FORMS OF A PI3K DELTA SELECTIVE INHIBITOR FOR USE IN PHARMACEUTICAL FORMULATIONS
The present invention relates to solid state forms of a p-toluenesulfonic acid salt (PTSA) of the selective PI3K delta inhibitor (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (TGR-1202). The present invention also relates to methods of preparing the same, pharmaceutical compositions containing them, and methods of treating a PI3K kinase mediated disease or disorder, such as cancer, by administering the same.
1 - 43 . (canceled)
44 . A pharmaceutical composition comprising (i) a p-toluenesulfonic acid salt of (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and (ii) a solubilizer, wherein the salt has a d(0.9) of from about 5 to about 50 μm.
45 . The pharmaceutical composition of claim 44 , wherein the solubilizer is hydroxypropyl betadex.
46 . The pharmaceutical composition of claim 44 , wherein the weight ratio of the p-toluenesulfonic acid salt to the solubilizer is from about 1.5:1 to about 1:1.5.
47 . The pharmaceutical composition of claim 45 , wherein the weight ratio of the p-toluenesulfonic acid salt to the solubilizer is from about 1.5:1 to about 1:1.5.
48 . The pharmaceutical composition of claim 44 , wherein the tablet further comprises one or more excipients selected from suspending agents, dispersing agents, disintegrants, lubricants, and any combination of any of the foregoing.
49 . The pharmaceutical composition of claim 44 , wherein the salt has a d(0.9) of from about 5 to about 25 μm.
50 . The pharmaceutical composition of claim 44 , wherein the salt has a d(0.9) of from about 5 to about 15 μm.
51 . The pharmaceutical composition of claim 44 , wherein the salt has a d(0.5) of from about 1 to about 10 μm.
52 . The pharmaceutical composition of claim 44 , wherein the salt has a d(0.5) of from about 2 to about 5 μm.
53 . A pharmaceutical composition comprising (i) a p-toluenesulfonic acid salt of (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and (ii) a solubilizer, wherein the salt exhibits a XRPD pattern having one or more peaks selected from 5.0, 10.1, 22.1, and 24.5±0.2° 2Θ.
54 . The pharmaceutical composition of claim 44 , wherein the ratio of p-toluenesulfonic acid to (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one is about 1:1.
55 . A pharmaceutical composition comprising (i) 200 mg of a p-toluenesulfonic acid salt of (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and (ii) a solubilizer, wherein the salt has a d(0.9) of from about 5 to about 50 μm.
56 . The pharmaceutical composition of claim 55 , wherein the solubilizer is hydroxypropyl betadex.
57 . The pharmaceutical composition of claim 55 , wherein the weight ratio of the p-toluenesulfonic acid salt to the solubilizer is from about 1.5:1 to about 1:1.5.
58 . The pharmaceutical composition of claim 56 , wherein the weight ratio of the p-toluenesulfonic acid salt to the solubilizer is from about 1.5:1 to about 1:1.5.
59 . The pharmaceutical composition of claim 55 , wherein the tablet further comprises one or more excipients selected from suspending agents, dispersing agents, disintegrants, lubricants, and any combination of any of the foregoing.
60 . The pharmaceutical composition of claim 55 , wherein the p-toluenesulfonic acid salt has a d(0.9) of from about 5 to about 25 μm.
61 . The pharmaceutical composition of claim 55 , wherein the p-toluenesulfonic acid salt has a d(0.9) of from about 5 to about 15 μm.
62 . The pharmaceutical composition of claim 55 , wherein the p-toluenesulfonic acid salt has a d(0.5) of from about 1 to about 10 μm.
63 . The pharmaceutical composition of claim 55 , wherein the p-toluenesulfonic acid salt has a d(0.5) of from about 2 to about 5 μm.
64 . The pharmaceutical composition of claim 55 , wherein the p-toluenesulfonic acid salt exhibits a XRPD pattern having one or more peaks selected from 5.0, 10.1, 22.1, and 24.5±0.2°2Θ.
65 . The pharmaceutical composition of claim 55 , wherein the ratio of p-toluenesulfonic acid to (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one is about 1:1.
66 . A method of treating indolent non-Hodgkin's lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of claim 44 .
67 . A method of treating B-cell lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of claim 44 .
68 . A method of treating follicular lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of claim 44 .
69 . A method of treating indolent non-Hodgkin's lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of claim 55 .
70 . A method of treating B-cell lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of claim 55 .
71 . A method of treating follicular lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of claim 55 .
72 . A pharmaceutical composition comprising (i) a p-toluenesulfonic acid salt of (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and (ii) a solubilizer.