CRYSTALLINE FORMS OF PITAVASTATIN CALCIUM
The present invention is directed to new crystalline forms of Pitavastatin hemicalcium salt, referred to hereinafter as polymorphic Forms A, B, C, D, E and F, as well as the amorphous form. Furthermore, the present invention is directed to processes for the preparation of these crystalline forms and the amorphous form and pharmaceutical compositions comprising these crystalline forms or the amorphous form.
1 - 14 . (canceled)
15 . A process for the preparation of a crystalline polymorph A according to claim 39 , which comprises the reaction of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoic acid sodium salt with CaCl 2 in an aqueous reaction medium, or the reaction of the free acid (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoic acid or the corresponding lactone with Ca(OH) 2 .
16 . A process for the preparation of crystalline polymorph B according to claim 39 , which comprises suspending crystalline polymorph A according to claim 39 in ethanol containing water as a cosolvent.
17 . A process according to claim 16 , wherein the amount of water is 1 to 50% by volume of the suspension of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-(E)-heptanoic acid hemicalcium salt.
18 . A process for the preparation of a crystalline polymorph C according to claim 39 , which comprises suspending crystalline polymorph A according to claim 39 in isopropanol containing water as a cosolvent.
19 . A process according to claim 18 , wherein the amount of water is 1 to 50% by volume of the suspension of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoic acid hemicalcium salt.
20 . A process for the preparation of crystalline polymorph C according to claim 39 , which comprises suspending crystalline polymorph A according to claim 39 in a mixture of isopropanol and a ketone solvent, containing water as a cosolvent.
21 . A process according to claim 20 in which the ketone solvent is acetone.
22 . A process according to claim 20 , wherein the amount of ketone solvent is 1 to 30% by volume of the suspension of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoic acid hemicalcium salt.
23 . A process according to claim 20 , wherein the amount of water is 1 to 20% by volume of the suspension of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoic acid hemicalcium salt.
24 . A process for the preparation of crystalline polymorph D according to claim 39 , which comprises suspending crystalline polymorph A according to claim 39 in absolute ethanol.
25 . A process for the preparation of crystalline polymorph E according to claim 39 , which comprises suspending crystalline polymorph A according to claim 39 in 1,4-dioxane containing water as a cosolvent.
26 . A process according to claim 25 , wherein the amount of water is 1 to 50% by volume of the suspension of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoic acid hemicalcium salt.
27 . A process for the preparation of crystalline polymorph E according to claim 39 , which comprises suspending crystalline polymorph A according to claim 39 in methanol containing water as a cosolvent.
28 . A process according to claim 27 , wherein the amount of water is 1 to 50% by volume of the suspension of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoic acid hemicalcium salt.
29 . A process according to claim 15 , wherein (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoic acid hemicalcium salt is isolated by filtration and dried in air or vacuum.
30 . A process according to claim 15 , wherein seeding is carried out with crystals of the desired crystalline polymorph.
31 . A process for the preparation of the amorphous form according claim 39 , wherein a non-solvent is added to a solution of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoic acid hemicalcium salt in an organic solvent.
32 . A process according to claim 31 , wherein the non-solvent is selected from heptane and methyl tert-butyl ether.
33 . A process according to claim 31 , wherein the organic solvent is selected from 1,4-dioxane, tetrahydrofuran and ethyl methyl ketone.
34 . A process for the preparation for the amorphous form according claim 39 , wherein an aqueous solution of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoic acid hemicalcium salt is dried by lyophilization.
35 . A process for the preparation of crystalline form A, B, C, D, E, F, or the amorphous form of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoic acid hemicalcium salt according to claim 39 essentially free of residual organic solvents by exposing this crystalline form or amorphous form to an atmosphere with a relative air humidity of 5 to 100%.
36 . A process for the preparation of a crystalline form A, B, C, D, E, F, or the amorphous form of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoic acid hemicalcium salt according to claim 39 essentially free of residual organic solvents by equilibrating this crystalline form or amorphous form in an inert gas flow with a relative air humidity of 5 to 100%.
37 . A process according to claim 31 in which the relative air humidity is 40 to 80%.
38 . A pharmaceutical composition comprising an effective amount of a crystalline polymorphic form according to claim 39 , and a pharmaceutically acceptable carrier.
