Crystalline phases of 5,6-dichloro-2-(isopropylamino)-(1-beta-L-ribofuranosyl)-1H-benzimidazole
The invention relates to novel crystalline phases of 5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole (Maribavir), pharmaceutical compositions thereof and their use in medical therapy.
1. A composition comprising an admixture of a crystalline form VI solvate of 5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole and a crystalline form VII of 5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole, wherein the crystalline form VI solvate comprises an organic solvent selected from the group of: ethyl acetate and diethylether.
2. The composition of claim 1 , wherein the organic solvent is ethyl acetate and the crystalline form VI solvate is characterized by a powder X-ray diffraction pattern having peaks at 5.955±0.1 and 23.639±0.1 2-theta.
3. The composition of claim 1 , wherein the organic solvent is ethyl acetate and the crystalline form VI solvate is characterized by a powder X-ray diffraction pattern having peaks at 5.955±0.1, 17.956±0.1, 18.360±0.1, and 23.639±0.1 2-theta.
4. The composition of claim 1 , wherein the organic solvent is ethyl acetate and the crystalline form VI solvate is characterized by a powder X-ray diffraction pattern having peaks at 5.955±0.1, 15.993±0.1, 17.956±0.1, 18.360±0.1, 23.639±0.1, and 23.992±0.1 2-theta.
5. The composition of claim 1 , wherein the organic solvent is ethyl acetate and the crystalline form VI solvate is characterized by a powder X-ray diffraction pattern having peaks at 5.955±0.1, 15.703±0.1, 15.993±0.1, 17.956±0.1, 18.360±0.1, 20.063±0.1, 23.639±0.1, and 23.992±0.1 2-theta.
6. The composition of claim 1 , wherein the organic solvent is ethyl acetate and the crystalline form VI solvate is characterized by a powder X-ray diffraction pattern having peaks at 5.955±0.1, 11.917±0.1, 14.933±0.1, 15.703±0.1, 15.993±0.1, 17.956±0.1, 18.360±0.1, 20.063±0.1, 21.508±0.1, 23.095±0.1, 23.639±0.1, 23.992±0.1, and 28.167±0.1 degrees 2-theta.
7. The composition of claim 2 , wherein the powder X-ray diffraction pattern is collected using a temperature controlled sample TTK450 chamber.
8. The composition of claim 2 , wherein the powder X-ray diffraction pattern is collected using copper K-alpha radiation.
9. The composition of claim 1 , prepared by steps of:
i) providing a solution of crystalline form VI 5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole in ethyl acetate,
ii) maintaining the solution temperature at room temperature to provide crystallization of the crystalline form VI solvate,
iii) heating the crystalline form VI solvate to afford a partial solid-solid phase transition and provide the admixture of crystalline form VII and the crystalline form VI solvate.
10. The composition of claim 9 , wherein the crystalline form VI solvate is heated to a temperature of 30° C. to 70° C.
11. The composition of claim 1 , wherein the organic solvent is diethyl ether and the crystalline form VI solvate is characterized by a powder X-ray diffraction pattern having peaks at 6.033±0.1, 18.145±0.1, 18.778±0.1, and 24.113±0.1 2-theta.
12. The composition of claim 1 , wherein the organic solvent is diethyl ether and the crystalline form VI solvate is characterized by a powder X-ray diffraction pattern having peaks at 6.033±0.1, 10.880±0.1, 16.442±0.1, 18.145±0.1, 18.778±0.1, and 24.113±0.1 2-theta.
13. The composition of claim 1 , wherein the organic solvent is diethyl ether and the crystalline form VI solvate is characterized by a powder X-ray diffraction pattern having peaks at 6.033±0.1, 10.880±0.1, 13.647±0.1, 14.139±0.1, 15.109±0.1, 16.442±0.1, 18.145±0.1, 18.778±0.1, 19.140±0.1, 21.164±0.1, 21.597±0.1, 23.741±0.1, and 24.113±0.1 2-theta.
14. The composition of claim 1 , wherein the organic solvent is diethyl ether and the crystalline form VI solvate is characterized by a powder X-ray diffraction pattern having peaks at 6.033±0.1, 10.880±0.1, 13.647±0.1, 14.139±0.1, 15.109±0.1, 15.736±0.1, 16.442±0.1, 16.844±0.1, 18.145±0.1, 18.778±0.1, 19.140±0.1, 20.361±0.1, 21.164±0.1, 21.597±0.1, 23.469±0.1, 23.741±0.1, 24.113±0.1, 26.000±0.1, and 28.941±0.1 degrees 2-theta.
15. The composition of claim 1 , prepared by steps of:
i) providing a suspension of crystalline form VI 5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole in diethyl ether,
ii) stirring the suspension for a period of time,
iii) collecting the crystalline form VI solvate,
iii) heating the crystalline form VI solvate to afford a partial solid-solid phase transition and provide the admixture of crystalline form VII and the crystalline form VI solvate.
16. The composition of claim 15 , wherein the crystalline solvate is heated to a temperature of 40° C. to 100° C.
17. The composition of claim 11 , wherein the powder X-ray diffraction pattern is collected using a TTK 450 chamber.
18. The composition of claim 11 , wherein the powder X-ray diffraction pattern is collected using copper K-alpha radiation.
19. The composition of claim 10 , wherein the crystalline form VI solvate is heated to a temperature of 30, 40, 50, 60, or 70° C.
20. The composition of claim 15 , wherein the crystalline form VI solvate is heated to a temperature of 40, 60, 80, or 100° C.