Details for Patent: 8,372,415

Title:	Wet granulation using a water sequestering agent
Abstract:	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.
Inventor(s):	Sun; Thomas (Palo Alto, CA), Lo; Ray (San Leandro, CA)
Assignee:	Rigel Pharmaceuticals, Inc. (South San Francisco, CA)
Filing Date:	Jul 26, 2012
Application Number:	13/559,097
Claims:	1. A method for formulating (6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dime- thyl-3-oxo-2H-pyrido[3,2-b ][1,4]oxazin-4(3H)-yl)methyl phosphate disodium salt into a formulation for tablet compression, which method comprises: a) blending (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 with starch and optionally at least one of a filler, a lubricant, a suspending/dispersing agent, a binding agent and a disintegrant, at an impellor speed sufficient to form a homogenous powder mixture having a bulk density after drying of about 6 kp to about 30 kp; b) spraying into the homogenous powder mixture between about 15% and about 40% by weight of water with respect to the total weight of the powder mixture plus water and mixing to form wet granules; and c) drying the wet granules until a loss on drying of between about 5% and about 11% is achieved, to provide dried granules. 2. The method of claim 1, wherein the dried granules are sized between about 25 .mu.m to about 900 .mu.m in diameter. 3. The method of claim 1 which further comprises milling the dried granules, to provide milled granules. 4. The method of claim 3, wherein the dried granules are milled so that about 90 weight percent of the milled granules have a particle size between about 25 to about 900 .mu.m in diameter. 5. The method of claim 4, further comprising mixing the milled granules with a lubricant until homogenous, and then tabletting the resulting formulation. 6. A wet granulating process, comprising: a) blending a composition comprising (6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dime- thyl-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 for inhibiting the decomposition of (6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dime- thyl-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 while adding water to form wet granules; c) drying the wet granules at 65 .degree. 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 to provide blended granules. 7. The method of claim 6, further comprising: compressing the blended granules to form tablets.