Solid and crystalline ibandronic acid

Abstract

Provided are novel crystalline forms of ibandronic acid, physical data, methods for their preparation, and uses therefor. Also provided are methods for purifying and assaying ibandronic acid in any crystalline form.

1 . A crystalline form of ibandronic acid selected from the group consisting of:
 a) the crystalline form of ibandronic acid characterized by x-ray reflections at about 8.2, 11.5, 11.9, 13.9, 18.6, and 22.2°±0.2°2θ;   b) the crystalline form of ibandronic acid characterized by x-ray reflections at about 8.1, 14.2, 16.1, 18.2, and 24.4°±0.2°2θ;   c) the crystalline form of ibandronic acid characterized by x-ray reflections at about 4.4, 8.8, 11.3, 17.6, and 26.4°±0.2°2θ;   d) the crystalline form of ibandronic acid characterized by x-ray reflections at about 4.4, 8.6, 11.2, 17.3, 20.8, 22.5 and 26.0°±0.2°2θ;   e) the crystalline form of ibandronic acid characterized by x-ray reflections at about 4.5, 8.9, 12.0, 16.0, 16.3, 21.4, 22.1 and 26.9°±0.2°2θ;   f) the crystalline form of ibandronic acid characterized by x-ray reflections at about 5.7, 11.7, 14.3, 18.5, 21.2 and 21.7°±2θ;   g) the crystalline form of ibandronic acid characterized by x-ray reflections at about 4.6, 11.5, 16.3, 16.8, 21.0 and 22.8°±0.2°2θ;   h) the crystalline form of ibandronic acid characterized by x-ray reflections at about 4.5, 6.0, 11.9, 12.3, 16.2, 17.8 and 21.7±0.2°2θ;   i) the crystalline form of ibandronic acid characterized by x-ray reflections at about 4.8, 6.1, 12.0, 12.3, 16.4, 18.0 and 21.7°±0.2°2θ;   j) the crystalline form of ibandronic acid characterized by x-ray reflections at about 4.7, 9.0, 11.6, 20.9, 21.1, 21.7, 22.9 and 26.3°±0.2°2θ; and   k) the crystalline form of ibandronic acid characterized by x-ray reflections at about 4.5, 8.9, 12.0, 16.0, 16.3, 21.3°±0.2°2θ.   
     
     
         2 . The crystalline form of ibandronic acid of  claim 15  characterized by x-ray reflections at about 8.2, 11.5, 11.9, 13.9, 18.6, and 22.2°±0.2°2θ, denominated form S1, and further characterized by x-ray reflections at about 21.6, 23.8, 24.7 and 28.1°±0.2°2θ. 
     
     
         3 . The crystalline form of ibandronic acid of  claim 16  having a powder x-ray diffraction diagram substantially as shown in  FIG. 4 . 
     
     
         4 . The crystalline form of ibandronic acid of  claim 17 , wherein the crystalline form is hemihydrate. 
     
     
         5 . The crystalline form of ibandronic acid of  claim 15  characterized by x-ray reflections at about 8.1, 14.2, 16.1, 18.2, and 24.4°±0.2°2θ, denominated form S2, and further characterized by x-ray reflections at about 10.9, 19.2, 22.3, 23.3, and 28.2°±0.2°2θ. 
     
     
         6 . The crystalline form of ibandronic acid of  claim 19  having a powder x-ray diffraction diagram substantially as shown in  FIG. 5 . 
     
     
         7 . The crystalline form of ibandronic acid of  claim 15  characterized by x-ray reflections at about 4.4, 8.8, 11.3, 17.6, and 26.4°±0.2°2θ, denominated form S3, and further characterized by x-ray reflections at about 21.6, 23.8, 24.7 and 28.1°±0.2°2θ. 
     
     
         8 . The crystalline form of ibandronic acid of  claim 21  having a powder x-ray diffraction diagram substantially as shown in  FIG. 6 . 
     
     
         9 . The crystalline form of ibandronic acid of  claim 22 , wherein the crystalline form is a tert-butanolate. 
     
     
         10 . The crystalline form of ibandronic acid of  claim 15  characterized by x-ray reflections at about 4.4, 8.6, 11.2, 17.3, 20.8, 22.5 and 26.0°±0.2°2θ, denominated form S4, and further characterized by x-ray reflections at about 16.2, 20.5 and 21.3°±0.2°2θ. 
     
     
         11 . The crystalline form of ibandronic acid of  claim 24  having a powder x-ray diffraction diagram substantially as shown in  FIG. 7 . 
     
