Crystalline forms of pitavastatin calcium

• US 8,557,993 B2
• Filed: 10/31/2012
• Issued: 10/15/2013
• Est. Priority Date: 02/12/2003
• Status: Expired due to Term

• Current Assignee: Nissan Chemical Corporation
• Original Assignee: Nissan Chemical Industries Limited (Shin-Etsu Chemical Company Limited)
• Inventors: Van der Schaaf, Paul Adriaan, Blatter, Fritz, Szelagiewicz, Martin, Schoening, Kai-Uwe
• Primary Examiner(s): Seaman, D M
• Application Number:
  US13/664,498
• Publication Number:
  US 20130053413A1
• Time in Patent Office: 349 Days
• Field of Search: 546/101
• US Class Current: 546/101
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 215/14 Radicals substituted by oxygen atoms

Abstract

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 forms.

Claims

1. A crystalline polymorph A, B, C, D, E, F, or the amorphous form, of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenye)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic 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 2θ

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.

2. A process for preparing the crystalline polymorph or amorphous form according to claim 1, wherein:

the crystalline polymorph or amorphous form being prepared is the crystalline polymorph A; and

the process comprises reacting (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid sodium salt with CaCl² in an aqueous reaction medium.

3. A process for preparing the crystalline polymorph or amorphous form according to claim 1, wherein:

the crystalline polymorph or amorphous form being prepared is the crystalline polymorph B; and

the process comprises suspending the crystalline polymorph A in ethanol containing water as a cosolvent.

4. The process according to claim 3, wherein the water is present in an amount of 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)-heptenoic acid hemicalcium salt.

5. A process for preparing the crystalline polymorph or amorphous form according to claim 1, wherein:

the crystalline polymorph or amorphous form being prepared is the crystalline polymorph C; and

the process comprises suspending the crystalline polymorph A the process comprises suspending the crystalline polymorph A in isopropanol containing water as a cosolvent.

6. The process according to claim 5, wherein the water is present in an amount of 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)-heptenoic acid hemicalcium salt.

7. A process for preparing the crystalline polymorph or amorphous form according to claim 1, wherein:

the crystalline polymorph or amorphous form being prepared is the crystalline polymorph C; and

the process comprises suspending the crystalline polymorph A in a mixture of isopropanol and a ketone solvent, containing water as a cosolvent.

8. The process according to claim 7, wherein the ketone solvent is acetone.

9. The process according to claim 7, wherein the ketone solvent is present in an amount of 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)-heptenoic acid hemicalcium salt.

10. The process according to claim 7, wherein the water is present in an amount of 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)-heptenoic acid hemicalcium salt.

11. A process for preparing the crystalline polymorph or amorphous form according to claim 1, wherein:

the crystalline polymorph or amorphous form being prepared is the crystalline polymorph D; and

the process comprises suspending the crystalline polymorph A in absolute ethanol.

12. A process for preparing the crystalline polymorph or amorphous form according to claim 1, wherein:

the crystalline polymorph or amorphous form being prepared is the crystalline polymorph E; and

the process comprises suspending the crystalline polymorph A in 1,4-dioxane containing water as a cosolvent.

13. The process according to claim 12, wherein the water is present in the amount of 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)-heptenoic acid hemicalcium salt.

14. A process for perparing the crystalline polymorph or amorphous form according to claim 1, wherein:

the crystalline polymorph or amorphous form being prepared is the crystalline polymorph E; and

the process comprises suspending the crystalline polymorph A in methanol containing water as a cosolvent.

15. The process according to claim 14, wherein the water is present in an amount of 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)-heptenoic acid hemicalcium salt.

16. The process according to claim 2, wherein (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt is isolated by filtration and dried in air or vacuum.

17. The process according to claim 2, wherein seeding is carried out with crystals of the desired crystalline polymorph.

18. A process preparing the crystalline polymorph or amorphous form according claim 1, wherein:

the crystalline polymorph or amorphous form being prepared is the amorphous form; and

the process comprises adding a non-solvent to a solution of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt in an organic solvent.

