Crystallisation of a GLP-1 analogue

Abstract

Crystals of glucagon-like peptide-1 (GLP-1) and GLP-1 analogues, and processes for preparation of crystals of GLP-1 and GLP-1 analogues.

1 . A process for producing crystals of a GLP-1 analogue comprising: 
 a) preparing an aqueous solution comprising a GLP-1 analogue, a salt, and an organic solvent, and    b) isolation of the crystals after formation.    
     
     
         2 . The process according to  claim 1  wherein in step a) adjusting pH to pl−4<pH<pl, or to pl<pH<pl+4, wherein pl is the isoelectric point of the GLP-1 analogue.  
     
     
         3 . The process according to  claim 1  wherein the crystals are needle shaped crystals of a GLP-1 analogue.  
     
     
         4 . The process according to  claim 1  wherein the crystals has a length of at least 0.5 μm.  
     
     
         5 . The process according to  claim 1  wherein the GLP-1 analogue in the aqueous solution has a purity of less than 95%, as measured by HPLC.  
     
     
         6 . The process according to  claim 1  wherein the GLP-1 analogue in the aqueous solution is present in a concentration of at least 0.5 mg/ml.  
     
     
         7 . The process according to  claim 1  wherein the GLP-1 analogue is selected from non-synthetic GLP-1 analogues.  
     
     
         8 . The process according to  claim 1  wherein the GLP-1 analogue is Arg 34 GLP-1 (7-37) or Arg 26 GLP-1 (7-37).  
     
     
         9 . The process according to  claim 1  wherein the salt is present in a concentration of at least 25 mM.  
     
     
         10 . The process according to  claim 1  wherein the organic solvent is present in a concentration of from 0.5 to 50% (vol/vol).  
     
     
         11 . The process according to  claim 1  wherein the organic solvent is selected from C 1-6 alkanol, C 16 -alkenol, C 1-6 alkynol, urea, guanidine, C 1-6 alkanoic acid, ketone, DMSO, C 2-4 -glycol, C 3-7 -polyalcohol including sugars, or mixtures thereof.  
     
     
         12 . A method for producing a GLP-1 analogue or a GLP-1 analogue whereto is attached a lipophilic substituent comprising the steps: 
 a) preparing an aqueous solution comprising a GLP-1 analogue, a salt, and an organic solvent, and    b) isolation of the crystals after formation.    
     
     
         13 . Crystals of a GLP-1 analogue optainable by the method according to  claim 12 .  
     
     
         14 . Needle shaped crystals of a GLP-1 analogue.  
     
     
         15 . A pharmaceutical composition comprising needle shaped crystals of a GLP-1 analogue and a pharmaceutically acceptable carrier.