     
         12 . The crystalline form of ibandronic acid of  claim 25 , wherein the crystalline form is a propanolate. 
     
     
         13 . The crystalline form of ibandronic acid of  claim 15  characterized by x-ray reflections at about 4.5, 8.9, 12.0, 16.0, 16.3, 21.4, 22.1 and 26.9°±0.2°2θ, denominated form S5, and further characterized by x-ray reflections at about 5.9, 10.5 and 17.8°±0.2°2θ. 
     
     
         14 . The crystalline form of ibandronic acid of  claim 27  having an x-ray diffraction diagram substantially as shown in  FIG. 8 . 
     
     
         15 . The crystalline form of ibandronic acid of  claim 28 , wherein the crystalline form is a hemihydrate or an iso-propanolate. 
     
     
         16 . The crystalline form of ibandronic acid of  claim 15  characterized by x-ray reflections at about 5.7, 11.7, 14.3, 18.5, 21.2 and 21.7°, denominated form S6, and further characterized by x-ray reflections at about 14.8, 22.7, 22.8 and 30.60°±0.2°2θ. 
     
     
         17 . The crystalline form of ibandronic acid of  claim 30  having a powder x-ray diffraction diagram substantially as shown in  FIG. 9 . 
     
     
         18 . The crystalline form of ibandronic acid of  claim 31 , wherein the crystalline form is a hemihydrate or a tert-butanolate. 
     
     
         19 . The crystalline form of ibandronic acid of  claim 15  characterized by x-ray reflections at about 4.6, 11.5, 16.3, 16.8, 21.0 and 22.8°±0.2°2θ, denominated form S7, and further characterized by x-ray reflections at about 9.0, 17.7, 19.8 and 21.8°±0.2°2θ. 
     
     
         20 . The crystalline form of ibandronic acid of  claim 33  having a powder x-ray diffraction diagram substantially as shown in  FIG. 10 . 
     
     
         21 . The crystalline form of ibandronic acid of claim  34 , wherein the crystalline form is a hemihydrate, a 1-propanolate, or an iso-propanolate. 
     
     
         22 . The crystalline form of ibandronic acid of  claim 15  characterized by x-ray reflections at about 4.5, 6.0, 11.9, 12.3, 16.2, 17.8 and 21.7±0.2°2θ, denominated form S8, and further characterized by x-ray reflections at about 9.0, 16.5 and 18.9°±0.2°2θ. 
     
     
         23 . The crystalline form of ibandronic acid of claim  36  having a powder x-ray diffraction diagram substantially as shown in  FIG. 11 . 
     
     
         24 . The crystalline form of ibandronic acid of claim  37 , wherein the crystalline form is an ethanolate or an iso-propanolate. 
     
     
         25 . The crystalline form of ibandronic acid of  claim 15  characterized by x-ray reflections at about 4.8, 6.1, 12.0, 12.3, 16.4, 18.0 and 21.7°±0.2°2θ, denominated form S10, and further characterized by x-ray reflections at 18.9, 20.9 and 22.8°±0.2°2θ. 
     
     
         26 . The crystalline form of ibandronic acid of claim  39  having a powder x-ray diffraction diagram substantially as shown in  FIG. 12 . 
     
     
         27 . The crystalline form of ibandronic acid of claim  41 , wherein the crystalline form is an ethanolate. 
     
     
         28 . The crystalline form of ibandronic acid of  claim 15  characterized by x-ray reflections at about 4.7, 9.0, 11.6, 20.9, 21.1, 21.7, 22.9 and 26.3°±0.2°2θ, denominated form S12, and further characterized by x-ray reflections at about 13.8, 17.1 and 18.4°±0.2°2θ. 
     
     
         29 . The crystalline form of ibandronic acid of claim  42  having a powder x-ray diffraction diagram substantially as shown in  FIG. 13 . 
     
     
         30 . The crystalline form of ibandronic acid of claim  43 , wherein the crystalline form is a hemihydrate or an iso-propanolate. 
     
     
         31 . The crystalline form of ibandronic acid of  claim 15  characterized by x-ray reflections at about 4.5, 8.9, 12.0, 16.0, 16.3, 21.3°±0.2°2θ, denominated from S13, and further characterized by x-ray reflections at about 10.5, 17.8 and 26.9°±0.2°2θ. 
     
     
         32 . The crystalline form of ibandronic acid of claim  45  having a powder x-ray diffraction diagram substantially as shown in  FIG. 14 . 
     
     
         33 . The crystalline form of ibandronic acid of claim  46 , wherein the crystalline form is an iso-propanolate.