# Patent

## Title
Alpha crystalline form of strontium ranelate

## Abstract

Alpha crystalline form of strontium ranelate of formula (I):




characterized by its powder X-ray diffraction diagram and by a water content of from 22 to 24%.

Medicinal products containing the same which are useful in the treatment of osteoporosis and arthrosis.

## Background
The present invention relates to the alpha crystalline form of strontium ranelate.
BACKGROUND OF THE INVENTION
Strontium ranelate, represented by formula (I):




or the distrontium salt of 5-[bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid, and its hydrates have very valuable pharmacological and therapeutic properties, especially pronounced anti-osteoporotic properties, making these compounds useful in the treatment and prevention of bone diseases.

Strontium ranelate and its hydrates also have properties making them useful in the treatment and prevention of arthrosis.
DESCRIPTION OF THE PRIOR ART
The preparation and therapeutic use of strontium ranelate and its tetrahydrate, heptahydrate and octahydrate have been described in the European Patent Specification EP 0 415 850.
The use of strontium ranelate in the prevention and treatment of arthrosis has been described in the European Patent Specification EP 0 813 869.


DETAILED DESCRIPTION OF THE INVENTION
The Applicant has now found that strontium ranelate can be obtained in a well-defined crystalline form which is perfectly reproducible and which, by virtue of that fact, has valuable characteristics in terms of filtration and ease of formulation.
More specifically, the present invention relates to the alpha crystalline form of strontium ranelate, characterised by a water content of from 22 to 24% and 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)


















Area





Angle 2 theta
Height
(counts ×
FWHM
Interplanar


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




















1
7.6
4527
448
0.1004
11.649


2
8.0
1438
142
0.1004
11.069


3
8.3
3522
349
0.1004
10.642


4
8.6
11347
1123
0.1004
10.272


5
8.9
7332
726
0.1004
9.889


6
11.0
1047
104
0.1004
8.072


7
11.3
1655
164
0.1004
7.840


8
12.0
2186
216
0.1004
7.355


9
13.2
2887
381
0.1338
6.703


10
13.5
1705
169
0.1004
6.557


11
14.1
154
30
0.2007
6.275


12
14.7
803
79
0.1004
6.035


13
14.9
1346
178
0.1338
5.942


14
15.8
1556
154
0.1004
5.613


15
16.0
3339
441
0.1338
5.527


16
16.7
1845
183
0.1004
5.308


17
17.3
2835
281
0.1004
5.127


18
17.6
1252
124
0.1004
5.049


19
18.0
2183
216
0.1004
4.939


20
19.2
2303
228
0.1004
4.622


21
19.8
1298
128
0.1004
4.475


22
20.3
788
78
0.1004
4.373


23
20.6
1039
103
0.1004
4.317


24
21.1
882
116
0.1338
4.211


25
21.7
390
38
0.1004
4.103


26
22.3
1919
253
0.1338
3.990


27
22.7
1805
179
0.1004
3.923


28
23.0
4043
467
0.1171
3.861


29
23.5
650
86
0.1338
3.792


30
24.0
8677
1002
0.1171
3.711


31
24.7
229
30
0.1338
3.600


32
25.1
1246
164
0.1338
3.543


33
25.6
1659
219
0.1338
3.473


34
25.9
1773
175
0.1004
3.442


35
26.3
695
69
0.1004
3.385


36
26.6
401
46
0.1171
3.355


37
27.0
2800
370
0.1338
3.300


38
27.6
1415
140
0.1004
3.230


39
28.0
3250
429
0.1338
3.186


40
28.4
1513
250
0.1673
3.144


41
29.1
1456
144
0.1004
3.068


42
29.6
1943
192
0.1004
3.022


43
30.1
3637
540
0.1506
2.967


44
30.5
707
117
0.1673
2.929


45
30.9
596
59
0.1004
2.897


46
31.8
577
76
0.1338
2.816


47
32.0
1080
107
0.1004
2.796


48
32.5
512
51
0.1004
2.756


49
32.9
1268
167
0.1338
2.726


50
33.4
1180
117
0.1004
2.685









The invention relates also to a process for the preparation of the alpha crystalline form of strontium ranelate, characterised in that a solution of strontium ranelate or a hydrate thereof in water is heated to reflux and then cooled until crystallisation is complete, and the product is collected by filtration.

