Voriconazole sodium phosphate hydrates and polymorphs thereof
View Patent ↗The present invention relates to a voriconazole sodium phosphate hydrate, polymorphs thereof, a preparation method thereof, and use thereof, wherein the voriconazole phosphate salt hydrate prepared by using an isopropanol-water system, ethanol-water system, or an ethanol system comprises different crystal forms. And these kinds of crystal forms have favorable water solubility and stability and feature a simple manufacturing process. The voriconazole phosphate salt hydrate is principally used for treatment of fungal infections.
1. A voriconazole sodium phosphate hydrate, the sodium voriconazole phosphate hydrate has a chemical structure as shown below:
2. The voriconazole sodium phosphate hydrate of claim 1 , comprising crystal form A of voriconazole sodium phosphate hydrate, wherein 2θ value of X-ray powder diffraction pattern is about: 9.860, 10.600, 12.680, 14.839, 19.840, 20.148, or 29.940.
3. The voriconazole sodium phosphate hydrate of claim 1 , comprising crystal form B of voriconazole sodium phosphate hydrate, wherein 2θ value of X-ray powder diffraction pattern is about: 10.680, 12.639, 14.900, 19.940, 20.240, or 23.059.
4. The voriconazole sodium phosphate hydrate of claim 1 , comprising crystal form C of voriconazole sodium phosphate hydrate, wherein 2θ value of X-ray powder diffraction pattern is about: 11.640, 12.741, 14.939, 16.280, 19.960, or 21.700.
5. A pharmaceutical composition, wherein active ingredient of the composition is the voriconazole sodium phosphate hydrate of claim 1 in an amount of 0.01-99.99% by weight.
6. The composition in claim 5 , wherein the composition is a parenterally administered preparation.
7. The composition of claim 5 , wherein the composition is an orally administered preparation.
8. The composition of claim 6 , wherein the parenterally administered preparation is an injection or, powder for injection.
9. The composition of claim 7 , wherein the orally administered preparation is a tablet, a dispersible tablet, a capsule, a granule, or an oral liquid.
10. The composition of claim 5 , wherein the composition preparation contains 50-3000 mg of voriconazole sodium phosphate hydrate in each tablet, vial, pouch, or piece.
11. The pharmaceutical composition of claim 5 administered as an anti-fungal drug for treating fungal infections.
12. A method for preparing voriconazole sodium phosphate hydrate or its polymorphs, comprising steps of:
adding 1-20 L/Kg of alcohol-water system or ketone-water system to a container containing voriconazole sodium phosphate;
heating the resulting mixture to 40° C.-70° C. under stirring;
stirring the mixture for 5-30 minutes under incubation;
filtering the mixture when it is still hot and cooling the filtrate to room temperature;
allowing the filtrate to crystallized at 0° C.-15° C. for 1-48 hours;
filtering out resulting solids and washing the solids with acetone; and
drying the solids at 30° C.-75° C. to an approximate theoretical water content until formation of the voriconazole sodium phosphate hydrate of claim 1 .
13. A method for preparing polymorphs of the voriconazole sodium phosphate hydrate of claim 12 , wherein solution used to prepare crystal form A of the voriconazole sodium phosphate hydrate is a 90% (V/V) isopropanol-water system; solution used to prepare crystal form B of the voriconazole sodium phosphate hydrate is a ethanol-water system, and solution used prepare crystal form C of the voriconazole sodium phosphate hydrate is a 90% (V/V) ethanol-water system.
14. The method for preparing the voriconazole sodium phosphate hydrate of claim 12 , wherein the alcohol-water system is ethanol-water system, isopropanol-water system, and the ketone-water system is acetone-water.
15. A pharmaceutical composition, wherein active ingredient of the composition is the voriconazole sodium phosphate hydrate of claim 2 in an amount of 0.01-99.99% by weight.
16. The composition of claim 15 , wherein the composition preparation contains 50-3000 mg of voriconazole sodium phosphate hydrate in each tablet, vial, pouch, or piece.
17. A pharmaceutical composition, wherein active ingredient of the composition is the voriconazole sodium phosphate hydrate of claim 3 in an amount of 0.01-99.99% by weight.
18. The composition of claim 17 , wherein the composition preparation contains 50-3000 mg of voriconazole sodium phosphate hydrate in each tablet, vial, pouch, or piece.
19. A pharmaceutical composition, wherein active ingredient of the composition is the voriconazole sodium phosphate hydrate of claim 4 in an amount of 0.01-99.99% by weight.
20. The composition of claim 19 , wherein the composition preparation contains 50-3000 mg of voriconazole sodium phosphate hydrate in each tablet, vial, pouch, or piece.