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:
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&#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): 
     
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
               
                   
                 Angle 2 
                   
                 Area 
                   
                   
               
               
                   
                 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 EP0415 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&#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: 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 liters 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: 
     
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
               
                   
                 Angle 2 
                   
                 Area 
                   
                   
               
               
                   
                 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