Compositions of azimilide dihydrochloride

Abstract

The present invention is directed to solvates and various polymorphic forms of (E)-1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride and pharmaceutical compositions thereof.

1 . A method for preparing an isopropanol solvate of (E)-1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride in substantially pure form, wherein the method comprises:
 (a) heating a mixture of water and (E)-1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride to form a heated mixture;   (b) combining the heated mixture with acetone;   (c) isolating a hemi-hydrate of (E)-1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride; and   (d) combining the hemi-hydrate with isopropanol to form the isopropanol solvate of (E)-1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride.   
     
     
         2 . The method of  claim 1 , where method further comprises recrystallizing the isopropanol solvate in acetone in a step (e). 
     
     
         3 . The method of  claim 1 , wherein the isopropanol solvate comprises between about 9% and about 11% isopropanol by weight. 
     
     
         4 . The method of  claim 1 , wherein the isopropanol solvate comprises an X-ray diffraction pattern characterized substantially in accordance with the pattern of  FIG. 3 . 
     
     
         5 . The method of  claim 1 , wherein the isopropanol solvate comprises has a solid-state  13 C NMR spectrum characterized substantially in accordance with the solid-state  13 C NMR spectrum of  FIG. 6 . 
     
     
         6 . The method of  claim 1 , wherein the isopropanol solvate has an infrared spectrum characterized substantially in accordance with the infrared spectrum of  FIG. 9 . 
     
     
         7 . The method of  claim 1 , wherein the isopropanol solvate has a thermogravimetric analysis curve characterized substantially in accordance with the pattern of  FIG. 12 . 
     
     
         8 . The method of  claim 1 , wherein the isopropanol solvate comprises X-ray diffraction peaks at 2 theta values of about 4.33, about 9.51, about 12.8, about 17.16, about 18.5 and about 21.53 degrees. 
     
     
         9 . The method of  claim 1 , wherein the isopropanol solvate comprises has IR absorbance peaks at about 3428 and 3390 wave numbers.