    
    
        In the preparation process according to the invention it is possible to use strontium ranelate or a hydrate thereof obtained by any process, for example strontium ranelate octahydrate obtained by the preparation process described in the Patent Specification EP 0 415 850.
        An advantage of obtaining the said crystalline form is to allow especially rapid and efficient filtration and also the preparation of pharmaceutical formulations of consistent and reproducible composition, which is especially advantageous when the formulations are intended for oral administration.
        The form thereby obtained is sufficiently stable to allow its storage for an extended period without particular conditions in terms of temperature, light, humidity or oxygen levels.
    
    


The invention relates also to pharmaceutical compositions comprising as active ingredient the alpha crystalline form of strontium ranelate 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, granules, sublingual tablets, capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions and chewing gums.
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 0.2 to 10 g 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,
        voltage 45 kV, intensity 40 mA,
        mounting θ-θ,
        Kβ (Ni) filter,
        incident-beam and diffracted-beam Soller slit: 0.04 rad,
        divergence slits: automatic, irradiated length: 10 mm,
        mask: 10 mm,
        antiscatter slit: 1⁄2°,
        measurement mode: continuous from 3° to 34°, in increments of 0.017°,
        measurement time per step: 31.1 s,
        total time: 8 min 07 s,
        measurement speed: 0.068°/s,
        spinner: turning at 1 revolution/s,
        measurement temperature: ambient.
    
    


EXAMPLE 1
Alpha Crystalline Form of Strontium Ranelate
200 g of strontium ranelate octahydrate obtained according to the process described in Patent Specification EP 0 415 850 are mixed with 2 litres of water and heated to reflux.
The mixture is then cooled to 20° C.
The solid obtained is collected by filtration.
The water content of the product obtained, determined by loss on drying, is from 22 to 24%, which corresponds to from 8.1 to 9 molecules of water per molecule of strontium ranelate.
X-Ray Powder Diffraction Diagram:
The X-ray powder diffraction profile (diffraction angles) of the alpha form of strontium ranelate is given by the significant rays collated in the following table:


















Area





Angle 2 theta
Height
(counts ×
FWHM
Interplanar


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




















1
7.6
4527
448
0.1004
11.649


2
8.0
1438
142
0.1004
11.069


3
8.3
3522
349
0.1004
10.642


4
8.6
11347
1123
0.1004
10.272


5
8.9
7332
726
0.1004
9.889


6
11.0
1047
104
0.1004
8.072


7
11.3
1655
164
0.1004
7.840


8
12.0
2186
216
0.1004
7.355


9
13.2
2887
381
0.1338
6.703


10
13.5
1705
169
0.1004
6.557


11
14.1
154
30
0.2007
6.275


12
14.7
803
79
0.1004
6.035


13
14.9
1346
178
0.1338
5.942


14
15.8
1556
154
0.1004
5.613


15
16.0
3339
441
0.1338
5.527


16
16.7
1845
183
0.1004
5.308


17
17.3
2835
281
0.1004
5.127


18
17.6
1252
124
0.1004
5.049


19
18.0
2183
216
0.1004
4.939


20
19.2
2303
228
0.1004
4.622


21
19.8
1298
128
0.1004
4.475


22
20.3
788
78
0.1004
4.373


23
20.6
1039
103
0.1004
4.317


24
21.1
882
116
0.1338
4.211


25
21.7
390
38
0.1004
4.103


26
22.3
1919
253
0.1338
3.990


27
22.7
1805
179
0.1004
3.923


28
23.0
4043
467
0.1171
3.861


29
23.5
650
86
0.1338
3.792


30
24.0
8677
1002
0.1171
3.711


31
24.7
229
30
0.1338
3.600


32
25.1
1246
164
0.1338
3.543


33
25.6
1659
219
0.1338
3.473


34
25.9
1773
175
0.1004
3.442


35
26.3
695
69
0.1004
3.385


36
26.6
401
46
0.1171
3.355


37
27.0
2800
370
0.1338
3.300


38
27.6
1415
140
0.1004
3.230


39
28.0
3250
429
0.1338
3.186


40
28.4
1513
250
0.1673
3.144


41
29.1
1456
144
0.1004
3.068


42
29.6
1943
192
0.1004
3.022


43
30.1
3637
540
0.1506
2.967


44
30.5
707
117
0.1673
2.929


45
30.9
596
59
0.1004
2.897


46
31.8
577
76
0.1338
2.816


47
32.0
1080
107
0.1004
2.796


48
32.5
512
51
0.1004
2.756


49
32.9
1268
167
0.1338
2.726


50
33.4
1180
117
0.1004
2.685









EXAMPLE 2
Pharmaceutical Composition
Formula for the preparation of 1000 tablets each containing 0.5 g of active ingredient:

















