Crystalline form of linaclotide

Abstract

The present invention relates to crystalline forms of linaclotide, as well as to various methods and processes for the preparation and use of the crystalline forms.

1 . An α-crystalline form of linaclotide. 
     
     
         2 . The crystalline form of  claim 1 , having an X-ray powder diffraction pattern comprising peaks at about 7.8 and about 23.9+/−0.5 degrees 2θ. 
     
     
         3 . The crystalline form of  claim 1 , having an X-ray powder diffraction pattern having peaks at about 6.2, about 7.8 and about 23.9+/−0.5 degrees 2θ. 
     
     
         4 . The crystalline form of  claim 1 , having an X-ray powder diffraction pattern having peaks at about 6.2, about 7.8, about 19.5, about 22.6, and about 23.9+/−0.5 degrees 2θ. 
     
     
         5 . The crystalline form of  claim 1 , having an X-ray powder diffraction pattern substantially as shown in  FIG. 2 . 
     
     
         6 . A crystalline form of linaclotide, having an X-ray powder diffraction pattern comprising peaks at about 5.7, about 7.7 and about 23.8+/−0.5 degrees 2θ. 
     
     
         7 . The crystalline form of  claim 6 , wherein the X-ray powder diffraction pattern further comprises a peak at about 19.4+/−0.5 degrees 2θ and/or a peak at about 22.5+/−0.5 degrees 2θ. 
     
     
         8 . The crystalline form of  claim 6 , wherein the X-ray powder diffraction pattern further comprises peaks at about 19.4 and at about 22.5+/−0.5 degrees 2θ. 
     
     
         9 . The crystalline form of  claim 6 , having an X-ray powder diffraction pattern further comprising d spacing peaks at about 3.7, about 11.5 and about 15.5+/—0.5 angstroms. 
     
     
         10 . A pharmaceutical composition comprising the crystalline form of  claim 1 . 
     
     
         11 . A pharmaceutical composition comprising the crystalline form of  claim 6 . 
     
     
         12 . A process for preparing an α-crystalline form of linaclotide, comprising crystallizing linaclotide to form an α-crystalline form of linaclotide and optionally isolating the α-crystalline form of linaclotide. 
     
     
         13 . A method of treating a gastrointestinal disorder comprising administering to a patient in need thereof, the crystalline form of  claim 1 . 
     
     
         14 . The method of  claim 13 , wherein the gastrointestinal disorder is constipation-predominant irritable bowel syndrome. 
     
     
         15 . The method of  claim 13 , wherein the gastrointestinal disorder is chronic constipation. 
     
     
         16 . A method of treating a gastrointestinal disorder comprising administering to a patient in need thereof, the crystalline form of  claim 6 . 
     
     
         17 . The method of  claim 16 , wherein the gastrointestinal disorder is constipation-predominant irritable bowel syndrome. 
     
     
         18 . The method of  claim 16 , wherein the gastrointestinal disorder is chronic constipation.