19. The process according to claim 18, wherein the non-solvent is selected from heptane and methyl tert-butyl ether.

20. The process according to claim 18, wherein the organic solvent is selected from 1,4-dioxane, tetrahydrofuran and ethyl methyl ketone.

21. A process for preparing the crystalline polymorph or amorphous form according claim 1, wherein:

the crystalline polymorph or amorphous form being prepared is the amorphous form; and

the process comprises drying an aqueous solution of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt by lyophilization.

22. A pharmaceutical composition comprising an effective amount of the crystalline polymorph or amorphous form according to claim 1, and a pharmaceutically acceptable carrier.

23. A crystalline polymorph A, B, C, D, E, F, or the amorphous form, of (3 R,5 S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3 -yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt of claim 1, 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.

38. A process for preparing the crystalline polymorph or amorphous form according to claim 1, wherein:

the crystalline polymorph or amorphous form being prepared is the crystalline polymorph F; and

the process comprises suspending the crystalline polymorph A in methanol containing water as a cosolvent.

39. The process according to claim 38, wherein the water is present in an amount of 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)-heptenoic acid hemicalcium salt.

24. A crystalline polymorph A of (3R,5S)-7[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt, which 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), and 34.0 (w), wherein (vs) stands for very strong intensity, (s) stands for strong intensity, (m) stands for medium intensity, (w) stands for weak intensity, and (vw) stands for very weak intensity.

25. A crystalline polymorph A of (3R,5S)-7[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt, having an X-ray powder diffraction pattern substantially as depicted in FIG. 1.

26. A crystalline polymorph B of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt, which 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), and 28.9 (w), wherein (vs) stands for very strong intensity, (s) stands for strong intensity, (m) stands for medium intensity, (w) stands for weak intensity, and (vw) stands for very weak intensity.

27. A crystalline polymorph B of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt, having an X-ray powder diffraction pattern substantially as depicted in FIG. 2.

28. A crystalline polymorph C of (3R,5S)-7[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt, which 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), and 24.8 (w), wherein (vs) stands for very strong intensity, (s) stands for strong intensity, (m) stands for medium intensity, (w) stands for weak intensity, and (vw) stands for very weak intensity.

29. A crystalline polymorph C of (3R,5S)-7[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt, having an X-ray powder diffraction pattern substantially as depicted in FIGS. 3A and 3B.

30. A crystalline polymorph D of (3R,5S)-7[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt, which 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), and 26.2 (m), wherein (vs) stands for very strong intensity, (s) stands for strong intensity, (m) stands for medium intensity, (w) stands for weak intensity, and (vw) stands for very weak intensity.

31. A crystalline polymorph D of (3R,5S)-7[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt, having an X-ray powder diffraction pattern substantially as depicted in FIG. 4.

32. A crystalline polymorph E of (3R,5S)-7[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in 2θ

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), and 34.0 (vw), wherein (vs) stands for very strong intensity, (s) stands for strong intensity, (m) stands for medium intensity, (w) stands for weak intensity, and (vw) stands for very weak intensity.

33. A crystalline polymorph E of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt, having an X-ray powder diffraction pattern substantially as depicted in FIG. 5.

34. A crystalline polymorph F of (3R,5S)-7[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt, which 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), and 30.9 (m), wherein (vs) stands for very strong intensity, (s) stands for strong intensity, (m) stands for medium intensity, (w) stands for weak intensity, and (vw) stands for very weak intensity.

35. A crystalline polymorph F of (3R,5S)-7[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt, having an X-ray powder diffraction pattern substantially as depicted in FIG. 6.

36. The amorphous form of (3R,5S)-7[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt.

37. The amorphous form of (3R,5S)-7[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt, having an X-ray powder diffraction pattern substantially as depicted in FIGS. 7A and 7B.