# Patent

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

## Abstract

A γd-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 γd-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 γd-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 Å):
















Angle



Interplanar


Ray
2 theta
Height
Area
FWHM
distance


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




















 1
4.3
1077
124
0.1171
20.633


 2
6.9
132
70
0.5353
12.787


 3
8.4
269
35
0.1338
10.482


 4
10.6
322
26
0.0836
8.310


 5
11.9
733
97
0.1338
7.414


 6
12.5
1406
278
0.2007
7.069


 7
13.4
2975
442
0.1506
6.619


 8
14.4
825
122
0.1506
6.134


 9
15.8
1036
205
0.2007
5.598


10
16.3
540
107
0.2007
5.450


11
16.9
1007
183
0.184
5.233


12
17.8
499
58
0.1171
4.978


13
18.9
1062
140
0.1338
4.686


14
19.8
570
85
0.1506
4.485


15
20.2
549
63
0.1171
4.399


16
20.9
2565
635
0.2509
4.241


17
21.6
531
105
0.2007
4.104


18
22.3
213
35
0.1673
3.981


19
23.4
278
27
0.1004
3.807


20
24.1
1404
185
0.1338
3.694


21
24.4
1526
176
0.1171
3.650


22
24.8
676
100
0.1506
3.591


23
25.4
702
139
0.2007
3.504


24
26.2
1737
401
0.2342
3.403


25
26.8
258
51
0.2007
3.331


26
27.2
182
24
0.1338
3.282


27
27.9
838
249
0.3011
3.193


28
29.1
152
20
0.1338
3.071









The invention relates also to a process for the preparation of the γd-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 γd-crystalline form of ivabradine hydrochloride together with one or more appropriate, inert, nontoxic 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
γd-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 γd-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
4.3
1077
124
0.1171
20.633


 2
6.9
132
70
0.5353
12.787


 3
8.4
269
35
0.1338
10.482


 4
10.6
322
26
0.0836
8.310


 5
11.9
733
97
0.1338
7.414


 6
12.5
1406
278
0.2007
7.069


 7
13.4
2975
442
0.1506
6.619


 8
14.4
825
122
0.1506
6.134


 9
15.8
1036
205
0.2007
5.598


10
16.3
540
107
0.2007
5.450


11
16.9
1007
183
0.184
5.233


12
17.8
499
58
0.1171
4.978


13
18.9
1062
140
0.1338
4.686


14
19.8
570
85
0.1506
4.485


15
20.2
549
63
0.1171
4.399


16
20.9
2565
635
0.2509
4.241


17
21.6
531
105
0.2007
4.104


18
22.3
213
35
0.1673
3.981


19
23.4
278
27
0.1004
3.807


20
24.1
1404
185
0.1338
3.694


21
24.4
1526
176
0.1171
3.650


22
24.8
676
100
0.1506
3.591


23
25.4
702
139
0.2007
3.504


24
26.2
1737
401
0.2342
3.403


25
26.8
258
51
0.2007
3.331


26
27.2
182
24
0.1338
3.282


27
27.9
838
249
0.3011
3.193


28
29.1
152
20
0.1338
3.071









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 γd-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
4.3
1077
124
0.1171
20.633


 2
6.9
132
70
0.5353
12.787


 3
8.4
269
35
0.1338
10.482


 4
10.6
322
26
0.0836
 8.310


 5
11.9
733
97
0.1338
 7.414


 6
12.5
1406
278
0.2007
 7.069


 7
13.4
2975
442
0.1506
 6.619


 8
14.4
825
122
0.1506
 6.134


 9
15.8
1036
205
0.2007
 5.598


10
16.3
540
107
0.2007
 5.450


11
16.9
1007
183
0.184
 5.233


12
17.8
499
58
0.1171
 4.978


13
18.9
1062
140
0.1338
 4.686


14
19.8
570
85
0.1506
 4.485


15
20.2
549
63
0.1171
 4.399


16
20.9
2565
635
0.2509
 4.241


17
21.6
531
105
0.2007
 4.104


18
22.3
213
35
0.1673
 3.981


19
23.4
278
27
0.1004
 3.807


20
24.1
1404
185
0.1338
 3.694


21
24.4
1526
176
0.1171
 3.650


22
24.8
676
100
0.1506
 3.591


23
25.4
702
139
0.2007
 3.504


24
26.2
1737
401
0.2342
 3.403


25
26.8
258
51
0.2007
 3.331


26
27.2
182
24
0.1338
 3.282


27
27.9
838
249
0.3011
 3.193


28
29.1
152
20
0.1338
 3.071.

2. A process for the preparation of the γd-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 crystallization is complete, and the crystals thus obtained are collected by filtration and dehydrated.

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