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. A p-toluenesulfonic acid salt of the compound
wherein the salt has a d(0.9) of from about 5 to about 50 μm.
2. The salt of claim 1 , wherein the salt has a d(0.9) of from about 5 to about 25 μM.
3. The salt of claim 1 , wherein the salt has a d(0.9) of from about 5 to about 15 μm.
4. The salt of claim 1 , wherein the salt has a d(0.5) of from about 1 to about 10 μm.
5. The salt of claim 1 , wherein the salt has a d(0.5) of from about 2 to about 5 μm.
6. The salt of claim 1 , wherein the salt has a d(0.1) of from about 0.5 to about 1.5 μm.
7. The salt of claim 1 , wherein the salt has a d(0.1) of from about 0.5 to about 1.0 μm.
8. The salt of claim 1 , 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.
9. The salt of claim 1 , wherein the salt exhibits a differential scanning calorimeter (DSC) pattern with a characteristic endothermic peak at about 146 ° C.
10. The salt of claim 1 , wherein the ratio of p-toluenesulfonic acid to the compound
is about 1:1.
11. A pharmaceutical composition comprising a salt of claim 1 and a pharmaceutically acceptable excipient.
12. A method of inhibiting a catalytic activity of a PI3 δkinase present in a cell, comprising contacting the cell with an effective amount of a salt of claim 1 .
13. The method of claim 12 , wherein the inhibition takes place in a subject suffering from a disease or disorder which is cancer, bone disorder, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease, thrombosis, or cardiac disease.
14. A method of preparing a crystalline p-toluenesulfonic acid salt of the compound
comprising the step of removing the solvent from a mixture of a p-toluenesulfonic acid salt of the compound
and an ether solvent, wherein the mixture is a suspension of crystalline p-toluenesulfonic acid salt of the compound
in an ether solvent.
15. A method of preparing a crystalline p-toluenesulfonic acid salt of the compound
comprising the step of removing the solvent from a mixture of a p-toluenesulfonic acid salt of the compound
and an ether solvent, wherein the method comprises stirring the mixture prior to removing the solvent.
16. The method of claim 15 , wherein the stirring is performed for at least 3 hours.
17. The method of claim 14 , wherein the solvent is removed by drying.
18. The salt of claim 2 , wherein the salt has a d(0.5) of from about 1 to about 10 μm.
19. The salt of claim 2 , wherein the salt has a d(0.5) of from about 2 to about 5 μm.
20. The salt of claim 3 , wherein the salt has a d(0.5) of from about 1 to about 10 μm.
21. The salt of claim 3 , wherein the salt has a d(0.5) of from about 2 to about 5 μm.
22. The salt of claim 2 , wherein the salt has a d(0.1) of from about 0.5 to about 1.5 μm.
23. The salt of claim 2 , wherein the salt has a d(0.1) of from about 0.5 to about 1.0 μm.
24. The salt of claim 18 , wherein the salt has a d(0.1) of from about 0.5 to about 1.5 μm.
25. The salt of claim 18 , wherein the salt has a d(0.1) of from about 0.5 to about 1.0 μm.
26. The salt of claim 8 , wherein the salt exhibits a XRPD pattern having two or more peaks selected from 5.0, 10.1, 22.1, and 24.5±0.2°2Θ.
27. The salt of claim 8 , wherein the salt exhibits a XRPD pattern having three or more peaks selected from 5.0, 10.1, 22.1, and 24.5±0.2°2Θ.
28. The salt of claim 8 , wherein the salt exhibits a XRPD pattern having peaks at 5.0, 10.1, 22.1, and 24.5±0.2°2Θ.
29. The pharmaceutical composition of claim 1 , wherein (i) 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, and (ii) the composition contains less than 5% of other solid state forms of the p-toluenesulfonic acid salt of the compound
based on the total amount of the p-toluenesulfonic acid salt present in the composition.