Forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid magnesium
View Patent ↗Novel forms of atorvastatin magnesium salt designated Form A, Form B, Form C, Form D, Form E, and Form F, pharmaceutical compositions containing such compounds, methods for their preparation and methods utilizing the compounds for treatment of hyperlipidemia, hypercholesterolemia, osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer's disease are described.
1. A Form B atorvastatin magnesium having an X-ray powder diffraction containing the following 2θ values measured using CuK a radiation: 6.1, 8.0, 10.9, 19.8, and 23.0.
2. A Form B atorvastatin magnesium having a solid state NMR shift selected from the group consisting of:
A) a 13 C shift containing values: 118.3, 125.4, 126.8, 132.2, and 133.8 ppm; and
B) an 19 F shift containing value: −115.7 ppm.
3. A Form C atorvastatin magnesium having an X-ray diffraction containing the following 2θ values measured using CuK a radiation: 5.2, 6.6, and 12.3.
4. A Form C atorvastatin magnesium having a solid state NMR shift selected from the group consisting of:
A) a 13 C shift containing the values: 129.2, 133.3, and 139.1 ppm; and
B) an 19 F shift containing the values: −109.6, and −113.0 ppm.
5. A Form D atorvastatin magnesium having an X-ray diffraction containing the following 2θ values measured using CuK a radiation: 7.7, 20.5, and 24.2.
6. A Form D atorvastatin magnesium having a solid state NMR shift selected from the group consisting of:
A) a 13 C shift containing the values: 132.6, 134.4, 136.9, and 138.6 ppm; and
B) an 19 F shift containing the values: −110.0, −111.7, −114.7, and −119.8 ppm.
7. A Form F atorvastatin magnesium having an X-ray diffraction containing the following 2θ values measured using CuK a radiation: 8.7, 10.1, 11.7, and 16.1.
8. A Form F atorvastatin magnesium having a solid state NMR shift selected from the group consisting of:
A) a 13 C shift containing the values: 128.5, 130.4, and 138.2 ppm; and
B) an 19 F shift containing the values: −114.7, −118.8, −119.8, and −122.3 ppm.
9. A pharmaceutical composition comprising atorvastatin magnesium selected from the group consisting of Form B, Form C, Form D, and Form F; and at least one pharmaceutically acceptable excipient, diluent, or carrier.
10. A Form B atorvastatin magnesium having an X-ray powder diffraction containing the following 2θ values measured using CuK a radiation: 5.3, 6.1, 8.0, 9.1, 10.5, 10.9, 13.2, 13.9, 15.6, 16.1, 16.7, 17.2, 18.1, 18.4, 19.8, 20.7, 21.2, 21.8, 23.0, 24.1, 24.8, 25.6, 27.3, and 29.1.
11. A Form B atorvastatin magnesium having a solid state NMR spectrum containing the following 13 C chemical shift values: 19.5, 22.1, 24.3, 24.9, 26.9, 27.1, 41.0, 41.6, 43.3, 45.6, 71.0, 72.9, 115.8, 118.3, 119.7, 120.9, 122.9, 125.4, 126.8, 129.6, 132.2, 133.8, 136.1, 139.3, 161.7, 163.6, 166.0, 178.7, 180.4, and 183.5 ppm.
12. A Form B atorvastatin magnesium having a solid state NMR spectrum containing the following 13 C chemical shift values: 118.3, 125.4, 126.8, 132.2, and 133.8 ppm.
13. A Form B atorvastatin magnesium having a solid state NMR spectrum containing the following 19 F chemical shift values: −115.7 ppm.
14. A Form C atorvastatin magnesium having an X-ray powder diffraction containing the following 2θ values measured using CuK a radiation: 5.2, 6.6, 8.7, 9.8, 11.6, 12.3, 13.5, 14.6, 16.2, 18.7, 19.9, and 23.2.
15. A Form C atorvastatin magnesium having a solid state NMR spectrum containing the following 13 C chemical shift values: 22.4, 26.6, 42.4, 43.1, 67.6, 71.1, 116.0, 117.8, 119.7, 123.1, 126.3, 129.2, 133.3, 135.3, 139.1, 141.2, 161.5, 163.3, 167.6, 179.9, and 180.6 ppm.
16. A Form C atorvastatin magnesium having a solid state NMR spectrum containing the following 13 C chemical shift values: 129.2, 133.3, and 139.1 ppm.
17. A Form C atorvastatin magnesium having a solid state NMR spectrum containing the following 19 F chemical shift values: −109.6, and −113.0 ppm.
18. A Form D atorvastatin magnesium having an X-ray powder diffraction containing the following 2θ values measured using CuK a radiation: 7.7, 8.8, 10.2, 11.9, 13.8, 15.9, 17.3, 18.7, 20.5, 24.2, 26.7, and 30.6.
19. A Form D atorvastatin magnesium having a solid state NMR spectrum containing the following 13 C chemical shift values: 19.1, 20.9, 21.5, 22.9, 23.7, 24.6, 26.8, 27.2, 37.6, 39.7, 41.4, 43.2, 44.2, 45.6, 46.5, 66.6, 67.4, 69.3, 70.4, 71.5, 114.3, 115.2, 117.1, 121.0, 123.2, 124.1, 126.4, 128.3, 129.4, 130.5, 131.5, 132.6, 134.4, 135.0, 136.4, 136.9, 138.6, 141.3, 160.8, 161.4, 162.7, 163.4, 165.9, 176.5, 179.9, 182.4, and 183.1 ppm.
20. A Form D atorvastatin magnesium having a solid state NMR spectrum containing the following 13 C chemical shift values: 132.6, 134.4, 136.9, and 138.6 ppm.
21. A Form D atorvastatin magnesium having a solid state NMR spectrum containing the following 19 F chemical shift values: −110.0, −111.7, −114.7, and −119.8 ppm.
22. A Form F atorvastatin magnesium having an X-ray powder diffraction containing the following 2θ values measured using CuK a radiation: 8.7, 10.1, 11.7, 12.7, 14.7, 16.1, 17.5, 18.5, 20.4, 21.4, 23.7, 26.8, and 30.4.
23. A Form F atorvastatin magnesium having a solid state NMR spectrum containing the following 13 C chemical shift values: 19.4, 23.1, 23.4, 27.0, 39.3, 40.0, 43.2, 45.6, 46.4, 66.4, 67.4, 69.1, 114.2, 115.1, 117.4, 121.0, 124.0, 128.5, 129.4, 130.4, 131.4, 135.1, 136.3, 138.2, 160.7, 161.1, 162.6, 162.9, 166.0, 180.0, and 182.6 ppm.
24. A Form F atorvastatin magnesium having a solid state NMR spectrum containing the following 13 C chemical shift values: 128.5, 130.4, and 138.2 ppm.
25. A Form F atorvastatin magnesium having a solid state NMR spectrum containing the following 19 F chemical shift values: −114.7, −118.8, −119.8, and −122.3 ppm.