Title of Invention

"A PROCESS FOR PREPARATION OF DELTA-D-CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE"

Abstract The present invention relates to process for the preparation of the 5d-crystalline form of ivabradine hydrochloride, wherein 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 crystallization is complete, and the crystals formed are dehydrated.
Full Text The present invention relates to the 8d-crystalline form of ivabradine hydrochloride of formula (I)

**Diagram delete
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 EP0534859 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 5d-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 x degrees), line width at half-height ("FWHM", expressed in degrees) and interplanar distance d (expressed in A):

s Line no. Angle 2 theta (degrees) Height (counts) Area (counts
*"•'.' ' degrees) FWHM
(degrees) Interplanar distance (A)
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

Line no. Angle 2 theta (degrees) Height (counts) Area (counts x degrees) FWHM
(degrees) Interplanar distance (A)
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 8d-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 0534 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 6d-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 dragees, 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 6-6,
- nickel (K/3) filter,
- incident-beam and diffracted-beam Soller slit: 0.04 rad,
automatic divergence slits : irradiated length of 10 mm,
- mask: 10mm,
- antiscatter slit: 1/2°,
- measurement mode : continuous from 3° to 30°, 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 : fid-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 vacua 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 8d-form of ivabradine hydrochloride is given by the significant lines collated in the following table:

Line no. Angle 2 theta (degrees) Height (counts) Area (counts
X
degrees) FWHM
(degrees) Interplanar distance (A)
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

Line no. Angle 2 theta (degrees) Height (counts) Area (counts x degrees) FWHM
(degrees) Interplanar distance (A)
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





We Claim:
1. Process for the preparation of the 8d-crystalline form of ivabradine hydrochloride,
wherein 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 crystallization is complete, and the crystals formed are
dehydrated.
2. Process as claimed in claim 1, wherein the solution of ivabradine hydrochloride is seeded during the cooling step.

Documents:

2224-DEL-2006-Abstract-(09-10-2009).pdf

2224-del-2006-abstract.pdf

2224-DEL-2006-Claims-(09-10-2009).pdf

2224-DEL-2006-Claims-(22-03-2011).pdf

2224-del-2006-claims.pdf

2224-DEL-2006-Correspondence Others-(22-03-2011).pdf

2224-DEL-2006-Correspondence-Others-(02-12-2010).pdf

2224-DEL-2006-Correspondence-Others-(09-10-2009).pdf

2224-DEL-2006-Correspondence-Others-(18-05-2010).pdf

2224-del-2006-correspondence-others.pdf

2224-del-2006-description (complete).pdf

2224-del-2006-form-1.pdf

2224-del-2006-form-18.pdf

2224-del-2006-form-2.pdf

2224-DEL-2006-Form-3-(02-12-2010).pdf

2224-DEL-2006-Form-3-(09-10-2009).pdf

2224-del-2006-form-3.pdf

2224-del-2006-form-5.pdf

2224-DEL-2006-GPA-(09-10-2009).pdf

2224-del-2006-gpa.pdf

2224-DEL-2006-Petition-137-(09-10-2009).pdf

2224-DEL-2006-Petition-138-(09-10-2009).pdf

abstract.jpg


Patent Number 248308
Indian Patent Application Number 2224/DEL/2006
PG Journal Number 27/2011
Publication Date 08-Jul-2011
Grant Date 04-Jul-2011
Date of Filing 09-Oct-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 BLUE, 45000 ORLEANS, FRANCE
3 GERARD DAMIEN 5 BIS, IMPASSE DES MARINIERS, 78220 VIROFLAY, FRANCE
PCT International Classification Number C07D223/16; C07D223/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 05.10354 2005-10-11 France