Compound of Example 1
658
g



Sodium carboxymethyl starch
25.5
g



Microcrystalline cellulose
119.4
g



Povidone
38
g



Anhydrous colloidal silica
1.5
g



Magnesium stearate
7.6
g

## Claims

1. The alpha crystalline form of the compound of formula (I):




wherein the compound has a water content of from 22 to 24% and exhibits essentially the following powder X-ray diffraction diagram 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):


















Surface





Angle 2 theta
Height
(counts ×
FWHM
Interplanar


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




















1
7.6
4527
448
0.1004
11.649


2
8.0
1438
142
0.1004
11.069


3
8.3
3522
349
0.1004
10.642


4
8.6
11347
1123
0.1004
10.272


5
8.9
7332
726
0.1004
9.889


6
11.0
1047
104
0.1004
8.072


7
11.3
1655
164
0.1004
7.840


8
12.0
2186
216
0.1004
7.355


9
13.2
2887
381
0.1338
6.703


10
13.5
1705
169
0.1004
6.557


11
14.1
154
30
0.2007
6.275


12
14.7
803
79
0.1004
6.035


13
14.9
1346
178
0.1338
5.942


14
15.8
1556
154
0.1004
5.613


15
16.0
3339
441
0.1338
5.527


16
16.7
1845
183
0.1004
5.308


17
17.3
2835
281
0.1004
5.127


18
17.6
1252
124
0.1004
5.049


19
18.0
2183
216
0.1004
4.939


20
19.2
2303
228
0.1004
4.622


21
19.8
1298
128
0.1004
4.475


22
20.3
788
78
0.1004
4.373


23
20.6
1039
103
0.1004
4.317


24
21.1
882
116
0.1338
4.211


25
21.7
390
38
0.1004
4.103


26
22.3
1919
253
0.1338
3.990


27
22.7
1805
179
0.1004
3.923


28
23.0
4043
467
0.1171
3.861


29
23.5
650
86
0.1338
3.792


30
24.0
8677
1002
0.1171
3.711


31
24.7
229
30
0.1338
3.600


32
25.1
1246
164
0.1338
3.543


33
25.6
1659
219
0.1338
3.473


34
25.9
1773
175
0.1004
3.442


35
26.3
695
69
0.1004
3.385


36
26.6
401
46
0.1171
3.355


37
27.0
2800
370
0.1338
3.300


38
27.6
1415
140
0.1004
3.230


39
28.0
3250
429
0.1338
3.186


40
28.4
1513
250
0.1673
3.144


41
29.1
1456
144
0.1004
3.068


42
29.6
1943
192
0.1004
3.022


43
30.1
3637
540
0.1506
2.967


44
30.5
707
117
0.1673
2.929


45
30.9
596
59
0.1004
2.897


46
31.8
577
76
0.1338
2.816


47
32.0
1080
107
0.1004
2.796


48
32.5
512
51
0.1004
2.756


49
32.9
1268
167
0.1338
2.726


50
33.4
1180
117
0.1004
2.685.

2. A process for the preparation of the alpha crystalline form of the compound of claim 1, wherein a solution of strontium ranelate or a hydrate thereof in water is heated at reflux and then cooled until crystallisation is complete, and the product is collected by filtration.

3. A pharmaceutical composition comprising as active ingredient an effective amount of the compound of claim 1 in combination with one or more pharmaceutically acceptable, inert and non-toxic carriers.

4. A method of treating a living animal body, including a human, afflicted with osteoporosis, comprising the step of administering to the living animal body, including a human, an amount of a compound of claim 1 which is effective for alleviation of osteoporosis.

5. A method of treating a living animal body, including a human, afflicted with arthrosis, comprising the step of administering to the living animal body, including a human, an amount of a compound of claim 1 which is effective for alleviation of arthrosis.