Solid forms of a selective cdk4/6 inhibitor

Abstract

This invention relates to the crystalline free base of acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, formula (1) having improved properties, to pharmaceutical compositions and dosage forms comprising the free base, and to methods for making and using such compounds, compositions and dosage forms in the treatment of cell proliferative diseases, such as cancer.

We claim: 
     
         1 . A crystalline free base of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, having a specific surface area of ≦2 m 2 /g. 
     
     
         2 . The free base of  claim 1 , having a specific surface area of ≦1 m 2 /g. 
     
     
         3 . The free base of  claim 1 , wherein the crystalline free base is a polymorph Form A of the free base. 
     
     
         4 . The free base of  claim 3 , having a powder X-ray diffraction pattern comprising a peak at diffraction angle (2θ) of 10.1±0.2. 
     
     
         5 . The free base of  claim 3 , having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2θ) of 8.0±0.2 and 10.1±0.2. 
     
     
         6 . The free base of  claim 3 , having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2θ) of 8.0±0.2, 10.1±0.2, and 11.5±0.2. 
     
     
         7 . The free base of  claim 3 , having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2θ) of 8.0±0.2, 10.1±0.2, 10.3±0.2, and 11.5±0.2. 
     
     
         8 . The free base of  claim 3 , having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2θ) essentially the same as shown in  FIG. 1 . 
     
     
         9 . The free base of  claim 1 , having a  13 C solid state NMR spectrum comprising the following resonance (ppm) values: 12.5 ppm±0.2 ppm. 
     
     
         10 . The free base of  claim 9 , having a  13 C solid state NMR spectrum comprising the following resonance (ppm) values: 12.5 ppm and 112.4 ppm±0.2 ppm. 
     
     
         11 . The free base of  claim 9 , having a  13 C solid state NMR spectrum comprising the following resonance (ppm) values: 12.5 ppm, 112.4 ppm and 143.2 ppm±0.2 ppm. 
     
     
         12 . The free base of  claim 1 , having a primary particle size of from about 5 mm to about 150 mm. 
     
     
         13 . The free base of  claim 1 , having a primary particle size distribution characterized by: (i) a D10 value of from about 5 mm to about 10 mm; (ii) a D90 value of from about 30 mm to about 125 mm; or (iii) a D50 value of from about 10 mm to about 45 mm; or a combination of (i), (ii) and (iii). 
     
     
         14 . The free base of  claim 1 , having a primary particle size distribution ratio of (D90-D10)/D50 of from about 2 to about 3. 
     
     
         15 . A pharmaceutical composition comprising the free base of  claim 1 , and at least one pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         16 . A capsule comprising the pharmaceutical composition of  claim 15 , containing from 0.1 to 200 mg of the polymorph Form A of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one free base. 
     
     
         17 - 20 . (canceled)