39 . A crystalline polymorph A, B, C, D, E, F, or the amorphous form, of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoic acid hemicalcium salt wherein
A) polymorph A exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in 2θ at 5.0 (s), 6.8 (s), 9.1 (s), 10.0 (w), 10.5 (m), 11.0 (m), 13.3 (vw), 13.7 (s), 14.0 (w), 14.7 (w), 15.9 (vw), 16.9 (w), 17.1 (vw), 18.4 (m), 19.1 (w), 20.8 (vs), 21.1 (m), 21.6 (m), 22.9 (m), 23.7 (m), 24.2 (s), 25.2 (w), 27.1 (m), 29.6 (vw), 30.2 (w), 34.0 (w);
B) polymorph B exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in 2θ at 4.6 (w), 5.3 (vs), 6.2 (s), 7.7 (s), 9.2 (m), 9.6 (m), 10.3 (w), 11.3 (m), 11.7 (w), 12.6 (vw), 13.0 (w), 13.9 (m), 14.7 (vw), 14.9 (w), 15.6 (w), 16.3 (m), 17.0 (vw), 17.4 (vw), 18.0 (w), 18.7 (m), 19.3 (m), 20.0 (s), 20.5 (w), 20.8 (m), 21.2 (w, shoulder), 21.5 (m), 22.4 (m), 23.2 (s), 23.8 (m), 24.4 (vw), 25.2 (w, broad), 26.0 (w), 26.4 (vw), 27.0 (w), 27.9 (vw), 28.9 (w);
C) polymorph C exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in 2θ at 4.1 (m), 5.6 (s), 7.8 (m), 8.3 (m), 10.3 (m), 11.6 (w), 17.5 (w), 17.9 (w), 18.7 (m), 19.5 (s), 20.6 (m), 21.5 (vw), 21.9 (m), 23.1 (m), 24.0 (w), 24.8 (w);
D) polymorph D exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in 2θ at 5.0 (m), 6.5 (m), 6.8 (s), 8.7 (m), 10.0 (m), 10.2 (m), 10.8 (m), 13.1 (w), 13.5 (m), 14.3 (s), 15.3 (vw), 16.1 (m), 16.8 (w), 18.2 (w), 18.5 (m), 19.0 (w), 19.9 (m), 20.5 (m), 21.0 (vs), 21.7 (s), 22.3 (w), 23.4 (m), 24.0 (m), 25.6 (w), 26.2 (m);
E) polymorph E exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in 20 at 4.4 (vw), 5.0 (s), 6.6 (s), 6.8 (s), 8.9 (s), 10.0 (m), 10.3 (s), 10.8 (m), 13.3 (s), 13.6 (m), 14.0 (s), 15.2 (vw), 15.9 (w), 16.4 (w), 16.9 (vw), 17.8 (vw), 18.3 (m), 18.9 (w), 20.2 (vs), 20.4 (m), 20.7 (m), 20.9 (m), 21.1 (vs), 21.6 (m), 21.7 (m), 22.3 (m), 23.5 (m), 23.8 (m), 24.1 (w), 24.7 (vw), 25.4 (vw), 26.6 (m), 30.2 (w), 34.0 (vw); and
F) polymorph F exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in 2θ at 5.1 (m), 5.6 (w), 7.0 (s), 8.8 (m), 9.6 (s), 10.2 (w), 10.9 (m), 11.3 (w), 11.9 (m), 12.5 (m), 13.0 (s), 13.7 (m), 14.4 (s), 14.7 (m), 15.3 (vw), 15.5 (w), 16.8 (m), 17.6 (w), 18.3 (m), 19.3 (m), 19.7 (m), 20.6 (m), 21.2 (vs), 21.8 (s), 22.8 (s), 23.1 (w), 23.8 (w, shoulder), 24.1 (s), 24.8 (s), 25.7 (m), 26.2 (vw), 26.6 (m), 26.9 (w), 28.4 (w), 29.5 (w), 29.8 (vw), 30.9 (m); wherein, for each of said polymorphs, (vs) stands for very strong intensity; (s) stands for strong intensity; (m) stands for medium intensity; (w) stands for weak intensity; (vw) stands for very weak intensity.
40 . A crystalline polymorph A, B, C, D, E, F, or the amorphous form, of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoic acid hemicalcium salt of claim 39 , wherein
polymorph A has an X-ray powder diffraction pattern substantially as depicted in FIG. 1 , polymorph B has an X-ray powder diffraction pattern substantially as depicted in FIG. 2 , polymorph C has an X-ray powder diffraction pattern substantially as depicted in FIGS. 3A and 3B , polymorph D has an X-ray powder diffraction pattern substantially as depicted in FIG. 4 , polymorph E has an X-ray powder diffraction pattern substantially as depicted in FIG. 5 , polymorph F has an X-ray powder diffraction pattern substantially as depicted in FIG. 6 , and
the amorphous form has an X-ray powder diffraction pattern substantially as depicted in FIGS. 7A and 7B .