Process for modifying drug crystal formation

Abstract

A process for modifying the crystal habit of acicular drug substances, crystals obtained by such a process, and particular crystal forms or modifications of mycophenolic acid or mycophenolate sodium are provided, as well as pharmaceutical compositions comprising the crystals, methods of treatment and uses thereof.

1 . A process for modifying the crystal habit of an acicular drug substance comprising suspending said crystalline drug substance in a solvent system having an effect on the crystal habit and subjecting said suspension to a temperature oscillation.  
     
     
         2 . A process for recrystallising an acicular drug substance comprising suspending said crystals in a solvent system having an effect on the crystal habit and subjecting said suspension to a temperature oscillation.  
     
     
         3 . A process according to  claim 1  wherein the crystal habit is modified in that the mean aspect ratio of the processed crystals is smaller than about 10:1.  
     
     
         4 . A process according to  claim 1  wherein the drug substance after temperature oscillation has a bulk density of about above 200 kg/m 3.    
     
     
         5 . A process according to  claim 1  wherein the temperature oscillation is in form of a zig-zag curve.  
     
     
         6 . A process according to any one of  claim 1  wherein the crystals produced have a mean aspect ratio of the processed crystals smaller than about 10:1 or a bulk density of about 200 kg/m 3 .  
     
     
         7 . Crystals of an acicular drug substance with an aspect ratio of about 10:1 to 1:1 and/or a bulk density of above about 200 kg/m 3.    
     
     
         8 . Crystals according to  claim 7  wherein the acicular drug substance is mycophenolic acid, or a mycophenolate salt.  
     
     
         9 . A pharmaceutical composition in the form of tablets, comprising crystals of  claim 7  in association with a pharmaceutically acceptable carrier.  
     
     
         10 . Crystals of  claim 8  for use as a pharmaceutical.  
     
     
         11 . A crystal modification of mycophenolic acid or mycophenolate sodium having one of the following characteristic crystal structures, determined by means of an X-ray single crystal analysis, or having an X-ray powder diffraction pattern as defined below: 
 a) mycophenolate sodium anhydrate, modification A;                                                crystal system:   monoclinic         space group:   P2 1 /c         a:   16.544(4)         b:   4.477(1)         c:   21.993(3)         β:   92.14(1)°         V:   1627.8(6)         Z:   4         cal. Density:   1.397 g/cm                                                     b) mycophenolate sodium hydrate; 
 having an X-ray powder diffraction pattern with characteristic signals substantially the same as those shown in  FIG. 2 ;  
   c) hemisalt of mycophenolate sodium anhydrate;                                                crystal system:   triclinic         space group:   P-1         a:   11.172(6)         b:   12.020(6)         c:   13.441(2)         α:   73.09(7)°         β:   71.79(6)°         Y:   84.63(6)°         V:   1641(2)         Z:   2                                                      d) mycophenolate sodium methanol solvate;                                                crystal system:   triclinic         space group:   P-1         a:   7.761         b:   9.588         c:   14.094         α:   109.96°         β:   95.99°         Y:   83.05°         V:   976.3         Z:   2                                                      e) mycophenolate sodium methanol solvate II;                                                crystal system:   triclinic         space group:   P-1         a:   9.179         b:   10.724         c:   12.098         α:   113.27°         β:   101.76°         Y:   104.44°         V:   996.4         Z:   2                                                      f) mycophenolate disodium salt, monohydrate; 
 having an X-ray powder diffraction pattern with characteristic signals substantially the same as those shown in  FIG. 6 ;  
   g) mycophenolate disodium salt, pentahydrate;                                                crystal system:   monocimic         space group:   P 2 1 /c,         a:   14.495         b:   17.613         c:   8.401         β:   97.15°         V:   2128         Z:   4                                                    h) mycophenolic acid;                                                crystal system:   triclinic         space group:   P-1         a:   7.342         b:   9.552         c:   11.643         α:   102.70°         β:   90.89°         Y:   90.74°         V:   796.3         Z:   2                                                      i) mycophenolate sodium hydrate form B; 
 having an X-ray powder diffraction pattern with characteristic signals substantially the same as those shown in  FIG. 10 ;  
   j) mycophenolate sodium hydrate form C; 
 having an X-ray powder diffraction pattern with characteristic signals substantially the same as those shown in  FIG. 12 ;  
   
     
     
         12 . A process according to  claim 2  wherein the crystal habit is modified in that the mean aspect ratio of the processed crystals is smaller than about 10:1.  
     
     
         13 . A process according to  claim 2  wherein the drug substance after temperature oscillation has a bulk density of about above 200 kg/m 3 .  
     
     
         14 . A process according to  claim 2  wherein the temperature oscillation is in form of a zig-zag curve.  
     
     
         15 . A process according to  claim 2  wherein the crystals produced have a mean aspect ratio of the processed crystals smaller than about 10:1 or a bulk density of about 200 kg/m 3 .  
     
     
         16 . A pharmaceutical composition in the form of tablets, comprising crystals of  claim 2  in association with a pharmaceutically acceptable carrier.