Compositions of azimilide dihydrochloride
View Patent ↗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 , wherein the 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 has 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 has a solid-state 13C NMR spectrum characterized substantially in accordance with the solid-state 13C 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 has 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 has IR absorbance peaks at about 3428 and 3390 wave numbers.
10. The method of claim 1 , wherein the isopropanol solvate has an X-ray powder diffraction pattern comprising peaks at about 4.33+/−0.2 degrees 2 theta, at about 12.8 +/−0.2 degrees 2 theta, and at about 21.53+/−0.2 degrees 2 theta.
11. The method of claim 1 , wherein step (a) comprises heating the mixture to a temperature of about 60-80° C.
12. The method of claim 1 , wherein step (b) comprises combining the heated mixture with acetone, maintaining the mixture at a temperature of about 50° C., and then cooling the mixture to induce crystallization.
13. An isopropanol solvate of (E)-1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride prepared by the process of any of claims 1 - 12 .