New stable salt of 5,10-methylene-(6r)-tetrahydrofolic acid

Abstract

The present invention is directed towards the hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid, preferably in substantially crystalline form, as well as pharmaceutical compositions and uses thereof in therapy, preferably chemotherapy.

1 . Hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid. 
     
     
         2 . Hemisulfate salt according to  claim 1  in substantially crystalline form. 
     
     
         3 . Hemisulfate salt according to  claim 1  having at least 80%, preferably 90%, preferably 95%, more preferably 97%, most preferably 99% or more crystalline purity. 
     
     
         4 . Hemisulfate salt according to  claim 1  having at least 80%, preferably 90%, preferably 95%, more preferably 97%, most preferably 99% or more chemical purity. 
     
     
         5 . Hemisulfate salt according to  claim 1  in anhydrous form. 
     
     
         6 . Hemisulfate salt according to  claim 1  having one or more X-ray pattern peak positions at an angle of diffraction 2 theta of 4.7°, 17.9°, and 23.3° expressed in 2θ±0.2° 2θ (CuKα radiation, reflection). 
     
     
         7 . Hemisulfate salt according to  claim 1  having one or more X-ray pattern peak positions at an angle of diffraction 2theta of 4.7°, 16.6°, 17.9°, 18.4°, 18.9°, 20.2°, 23.3°, 23.5°, 24.3° and 24.7° expressed in 2θ±0.2° 2θ (CuKα radiation, reflection). 
     
     
         8 . Hemisulfate salt according  claim 1  having a FT-Raman spectrum containing one or more peaks at wavenumbers (expressed in ±2 cm −1 ) of 1672, 1656, 1603, 1553, 1474, 1301, 637, 624 and 363. 
     
     
         9 . Hemisulfate salt according to  claim 1  having a FT-Raman spectrum substantially in accordance with  FIG. 1  and/or having an X-ray powder diffraction (XRPD) pattern substantially in accordance with  FIG. 2( a )  or  2 ( b ). 
     
     
         10 . Hemisulfate salt according to  claim 1  having at least 2 of the following 10 XRPD peaks (expressed in 2θ±0.2° 2θ (CuKα radiation)) at 4.7°, 16.6°, 17.9°, 18.4°, 18.9°, 20.2°, 23.3°, 23.5°, 24.3° and 24.7° and at least 2 of the following 9 FT-Raman peaks (expressed in ±2 cm −1 ) of 1672, 1656, 1603, 1553, 1474, 1301, 637, 624 and 363. 
     
     
         11 . Hemisulfate salt according to  claim 1  having at least 2 of the following 3 XRPD peaks (expressed in 2θ±0.2° 2θ (CuKα radiation)) at 4.7°, 17.9°, and 23.3° and at least 2 of the following 5 FT-Raman peaks (expressed in ±2 cm −1 ) of 1672, 1656, 1603, 1553, 1474, 1301, 637, 624 and 363. 
     
     
         12 . A pharmaceutical composition comprising a hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid according to  claim 1  and optionally a pharmaceutically acceptable carrier. 
     
     
         13 . The pharmaceutical composition according to  claim 12  in the form of tablets, capsules, oral liquid preparations, powders, lyophilisates, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories, preferably lyophilisates 
     
     
         14 . The pharmaceutical composition according to  claim 12  further comprising at least one additional therapeutic agent. 
     
     
         15 . The pharmaceutical composition according to  claim 12 , which is a pharmaceutical composition for oral, parenteral or rectal administration. 
     
     
         16 . Hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid according to  claim 1  or a pharmaceutical composition for use in therapy, preferably cancer chemotherapy. 
     
     
         17 . A method for treatment of cancer comprising administering a hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid according to  claim 1  to a subject in need of such treatment.