° to 30°, in increments of 0.017°,
- measurement time per step : 19.7 s,
- total time : 4 min 32s,
- measurement speed : 0.108°/s,
- measurement temperature : ambient.
EXAMPLE 1 ; yd-Crystalline form of ivabradine hydrochloride
40 ml of 2-ethoxyethanol are preheated to 80°C, and then 8.4 g of ivabradine hydrochloride obtained according to the process described in the patent specification EP 0 534 859 are added in portions, with stirring, and the mixture is heated at 80°C until dissolution is complete. After returning to ambient temperature, the solution is stored for
8 days, and then the crystals formed are collected by filtration and rinsed with
cyclohexane.
The product thereby obtained is dehydrated by progressively heating at a rate of 5°C/min
up to a temperature of 80°C.
X-ray powder diffraction diagram :
The X-ray powder diffraction profile (diffraction angles) of the yd-form of ivabradine hydrochloride is given by the significant rays collated in the following table:

(Table Removed)
EXAMPLE 2 : Pharmaceutical composition
Formula for the preparation of 1000 tablets each containing 5 mg of ivabradine base:
Compound of Example 1 5.39g
Maize starch 20 g
Anhydrous colloidal silica 0.2 g
Mannitol 63.91 g
PVP 10 g
Magnesium stearate 0.5 g




WE CLAIM:
1. Process for the preparation of the γd-crystalline form of ivabradine hydrochloride, characterized in that a mixture of ivabradine hydrochloride and 2-ethoxyethanol, a mixture of ivabradine hydrochloride, 2-ethoxyethanol and water, or a mixture of ivabradine hydrochloride, ethanol and water is heated until dissolution is complete and is then cooled until crystallization is complete, and the crystals obtained are collected by filtration and dehydrated.
2. Process as claimed in claim 1, wherein the solution of ivabradine hydrochloride is seeded during the cooling step.
3. A process as claimed in claim 1, wherein the γd-crystalline form of ivabradine hydrochloride formed is used in preparing a pharmaceutical composition for preventing and treating the 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.




Documents:

484-DEL-2006-Abstract-(08-10-2008).pdf

484-DEL-2006-Abstract-(09-03-2009).pdf

484-DEL-2006-Abstract-(09-07-2009).pdf

484-DEL-2006-Abstract-(30-06-2009).pdf

484-del-2006-abstract.pdf

484-DEL-2006-Claims-(08-10-2008).pdf

484-DEL-2006-Claims-(09-03-2009).pdf

484-DEL-2006-Claims-(09-07-2009).pdf

484-DEL-2006-Claims-(30-06-2009).pdf

484-del-2006-claims.pdf

484-DEL-2006-Correspondence-Others-(08-10-2008).pdf

484-DEL-2006-Correspondence-Others-(09-03-2009).pdf

484-DEL-2006-Correspondence-Others-(09-07-2009).pdf

484-DEL-2006-Correspondence-Others-(27-08-2009).pdf

484-DEL-2006-Correspondence-Others-(30-04-2009).pdf

484-DEL-2006-Correspondence-Others-(30-06-2009).pdf

484-del-2006-correspondence-others-1.pdf

484-del-2006-correspondence-others.pdf

484-DEL-2006-Description (Complete)-(09-03-2009).pdf

484-DEL-2006-Description (Complete)-(30-06-2009).pdf

484-del-2006-description (complete).pdf

484-DEL-2006-Form-1-(08-10-2008).pdf

484-DEL-2006-Form-1-(09-03-2009).pdf

484-DEL-2006-Form-1-(30-06-2009).pdf

484-del-2006-form-1.pdf

484-del-2006-form-18.pdf

484-DEL-2006-Form-2-(09-03-2009).pdf

484-DEL-2006-Form-2-(30-06-2009).pdf

484-del-2006-form-2.pdf

484-DEL-2006-Form-3-(08-10-2008).pdf

484-DEL-2006-Form-3-(09-03-2009).pdf

484-DEL-2006-Form-3-(27-08-2009).pdf

484-del-2006-form-3.pdf

484-del-2006-form-5.pdf

484-DEL-2006-GPA-(08-10-2008).pdf

484-del-2006-gpa.pdf

abstract.jpg


Patent Number 235929
Indian Patent Application Number 484/DEL/2006
PG Journal Number 38/2009
Publication Date 18-Sep-2009
Grant Date 08-Sep-2009
Date of Filing 22-Feb-2006
Name of Patentee LES LABORATOIRES SERVIER
Applicant Address 12, PLACE DE LA DEFENSE, 92415 COURBEVOIE CEDEX, FRANCE.
Inventors:
# Inventor's Name Inventor's Address
1 STEPHANE HORVATH 35, ROUTE D'ORLEANS, 45380 LA CHAPELLE- SAINT- MESMIN, FRANCE.
2 MARIE-NOELLE AUGUSTE 3 BIS, RUE BLEUE, 45000 ORLEANS, FRANCE.
3 GERARD DAMIEN 31 BIS, AVENUE DU BLENOIS, 45130 MEUNG-SUR-LOIRE, FRANCE.
PCT International Classification Number C07D 223/16
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 05.01990 2005-02-28 France