# Patent

## Title
γ-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it

## Abstract

A γ-Crystalline form of ivabradine hydrochloride of formula (I):




characterised by its powder X-ray diffraction data.

Medicinal products containing the same which are useful as bradycardics.

## Background
The present invention relates to the new γ-crystalline form of ivabradine hydrochloride of formula (I), 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 crystalline form that is well defined and that exhibits valuable characteristics of stability and processability.
More specifically, the present invention relates to the γ-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-weight (“FWHM”, expressed in degrees) and interplanar distance d (expressed in Å):
















Angle



Interplanar


Ray
2 theta
Height
Area
FWHM
distance


no.
(degrees)
(counts)
(counts × degrees)
(degrees)
(Å)




















 1
4.2
1456
144
0.1004
20.762


 2
6.9
125
99
0.8029
12.880


 3
8.4
182
18
0.1004
10.503


 4
10.7
240
32
0.1338
8.249


 5
11.3
74
15
0.2007
7.858


 6
12.0
644
64
0.1004
7.392


 7
12.5
1476
219
0.1506
7.060


 8
13.4
2691
400
0.1506
6.612


 9
14.5
541
80
0.1506
6.119


10
14.8
104
17
0.1673
5.981


11
15.9
815
67
0.0836
5.559


12
16.3
501
74
0.1506
5.419


13
17.0
1168
154
0.1338
5.210


14
17.9
430
43
0.1004
4.962


15
19.0
667
121
0.184
4.672


16
19.8
527
104
0.2007
4.483


17
20.2
726
144
0.2007
4.392


18
20.5
282
28
0.1004
4.323


19
21.1
2255
260
0.1171
4.208


20
21.4
694
68
0.1004
4.147


21
21.6
744
86
0.1171
4.111


22
22.3
175
35
0.2007
3.987


23
23.5
310
61
0.2007
3.784


24
24.2
1635
270
0.1673
3.683


25
24.5
1335
220
0.1673
3.625


26
24.9
523
95
0.184
3.568


27
25.5
657
130
0.2007
3.485


28
26.0
933
154
0.1673
3.431


29
26.4
1549
230
0.1506
3.380


30
26.8
419
83
0.2007
3.323


31
27.3
350
69
0.2007
3.267


32
28.0
1108
146
0.1338
3.186


33
29.1
144
19
0.1338
3.066









The invention relates also to a process for the preparation of the γ-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 product is collected by filtration.

    
    
        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 γ-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 dragées, 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 θ-θ,
    nickel (Kβ) 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 32 s,
    measurement speed: 0.108°/s,
    measurement temperature: ambient.




EXAMPLE 1
γ-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 water content of the crystals obtained, determined by coulometry, is 3.5%, which corresponds to a monohydrate.
X-Ray Powder Diffraction Diagram:
The X-ray powder diffraction profile (diffraction angles) of the γ-form of ivabradine hydrochloride is given by the significant rays collated in the following table:
















Angle



Interplanar


Ray
2 theta
Height
Area
FWHM
distance


no.
(degrees)
(counts)
(counts × degrees)
(degrees)
(Å)




















 1
4.2
1456
144
0.1004
20.762


 2
6.9
125
99
0.8029
12.880


 3
8.4
182
18
0.1004
10.503


 4
10.7
240
32
0.1338
8.249


 5
11.3
74
15
0.2007
7.858


 6
12.0
644
64
0.1004
7.392


 7
12.5
1476
219
0.1506
7.060


 8
13.4
2691
400
0.1506
6.612


 9
14.5
541
80
0.1506
6.119


10
14.8
104
17
0.1673
5.981


11
15.9
815
67
0.0836
5.559


12
16.3
501
74
0.1506
5.419


13
17.0
1168
154
0.1338
5.210


14
17.9
430
43
0.1004
4.962


15
19.0
667
121
0.184
4.672


16
19.8
527
104
0.2007
4.483


17
20.2
726
144
0.2007
4.392


18
20.5
282
28
0.1004
4.323


19
21.1
2255
260
0.1171
4.208


20
21.4
694
68
0.1004
4.147


21
21.6
744
86
0.1171
4.111


22
22.3
175
35
0.2007
3.987


23
23.5
310
61
0.2007
3.784


24
24.2
1635
270
0.1673
3.683


25
24.5
1335
220
0.1673
3.625


26
24.9
523
95
0.184
3.568


27
25.5
657
130
0.2007
3.485


28
26.0
933
154
0.1673
3.431


29
26.4
1549
230
0.1506
3.380


30
26.8
419
83
0.2007
3.323


31
27.3
350
69
0.2007
3.267


32
28.0
1108
146
0.1338
3.186


33
29.1
144
19
0.1338
3.066









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

1. A γ-Crystalline form of ivabradine hydrochloride of formula (I):



exhibiting essentially the following powder X-ray diffraction data, 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 Å):

















Angle



Interplanar


Ray
2 theta
Height
Area
FWHM
distance


no.
(degrees)
(counts)
(counts × degrees)
(degrees)
(Å)




















 1
4.2
1456
144
0.1004
20.762 


 2
6.9
125
99
0.8029
12.880 


 3
8.4
182
18
0.1004
10.503 


 4
10.7
240
32
0.1338
8.249


 5
11.3
74
15
0.2007
7.858


 6
12.0
644
64
0.1004
7.392


 7
12.5
1476
219
0.1506
7.060


 8
13.4
2691
400
0.1506
6.612


 9
14.5
541
80
0.1506
6.119


10
14.8
104
17
0.1673
5.981


11
15.9
815
67
0.0836
5.559


12
16.3
501
74
0.1506
5.419


13
17.0
1168
154
0.1338
5.210


14
17.9
430
43
0.1004
4.962


15
19.0
667
121
0.184
4.672


16
19.8
527
104
0.2007
4.483


17
20.2
726
144
0.2007
4.392


18
20.5
282
28
0.1004
4.323


19
21.1
2255
260
0.1171
4.208


20
21.4
694
68
0.1004
4.147


21
21.6
744
86
0.1171
4.111


22
22.3
175
35
0.2007
3.987


23
23.5
310
61
0.2007
3.784


24
24.2
1635
270
0.1673
3.683


25
24.5
1335
220
0.1673
3.625


26
24.9
523
95
0.184
3.568


27
25.5
657
130
0.2007
3.485


28
26.0
933
154
0.1673
3.431


29
26.4
1549
230
0.1506
3.380


30
26.8
419
83
0.2007
3.323


31
27.3
350
69
0.2007
3.267


32
28.0
1108
146
0.1338
3.186


33
29.1
144
19
0.1338
 3.066.

2. A process for the preparation of the γ-crystalline form of ivabradine hydrochloride of claim 1, wherein 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 product thus obtained is collected by filtration.

3. The process of claim 2, wherein the solution of ivabradine hydrochloride is seeded during the cooling step.

4. A solid pharmaceutical composition comprising as active ingredient the γ-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 a condition selected from angina pectoris, myocardial infarct and heart failure, such method comprising administering to a living animal body, including a human, a therapeutically effective amount of a γ-crystalline form of ivabradine hydrochloride of claim 1.