Title of Invention	"PROCESS FOR THE PREPARATION OF THE ß-CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE"
Abstract	The present invention relates to process for the preparation of the ß-crystalline form of ivabradine hydrochloride of formula (I), characterized by the powder X-ray diffraction diagram as hereinbefore desribed, and wherein the said process is characterized in that a mixture of ivabradine hydrochloride and water or a mixture of ivabradine hydrochloride, isopropanol and water is heated until dissolution is complete and is then progressively cooled until crystallisation is complete, and the crystals formed are collected.

Title of Invention

"PROCESS FOR THE PREPARATION OF THE ß-CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE"

Abstract

The present invention relates to process for the preparation of the ß-crystalline form of ivabradine hydrochloride of formula (I), characterized by the powder X-ray diffraction diagram as hereinbefore desribed, and wherein the said process is characterized in that a mixture of ivabradine hydrochloride and water or a mixture of ivabradine hydrochloride, isopropanol and water is heated until dissolution is complete and is then progressively cooled until crystallisation is complete, and the crystals formed are collected.

Full Text	The present invention relates to process for the preparation of the ß-crystalline form of ivabradine hydrochloride. The present invention relates to the ß-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 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 mis 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 p-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 m 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 p-crystalline form of ivabradine hydrochloride, which process is characterised in that a mixture of ivabradine hydrochloride and water or a mixture of ivabradine hydrochloride, isopropanol and water is heated until dissolution is complete and is then progressively cooled until crystallisation is complete, and the crystals formed are collected. • 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 p-crystalline form of ivabradine hydrochloride together with one or more appropriate, inert, non-toxic exapients. 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 0-0, - nickel (Kp) filter, incident-beam and diffracted-beam Seller 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 32 s, - measurement speed : 0.108°/s, measurement temperature : ambient. EXAMPLE 1 : p-( rystalline form of ivabradine hydrochloride 720 ml of purified water are preheated to 50°C, and then 250 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 74°C until dissolution is 5 complete. The resulting clear solution is heated for 2 more hours at 74°C and is then progressively cooled, first to 40°C, and then to ambient temperature. The solution is subsequently stored at ambient temperature for 2 days, and then the solid suspension is spread out in a thin layer on a crystallisation plate. The excess water is driven off under a gentle current of nitrogen. The water content of the resulting product, determined by coulometry, is 12.4 %, which corresponds to a tetrahydrate. X-ray powder diffraction diagram : The X-ray powder diffraction profile (diffraction angles) of the p-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...... 5.39 g Maize starch , ........20 g Anhydrous colloidal silica 0.2 g Mannitol 63.91 g PVP 10 g Magnesium stearate 0.5 g The present invention relates to process for the preparation of the ß-crystalline form of ivabradine hydrochloride of formula (I), characterized by the powder X-ray diffraction diagram as hereinbefore desribed, and wherein the said process is characterized in that a mixture of ivabradine hydrochloride and water or a mixture of ivabradine hydrochloride, isopropanol and water is heated until dissolution is complete and is then progressively cooled until crystallisation is complete, and the crystals formed are collected.

Full Text

The present invention relates to process for the preparation of the ß-crystalline form of ivabradine hydrochloride.
The present invention relates to the ß-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 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 mis 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 p-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 m 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 p-crystalline form of ivabradine hydrochloride, which process is characterised in that a mixture of ivabradine hydrochloride and water or a mixture of ivabradine hydrochloride, isopropanol and water is heated until dissolution is complete and is then progressively cooled until crystallisation is complete, and the crystals formed are collected.
• 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 p-crystalline form of ivabradine hydrochloride together with one or more appropriate,

inert, non-toxic exapients. 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 0-0,
- nickel (Kp) filter,
incident-beam and diffracted-beam Seller 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 32 s,
- measurement speed : 0.108°/s,
measurement temperature : ambient.

EXAMPLE 1 : p-( rystalline form of ivabradine hydrochloride
720 ml of purified water are preheated to 50°C, and then 250 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 74°C until dissolution is 5 complete. The resulting clear solution is heated for 2 more hours at 74°C and is then progressively cooled, first to 40°C, and then to ambient temperature. The solution is subsequently stored at ambient temperature for 2 days, and then the solid suspension is spread out in a thin layer on a crystallisation plate. The excess water is driven off under a gentle current of nitrogen.
The water content of the resulting product, determined by coulometry, is 12.4 %, which corresponds to a tetrahydrate.
X-ray powder diffraction diagram :
The X-ray powder diffraction profile (diffraction angles) of the p-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...... 5.39 g
Maize starch , ........20 g
Anhydrous colloidal silica 0.2 g
Mannitol 63.91 g
PVP 10 g
Magnesium stearate 0.5 g

The present invention relates to process for the preparation of the ß-crystalline form of ivabradine hydrochloride of formula (I),
characterized by the powder X-ray diffraction diagram as hereinbefore desribed, and wherein the said process is characterized in that a mixture of ivabradine hydrochloride and water or a mixture of ivabradine hydrochloride, isopropanol and water is heated until dissolution is complete and is then progressively cooled until crystallisation is complete, and the crystals formed are collected.

Documents:

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Patent Number

269993

Indian Patent Application Number

486/DEL/2006

PG Journal Number

48/2015

Publication Date

27-Nov-2015

Grant Date

23-Nov-2015

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	GERARD DAMIEN	31 BIS, AVENUE DU BLENOIS, 45130 MEUNG-SUR-LOIRE, FRANCE.
3	MARIE-NOELLE AUGUSTE	3 BIS, RUE BLEUE, 45000 ORLEANS, 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	05.01985	2005-02-28	France