CRYSTALLINE FORMS OF 2-[3-[4-AMINO-3-(2-FLUORO-4-PHENOXY-PHENYL)PYRAZOLO[3,4-D]PYRIMIDIN-1-YL]PIPERIDINE-1-CARBONYL]-4-METHYL-4-[4-(OXETAN-3-YL)PIPERAZIN-1-YL]PENT-2-ENENITRILE
Provided herein are substantially crystalline solid forms of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pen-t-2-enenitrile (identified herein as Compound (I), and also known as PRN 1008 or rilzabrutinib) as a pharmaceutically-acceptable salt selected from an HCI, oxalate, and/or a maleate salt or alternatively, as a pharmaceutically-acceptable methyl paraben co-crystal, and pharmaceutical compositions comprising the substantially crystalline forms.
1 . A substantially crystalline form of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile chosen from an HCl salt, oxalate salt, or maleate salt form thereof.
2 . The substantially crystalline form of claim 1 , which is 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: HCl birefringent crystalline salt.
3 . The substantially crystalline form of claim 2 , wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: HCl birefringent crystalline salt is characterized by an XRPD pattern substantially the same as those in FIG. 1
4 . The substantially crystalline form of claim 1 , which is 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: HCl crystalline salt hydrate.
5 . The substantially crystalline form of claim 4 , wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: HCl crystalline salt hydrate is characterized by at least one of
an XRPD pattern substantially the same as FIG. 2 ;
a DSC/TGA profile substantially the same as FIG. 3 .
6 . The substantially crystalline form of claim 1 , which is 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: HCl crystalline salt Form A.
7 . The substantially crystalline form of claim 6 , wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: HCl crystalline salt Form A is characterized by at least one of
an XRPD pattern substantially the same as FIG. 4 ;
an XRPD pattern substantially the same as FIG. 5 ;
a DSC profile substantially the same as FIG. 6 ;
a TGA profile substantially the same as FIG. 7 .
8 . The substantially crystalline form of claim 6 or 7 , wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: HCl crystalline salt Form A is characterized by an XRPD pattern comprising four or more peaks, in terms of 2-theta degrees, chosen from peaks at about 9.7±0.2, 14.9±0.2, 17.6±0.2, 19.0±0.2, 19.6±0.2, 21.6±0.2, 22.3±0.2, and 29.3±0.3.
9 . The substantially crystalline form of claim 1 , which is 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: oxalate birefringent crystalline salt Form A.
10 . The substantially crystalline form of claim 9 , wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: oxalate birefringent crystalline salt Form A is characterized by at least one of:
an XRPD pattern substantially the same as FIG. 8 ;
a DSC/TGA profile substantially the same as FIG. 9 .
11 . The substantially crystalline form of claim 1 , which is 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: maleate birefringent crystalline salt.
12 . The substantially crystalline form of claim 11 , wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: maleate birefringent crystalline salt is characterized by at least one of:
an XRPD pattern substantially the same as FIG. 10 ;
a DSC/TGA profile substantially the same as FIG. 11 .
13 . The substantially crystalline form of claim 1 , which is 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: oxalate crystalline salt hydrate Form A.
14 . The substantially crystalline form of claim 13 , wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: oxalate crystalline salt hydrate Form A is characterized by at least one of:
an XRPD pattern substantially the same as FIG. 14 ;
a DSC profile substantially the same as FIG. 15 A ;
an XRPD pattern substantially the same as FIG. 16 ;
an XRPD pattern substantially the same as FIG. 17 ;
a TGA profile substantially the same as FIG. 18 ;
a DCS/TGA profile substantially the same as FIG. 19 .
15 . The substantially crystalline form of claim 1 , which is 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: oxalate crystalline salt hydrate Form B.
16 . The substantially crystalline form of claim 15 , wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: oxalate crystalline salt hydrate Form B is characterized by at least one of:
an XRPD pattern substantially the same as FIG. 12 ;
a DSC/TGA profile substantially the same as FIG. 13 ;
a DSC profile substantially the same as FIG. 15 B .
17 . The substantially crystalline form of claim 13 or 14 , wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: oxalate crystalline salt hydrate Form A is characterized by an XRPD pattern comprising four or more peaks, in terms of 2-theta degrees, chosen from peaks at about 4.8±0.2, 9.3±0.2, 14.0±0.2, 14.2±0.2, 17.0±0.2, 18.7±0.2, 19.6±0.2, and 22.6±0.2.
18 . The substantially crystalline form of claim 1 , which is 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: maleate crystalline salt Form B·MeCN solvate.
19 . The substantially crystalline form of claim 18 , wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: maleate crystalline salt Form B·MeCN solvate is characterized by at least one of:
an XRPD pattern substantially the same as FIG. 20 ;
a DSC/TGA profile substantially the same as FIG. 21 .
20 . The substantially crystalline form of claim 1 , which is 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: maleate crystalline salt Form A.
21 . The substantially crystalline form of claim 20 , wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: maleate crystalline salt Form A is characterized by at least one of:
an XRPD pattern substantially the same as shown in FIG. 22 ;
a TGA profile substantially the same as FIG. 23 .
22 . The substantially crystalline form of claim 20 or 21 , wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: maleate crystalline salt Form A is characterized by an XRPD pattern comprising four or more peaks, in terms of 2-theta degrees, chosen from peaks at about 9.7±0.2, 14.9±0.2, 17.6±0.2, 19.0±0.2, 19.6±0.2, 21.6±0.2, 22.3±0.2, and 22.8±0.2.
23 . A substantially crystalline form of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, which is a methyl paraben co-crystal.
24 . The substantially crystalline form of claim 23 , wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: methyl paraben co-crystal is characterized by at least one of:
an XRPD pattern substantially the same as FIG. 27 ;
a DCS/TGA profile substantially the same as FIG. 28 .
25 . The substantially crystalline form of claim 23 or 24 , wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: methyl paraben co-crystal is characterized by an XRPD pattern comprising four or more peaks, in terms of 2-theta degrees, chosen from peaks at about 4.6±0.2, 10.8±0.2, 16.6±0.2, 18.3±0.2, 19.3±0.2, 20.2±0.2, 21.6±0.2 and 22.5±0.2.
26 . The substantially crystalline form of any one of claims 1 to 25 , which is at least 50% crystalline form, such as at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% crystalline.
27 . A pharmaceutical composition comprising at least one substantially crystalline form of any of the preceding claims and a pharmaceutically acceptable excipient.
28 . A method of treating a disease mediated by activity of BTK in a subject in need of treatment comprising administering to the subject a crystalline form of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, according to any one of claims 1 to 26 , or pharmaceutical composition according to claim 27 .