Wet granulation using a water sequestering agent
View Patent ↗Disclosed are tablets comprising hydrolytically stable formulations of (6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate disodium salt (Compound 1) prepared by a wet granulation process.
1. A wet granulated formulation comprising water, a therapeutically effective amount of (6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate disodium salt and a sufficient amount of a water sequestering agent to inhibit decomposition of (6-(5-fluoro-2-(3,4,5-trimethoxyphenyl-amino)pyrimidin-4-ylamino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate disodium salt, wherein said wet granulated formulation after drying has a bulk density sufficient to form tablets having a hardness in the range of about 6 kp to about 30 kp.
2. The formulation of claim 1 , wherein after drying the formulation has a bulk density of between about 0.35 to about 0.65 g/mL.
3. The formulation of claim 1 , wherein the water sequestering agent is selected from the group consisting of starch, magnesium sulfate, calcium chloride, silica gel, and kaolin.
4. The formulation of claim 3 , wherein the water sequestering agent is starch.
5. The formulation of claim 4 , wherein the starch is partially pregelatinized.
6. The formulation of claim 5 , wherein the starch is derived from Maize.
7. The formulation of claim 1 which further comprises at least one of a filler, a lubricant, a suspending/dispersing agent, a binding agent, and a disintegrant.
8. A wet granulating process, comprising:
a) blending a composition comprising (6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate disodium salt and a sufficient amount of a water sequestering agent to inhibit the decomposition of 6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate disodium salt to form a blended mixture;
b) granulating the blended mixture of a) while adding water to form wet granules;
c) drying the wet granules of b) at below 65° C. until a loss on drying of between about 5% and 11% is achieved to provide dried granules; and
d) blending a lubricant into the dried granules of c) to provide blended granules.
9. The method of claim 8 , further comprising:
compressing the blended granules to form tablets.