# Patent

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

## Abstract

A δ-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 δ-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 well defined crystalline form that exhibits valuable characteristics for stability and processability.
More specifically, the present invention relates to the δ-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 Å):
















Angle 2

Area




Line
theta
Height
(counts ×
FWHM
Interplanar


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




















1
4.1
1115
110
0.1004
21.753


2
6.8
183
145
0.8029
12.907


3
8.4
755
75
0.1004
10.531


4
10.9
1104
128
0.1171
8.087


5
12.2
195
19
0.1004
7.268


6
14.3
569
75
0.1338
6.214


7
14.7
1847
274
0.1506
6.013


8
15.3
1734
315
0.184
5.802


9
16.3
1164
154
0.1338
5.442


10
16.8
3420
734
0.2175
5.269


11
17.5
790
78
0.1004
5.069


12
17.9
3389
503
0.1506
4.960


13
19.2
2467
407
0.1673
4.635


14
19.8
145
29
0.2007
4.477


15
20.4
313
52
0.1673
4.362


16
21.2
928
169
0.184
4.198


17
21.7
2093
414
0.2007
4.099


18
22.2
3850
635
0.1673
4.007


19
22.5
576
76
0.1338
3.948


20
23.1
1588
236
0.1506
3.855


21
24.8
1665
247
0.1506
3.594


22
25.2
1212
120
0.1004
3.534


23
25.6
1507
249
0.1673
3.477


24
26.7
2042
303
0.1506
3.342


25
27.6
2281
414
0.184
3.229


26
28.4
485
96
0.2007
3.138


27
29.6
599
99
0.1673
3.014









The invention relates also to a process for the preparation of the δ-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 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 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 invention relates also to pharmaceutical compositions comprising as active ingredient the δ-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 dragées, 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 θ-θ,
        nickel (Kβ) filter,
        incident-beam and diffracted-beam Soller slit: 0.04 rad,
        automatic divergence slits : irradiated length of 10 mm,
        mask: 10 mm,
        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,
        measurement temperature: ambient.
    
    


EXAMPLE 1
δ-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 vacuo and are spread out onto a crystallisation plate.
The water content of the product obtained, determined by coulometry, is 2.8%.
Powder X-ray diffraction diagram:
The powder X-ray diffraction profile (diffraction angles) of the δ-form of ivabradine hydrochloride is given by the significant lines collated in the following table:
















Angle 2

Area




Line
theta
Height
(counts ×
FWHM
Interplanar


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




















1
4.1
1115
110
0.1004
21.753


2
6.8
183
145
0.8029
12.907


3
8.4
755
75
0.1004
10.531


4
10.9
1104
128
0.1171
8.087


5
12.2
195
19
0.1004
7.268


6
14.3
569
75
0.1338
6.214


7
14.7
1847
274
0.1506
6.013


8
15.3
1734
315
0.184
5.802


9
16.3
1164
154
0.1338
5.442


10
16.8
3420
734
0.2175
5.269


11
17.5
790
78
0.1004
5.069


12
17.9
3389
503
0.1506
4.960


13
19.2
2467
407
0.1673
4.635


14
19.8
145
29
0.2007
4.477


15
20.4
313
52
0.1673
4.362


16
21.2
928
169
0.184
4.198


17
21.7
2093
414
0.2007
4.099


18
22.2
3850
635
0.1673
4.007


19
22.5
576
76
0.1338
3.948


20
23.1
1588
236
0.1506
3.855


21
24.8
1665
247
0.1506
3.594


22
25.2
1212
120
0.1004
3.534


23
25.6
1507
249
0.1673
3.477


24
26.7
2042
303
0.1506
3.342


25
27.6
2281
414
0.184
3.229


26
28.4
485
96
0.2007
3.138


27
29.6
599
99
0.1673
3.014









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 δ-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 line position (Bragg's angle 2 theta, expressed in degrees), line height (expressed in counts), line area (expressed in counts × degrees), line width at half-height (“FWHM”, expressed in degrees) and interplanar distance d (expressed in Å):
















Angle 2

Area




Line
theta
Height
(counts ×
FWHM
Interplanar


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




















1
4.1
1115
110
0.1004
21.753


2
6.8
183
145
0.8029
12.907


3
8.4
755
75
0.1004
10.531


4
10.9
1104
128
0.1171
8.087


5
12.2
195
19
0.1004
7.268


6
14.3
569
75
0.1338
6.214


7
14.7
1847
274
0.1506
6.013


8
15.3
1734
315
0.184
5.802


9
16.3
1164
154
0.1338
5.442


10
16.8
3420
734
0.2175
5.269


11
17.5
790
78
0.1004
5.069


12
17.9
3389
503
0.1506
4.960


13
19.2
2467
407
0.1673
4.635


14
19.8
145
29
0.2007
4.477


15
20.4
313
52
0.1673
4.362


16
21.2
928
169
0.184
4.198


17
21.7
2093
414
0.2007
4.099


18
22.2
3850
635
0.1673
4.007


19
22.5
576
76
0.1338
3.948


20
23.1
1588
236
0.1506
3.855


21
24.8
1665
247
0.1506
3.594


22
25.2
1212
120
0.1004
3.534


23
25.6
1507
249
0.1673
3.477


24
26.7
2042
303
0.1506
3.342


25
27.6
2281
414
0.184
3.229


26
28.4
485
96
0.2007
3.138


27
29.6
599
99
0.1673
 3.014.

2. A process for the preparation of the δ-crystalline form of ivabradine hydrochloride of claim 1, 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 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 δ-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 the step of administering to a living animal body, including a human, a therapeutically effective amount of δ-crystalline form of ivabradine hydrochloride of claim 1.