Crystalline forms of a factor Xa inhibitor
The instant invention provides crystalline forms of 3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one and its solvates thereof; processes for the production of such crystalline forms; pharmaceutical compositions comprising such crystalline forms; and methods of treating thromboembolic disorders with such crystalline forms or such pharmaceutical compositions.
1. Form N-1 of crystalline 3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one, which is characterized by unit cell parameters substantially equal to the following:
Cell dimensions:
a=9.534(1) Å
b=9.842(1) Å
c=13.469(1) Å
α=87.95(1)
β=83.18(1)
γ=70.22(1)
Space group P-1
Molecules/asymmetric unit 1
wherein said crystalline form is at about +22° C.
2. Form N-1 according to claim 1 , which is characterized by fractional atomic coordinates substantially as listed in Table 3.
3. Form N-1 according to claim 1 , which is characterized by a powder X-ray diffraction pattern substantially in accordance with that shown in FIG. 1 .
4. Form N-1 according to claim 1 having a powder X-ray diffraction pattern comprising the following 2θ values (CuKαλ=1.5418 Å) 6.6±0.1, 11.3±0.1, 12.5±0.1, 15.6±0.1, 19.2±0.1, and 20.3±0.1, at about 22° C.
5. Form N-1 according to claim 1 , which is characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 7 , having a peak onset at about 222 to 226° C.
6. Form N-3 of crystalline 3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one, which is characterized by unit cell parameters substantially equal to the following:
Cell dimensions:
a=8.959(3) Å
b=9.840(2) Å
c=14.826(6) Å
α=76.27(2)
β=86.38(2)
γ=69.18(2)
Space group P-1
Molecules/asymmetric unit 1
wherein the crystalline form is at about +22° C.
7. Form N-3 according to claim 6 , which is characterized by fractional atomic coordinates substantially as listed in Table 4.
8. Form N-3 according to claim 6 , which is characterized by a powder X-ray diffraction pattern substantially in accordance with that shown in FIG. 2 .
9. Form N-3 according to claim 6 having a powder X-ray diffraction pattern comprising the following 2θ values (CuKαλ=1.5418 Å) 6.1±0.1, 9.9±0.1, 12.2±0.1, 15.4±0.1, 19.3±0.1, 23.1±0.1 and 24.4±0.1, at about 22° C.
10. Form H2-2 of crystalline 3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one, which is characterized by unit cell parameters substantially equal to the following:
Cell dimensions:
a=16.445(2) Å
b=17.319(1) Å
c=18.997(2) Å
α=71.65(1) (1)
β=78.86(1)
γ=87.78(1)
Space group P-1
Molecules/asymmetric unit 4
wherein the crystalline form is at about −50° C.
11. Form H2-2 according to claim 10 , which is characterized by fractional atomic coordinates substantially as listed in Table 5.
12. Form H2-2 according to claim 10 , which is characterized by a powder X-ray diffraction pattern substantially in accordance with that shown in FIG. 4 .
13. Form H2-2 according to claim 10 having an X-ray powder diffraction comprising the following 2θ values (CuKαλ=1.5418 Å) 5.4±0.1, 9.7±0.1, 12.2±0.1, 14.6±0.1, 16.2±0.1 and 22.3±0.1, at about 22° C.
14. Form H2-2 according to claim 10 , which is characterized by a thermal gravimetric analysis having a weight loss of about 7.1% up to about 80° C.
15. Form DC-4 of crystalline 3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one, which is characterized by unit cell parameters substantially equal to the following:
Cell dimensions:
a=8.951(2) Å
b=9.789(3) Å
c=17.263(4) Å
α=69.30(2)
β=83.24(2)
γ=69.78(2)
Space group P-1
Molecules/asymmetric unit 1
wherein the crystalline form is at about +22° C.
16. Form DC-4 according to claim 15 , which is characterized by fractional atomic coordinates substantially as listed in Table 6.
17. Form DC-4 according to claim 15 , which is characterized by an X-ray powder diffraction pattern substantially in accordance with that shown in FIG. 5 .
18. Form DC-4 according to claim 15 having an X-ray powder diffraction comprising the following 2θ values (CuKαλ=1.5418 Å) 5.5±0.1, 11.8±0.1, 13.8±0.1, 15.2±0.1, 18.8±0.1, 21.1±0.1 and 23.8±0.1, at about 22° C.
19. Form DC-4 according to claim 15 , which is characterized by a thermal gravimetric analysis curve having a weight loss of about 15.2% up to about 85° C.
20. Form EGDA.5-5 of crystalline 3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one, which is characterized by unit cell parameters substantially equal to the following:
Cell dimensions:
a=9.005(3) Å
b=9.854(2) Å
c=16.283(5) Å
α=84.88(2)
β=81.95(2)
γ=68.19(1)
Space group P-1
Molecules/asymmetric unit 1
wherein said crystalline form is at about +22° C.
21. Form EGDA.5-5 according to claim 20 , which is characterized by fractional atomic coordinates substantially as listed in Table 7.
22. Form EGDA.5-5 according to claim 20 , which is characterized by a powder X-ray diffraction pattern substantially in accordance with that shown in FIG. 15 .
23. Form EGDA.5-5 according to claim 20 having a powder X-ray diffraction pattern comprising the following 2θ values (CuKαλ=1.5418 Å) 5.5±0.1, 12.0±0.1, 12.5±0.1, 14.8±0.1, 16.8±0.1, 20.6±0.1, 21.5±0.1, 22.7±0.1, 24.4±0.1, at about 22° C.