Crystalline form of triethylenetetramine tetrahydrochloride and its pharmaceutical use

Abstract

The present invention describes a new crystalline form of triethylenetetramine tetrachloride which has improved room temperature stability over known forms and over the dichloride salt. The new crystalline form is characterised by having peaks in an XRPD spectrum at 22.9, 25.4, 25.8, 26.6, 34.6 and 35.3±0.1° 2θ and Raman shifts 943, 1173, 1527 and 1612±5 cm −1 . The crystalline form of triethylenetetramine tetrachloride is useful in the treatment of Wilson's disease.

1 . A crystalline form of triethylenetetramine tetrahydrochloride Form B having at least one of the following characteristics:
 (i) an XRPD pattern having at least two peaks selected from the peaks at 22.9, 25.4, 25.8, 26.6, 34.6 and 35.3±0.1° 2θ; and   (ii) a Raman spectrum having at least two peaks selected from the peaks at a Raman shift of 943, 1173, 1527 and 1612±5 cm −1 ,   and which contains no more than 10 wt % of triethylenetetramine tetrahydrochloride Form A having an XRPD pattern having peaks at 25.2 and 35.7±0.1° 2θ, wherein XRPD pattern peaks are as measured using a wavelength of 1.5418 Å,   
       and wherein the crystalline form is obtainable by a method comprising:
 adding an anti-solvent to an aqueous solution of triethylenetetramine tetrahydrochloride and collecting the crystals obtained, wherein the anti-solvent addition is carried out at a temperature of about 15° C. or below. 
 
     
     
         2 . A crystalline form of triethylenetetramine tetrahydrochloride which consists essentially of triethylenetetramine tetrahydrochloride Form B having at least one of the following characteristics:
 (i) an XRPD pattern having at least two peaks selected from the peaks at 22.9, 25.4, 25.8, 26.6, 34.6 and 35.3±0.1° 2θ; and   (ii) a Raman spectrum having at least two peaks selected from the peaks at a Raman shift of 943, 1173, 1527 and 1612±5 cm −1      wherein XRPD pattern peaks are as measured using a wavelength of 1.5418 Å.   
     
     
         3 . A crystalline form of triethylenetetramine tetrahydrochloride Form B having at least one of the following characteristics:
 (i) an XRPD pattern having at least two peaks selected from the peaks at 22.9, 25.4, 25.8, 26.6, 34.6 and 35.3±0.1° 2θ; and   (ii) a Raman spectrum having at least two peaks selected from the peaks at a Raman shift of 943, 1173, 1527 and 1612±5 cm −1      wherein XRPD pattern peaks are as measured using a wavelength of 1.5418 Å,   and wherein the crystalline form is substantially free of triethylenetetramine tetrahydrochloride Form A having an XRPD pattern having peaks at 25.2 and 35.7±0.1° 2θ.   
     
     
         4 . A method of reducing copper levels in a subject, which method comprises the administration to said subject of an effective amount of a crystalline form of triethylenetetramine tetrahydrochloride Form B having at least one of the following characteristics:
 (i) an XRPD pattern having at least two peaks selected from the peaks at 22.9, 25.4, 25.8, 26.6, 34.6 and 35.3±0.1° 2θ; and   (ii) a Raman spectrum having at least two peaks selected from the peaks at a Raman shift of 943, 1173, 1527 and 1612±5 cm −1 ;   and which contains no more than 10 wt % of triethylenetetramine tetrahydrochloride Form A having an XRPD pattern having peaks at 25.2 and 35.7±0.1° 2θ,   wherein XRPD pattern peaks are as measured using a wavelength of 1.5418 Å.