Abstract:
Alpha crystalline form of strontium ranelate of formula (I):  
                         
characterised 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.

Description:
[0001]     The present invention relates to the alpha crystalline form of strontium ranelate.  
       BACKGROUND OF THE INVENTION  
       [0002]     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. 
 
         [0003]     Strontium ranelate and its hydrates also have properties making them useful in the treatment and prevention of arthrosis.  
       DESCRIPTION OF THE PRIOR ART  
       [0004]     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.  
         [0005]     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  
       [0006]     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.  
         [0007]     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&#39;Pert Pro diffractometer together with an X&#39;Celerator detector and expressed in terms of ray position (Bragg&#39;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                  
 
         [0008]     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.        
 
         [0012]     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.  
         [0013]     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.  
         [0014]     The Examples that follow illustrate the invention.  
         [0015]     The X-ray powder diffraction spectrum was measured under the following experimental conditions: 
        PANalytical X&#39;Pert Pro diffractometer, X&#39;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: ½°,     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  
       [0030]     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.  
         [0031]     The mixture is then cooled to 20° C.  
         [0032]     The solid obtained is collected by filtration.  
         [0033]     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.  
         [0000]     X-Ray Powder Diffraction Diagram:  
         [0034]     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  
       [0035]     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