# Patent

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

## Abstract

A β-Crystalline form of ivabradine 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 β-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 paten 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 β-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×degrees), ray width at half-height (“FWHM”, expressed in degrees) and interplanar distance d (expressed in Å):
















Angle

Area

Interplanar


Ray
2 theta
Height
(counts ×
FWHM
distance


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




















1
6.8
130
86
0.6691
13.019


2
9.2
6141
507
0.0836
9.613


3
9.7
882
58
0.0669
9.083


4
10.0
875
72
0.0836
8.837


5
11.9
190
19
0.1004
7.433


6
12.2
500
58
0.1171
7.236


7
13.2
224
30
0.1338
6.694


8
13.8
633
52
0.0836
6.419


9
14.3
466
54
0.1171
6.209


10
14.8
926
76
0.0836
5.977


11
15.0
716
94
0.1338
5.887


12
15.7
531
79
0.1506
5.636


13
16.1
121
16
0.1338
5.502


14
16.9
1354
223
0.1673
5.254


15
18.4
5672
562
0.1004
4.824


16
18.8
1328
131
0.1004
4.716


17
19.7
1617
347
0.2175
4.508


18
20.4
296
34
0.1171
4.341


19
20.7
767
51
0.0669
4.286


20
21.3
1419
211
0.1506
4.178


21
21.6
2458
243
0.1004
4.114


22
22.6
1737
258
0.1506
3.937


23
23.0
1467
73
0.0502
3.865


24
23.7
486
128
0.2676
3.751


25
23.9
504
50
0.1004
3.718


26
25.3
4606
304
0.0669
3.513


27
25.7
791
91
0.1171
3.464


28
26.2
458
91
0.2007
3.406


29
26.6
221
44
0.2007
3.352


30
27.4
706
151
0.2175
3.251


31
27.7
208
27
0.1338
3.215


32
28.1
483
40
0.0836
3.176


33
28.8
242
24
0.1004
3.096


34
29.3
450
74
0.1673
3.049









The invention relates also to a process for the preparation of the β-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 β-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
β-Crystalline 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 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 β-form of ivabradine hydrochloride is given by the significant rays collated in the following table:
















Angle

Area

Interplanar


Ray
2 theta
Height
(counts ×
FWHM
distance


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




















1
6.8
130
86
0.6691
13.019


2
9.2
6141
507
0.0836
9.613


3
9.7
882
58
0.0669
9.083


4
10.0
875
72
0.0836
8.837


5
11.9
190
19
0.1004
7.433


6
12.2
500
58
0.1171
7.236


7
13.2
224
30
0.1338
6.694


8
13.8
633
52
0.0836
6.419


9
14.3
466
54
0.1171
6.209


10
14.8
926
76
0.0836
5.977


11
15.0
716
94
0.1338
5.887


12
15.7
531
79
0.1506
5.636


13
16.1
121
16
0.1338
5.502


14
16.9
1354
223
0.1673
5.254


15
18.4
5672
562
0.1004
4.824


16
18.8
1328
131
0.1004
4.716


17
19.7
1617
347
0.2175
4.508


18
20.4
296
34
0.1171
4.341


19
20.7
767
51
0.0669
4.286


20
21.3
1419
211
0.1506
4.178


21
21.6
2458
243
0.1004
4.114


22
22.6
1737
258
0.1506
3.937


23
23.0
1467
73
0.0502
3.865


24
23.7
486
128
0.2676
3.751


25
23.9
504
50
0.1004
3.718


26
25.3
4606
304
0.0669
3.513


27
25.7
791
91
0.1171
3.464


28
26.2
458
91
0.2007
3.406


29
26.6
221
44
0.2007
3.352


30
27.4
706
151
0.2175
3.251


31
27.7
208
27
0.1338
3.215


32
28.1
483
40
0.0836
3.176


33
28.8
242
24
0.1004
3.096


34
29.3
450
74
0.1673
3.049









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 β-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

Area

Interplanar


Ray
2 theta
Height
(counts ×)
FWHM
distance


no
(degrees)
(counts)
degrees)
(degrees)
(Å)




















1
6.8
130
86
0.6691
13.019


2
9.2
6141
507
0.0836
9.613


3
9.7
882
58
0.0669
9.083


4
10.0
875
72
0.0836
8.837


5
11.9
190
19
0.1004
7.433


6
12.2
500
58
0.1171
7.236


7
13.2
224
30
0.1338
6.694


8
13.8
633
52
0.0836
6.419


9
14.3
466
54
0.1171
6.209


10
14.8
926
76
0.0836
5.977


11
15.0
716
94
0.1338
5.887


12
15.7
531
79
0.1506
5.636


13
16.1
121
16
0.1338
5.502


14
16.9
1354
223
0.1673
5.254


15
18.4
5672
562
0.1004
4.824


16
18.8
1328
131
0.1004
4.716


17
19.7
1617
347
0.2175
4.508


18
20.4
296
34
0.1171
4.341


19
20.7
767
51
0.0669
4.286


20
21.3
1419
211
0.1506
4.178


21
21.6
2458
243
0.1004
4.114


22
22.6
1737
258
0.1506
3.937


23
23.0
1467
73
0.0502
3.865


24
23.7
486
128
0.2676
3.751


25
23.9
504
50
0.1004
3.718


26
25.3
4606
304
0.0669
3.513


27
25.7
791
91
0.1171
3.464


28
26.2
458
91
0.2007
3.406


29
26.6
221
44
0.2007
3.352


30
27.4
706
151
0.2175
3.251


31
27.7
208
27
0.1338
3.215


32
28.1
483
40
0.0836
3.176


33
28.8
242
24
0.1004
3.096


34
29.3
450
74
0.1673
 3.049.

2. A process for the preparation of the β-crystalline form of ivabradine hydrochloride of claim 1, wherein 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 crystallization is complete, and the crystals thereby formed are collected.

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 β-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 β-crystalline form of ivabradine hydrochloride of claim 1.