Details for Patent: 8,853,405

Title:	Crystalline forms of pitavastatin calcium
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.
Inventor(s):	Van Der Schaaf; Paul Adriaan (Hagenthal-le-Haut, FR), Blatter; Fritz (Reinach, CH), Szelagiewicz; Martin (Muenchenstein, CH), Schoening; Kai-Uwe (Oberwil, CH)
Assignee:	Nissan Chemical Industries Ltd. (Tokyo, JP)
Filing Date:	Sep 03, 2013
Application Number:	14/016,399
Claims:	1. A process for preparing 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 2.theta. 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, the process comprising: reacting (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6- (E)-heptenoic acid sodium salt with CaCl.sub.2 in an aqueous reaction medium or reacting the free acid (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6- (E)-heptenoic acid or the corresponding lactone (4R,6S)-6-{(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-vinyl}-4- -hydroxy-tetrahydropyran-2-one with Ca(OH).sub.2; isolating the crystalline polymorph A; and exposing the isolated crystalline polymorph A to an atmosphere with a relative air humidity of 5 to 100%. 2. The process of claim 1, wherein exposing the isolated crystalline polymorph A to the atmosphere with the relative air humidity of 5 to 100%, comprises exposing the isolated crystalline polymorph A to an inert gas stream with a relative air humidity of 5 to 100%. 3. The process of claim 1, wherein the atmosphere has a relative air humidity of 40 to 80%. 4. A process for preparing 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 2.theta. 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, the process comprising: suspending a crystalline polymorph A of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydrox- y-6(E)-heptenoic acid hemicalcium salt in ethanol containing water as a cosolvent; isolating the crystalline polymorph B; and exposing the isolated crystalline polymorph B to an atmosphere with a relative air humidity of 5 to 100%; wherein the crystalline polymorph A exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in 2.theta. 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. 5. The process of claim 4, wherein exposing the isolated crystalline polymorph B to the atmosphere with the relative air humidity of 5 to 100%, comprises exposing the isolated crystalline polymorph B to an inert gas stream with a relative air humidity of 5 to 100%. 6. The process of claim 4, wherein the atmosphere has a relative air humidity of 40 to 80%. 7. A process for preparing 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 2.theta. 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, the process comprising: suspending a crystalline polymorph A of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydrox- y-6(E)-heptenoic acid hemicalcium salt in isopropanol containing water as a cosolvent; isolating the crystalline polymorph C; and exposing the isolated crystalline polymorph C to an atmosphere with a relative air humidity of 5 to 100%; wherein the crystalline polymorph A exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in 2.theta. 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. 8. The process of claim 7, wherein exposing the isolated crystalline polymorph C to the atmosphere with the relative air humidity of 5 to 100%, comprises exposing the isolated crystalline polymorph C to an inert gas stream with a relative air humidity of 5 to 100%. 9. The process of claim 7, wherein the atmosphere has a relative air humidity of 40 to 80%. 10. A process for preparing 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 2.theta. 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, the process comprising: suspending a crystalline polymorph A of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydrox- y-6(E)-heptenoic acid hemicalcium salt in a mixture of isopropanol and a ketone solvent, containing water as a cosolvent; isolating the crystalline polymorph C; and exposing the isolated crystalline polymorph C to an atmosphere with a relative air humidity of 5 to 100%; wherein the crystalline polymorph A exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in 2.theta. 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. 11. The process of claim 10, wherein exposing the isolated crystalline polymorph C to the atmosphere with the relative air humidity of 5 to 100%, comprises exposing the isolated crystalline polymorph C to an inert gas stream with a relative air humidity of 5 to 100%. 12. The process of claim 10, wherein the atmosphere has a relative air humidity of 40 to 80%. 13. A process for preparing 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 2.theta. 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, the process comprising: suspending 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 in absolute ethanol; isolating the crystalline polymorph D; and exposing the isolated crystalline polymorph D to an atmosphere with a relative air humidity of 5 to 100%; wherein the crystalline polymorph A exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in 2.theta. 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. 14. The process of claim 13, wherein exposing the isolated crystalline polymorph D to the atmosphere with the relative air humidity of 5 to 100%, comprises exposing the isolated crystalline polymorph D to an inert gas stream with a relative air humidity of 5 to 100%. 15. The process of claim 13, wherein the atmosphere has a relative air humidity of 40 to 80%. 16. A process for preparing 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 2.theta. 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, the process comprising: suspending 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 in 1,4-dioxane containing water as a cosolvent; isolating the crystalline polymorph E; and exposing the isolated crystalline polymorph E to an atmosphere with a relative air humidity of 5 to 100%; wherein the crystalline polymorph A exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in 2.theta. 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. 17. The process of claim 16, wherein exposing the isolated crystalline polymorph E to the atmosphere with the relative air humidity of 5 to 100%, comprises exposing the isolated crystalline polymorph E to an inert gas stream with a relative air humidity of 5 to 100%. 18. The process of claim 16, wherein the atmosphere has a relative air humidity of 40 to 80%. 19. A process for preparing 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 2.theta. 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, the process comprising: suspending 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 in methanol containing water as a cosolvent; isolating the crystalline polymorph E; and exposing the isolated crystalline polymorph E to an atmosphere with a relative air humidity of 5 to 100%; wherein the crystalline polymorph A exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in 2.theta. 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. 20. The process of claim 19, wherein exposing the isolated crystalline polymorph E to the atmosphere with the relative air humidity of 5 to 100%, comprises exposing the isolated crystalline polymorph E to an inert gas stream with a relative air humidity of 5 to 100%. 21. The process of claim 19, wherein the atmosphere has a relative air humidity of 40 to 80%. 22. A process for preparing 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 2.theta. 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, the process comprising: suspending the crystalline polymorph A of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydrox- y-6(E)-heptenoic acid hemicalcium salt in methanol containing water as a cosolvent; isolating the crystalline polymorph F; and exposing the isolated crystalline polymorph F to an atmosphere with a relative air humidity of 5 to 100%; wherein the crystalline polymorph A exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in 2.theta. 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. 23. The process of claim 22, wherein exposing the isolated crystalline polymorph F to the atmosphere with the relative air humidity of 5 to 100%, comprises exposing the isolated crystalline polymorph F to an inert gas stream with a relative air humidity of 5 to 100%. 24. The process of claim 22, wherein the atmosphere has a relative air humidity of 40 to 80%. 25. A process for preparing the amorphous form of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6- (E)-heptenoic acid hemicalcium salt, the process comprising: 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; isolating the amorphous form; and exposing the isolated amorphous form to an atmosphere with a relative air humidity of 5 to 100%. 26. The process of claim 25, wherein exposing the isolated amorphous form to the atmosphere with the relative air humidity of 5 to 100%, comprises exposing the isolated amorphous form to an inert gas stream with a relative air humidity of 5 to 100%. 27. The process of claim 25, wherein the atmosphere has a relative air humidity of 40 to 80%. 28. A process for preparing the amorphous form of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6- (E)-heptenoic acid hemicalcium salt, the process comprising: 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; isolating the amorphous form; and exposing the isolated amorphous form to an atmosphere with a relative air humidity of 5 to 100%. 29. The process of claim 28, wherein exposing the isolated amorphous form to the atmosphere with the relative air humidity of 5 to 100%, comprises exposing the isolated amorphous form to an inert gas stream with a relative air humidity of 5 to 100%. 30. The process of claim 28, wherein the atmosphere has a relative air humidity of 40 to 80%.