Crystalline form of lorlatinib free base
This invention relates to a crystalline form of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-5-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h] [2,5,11]benzoxadiazacyclo-tetradecine-3-carbonitrile (lorlatinib) free base (Form 7). This invention also relates to pharmaceutical compositions comprising Form 7, and to methods of using Form 7 and such compositions in the treatment of abnormal cell growth, such as cancer, in a mammal.
1. A crystalline form of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile (lorlatinib) free base, having a powder X-ray diffraction (PXRD) pattern comprising peaks at 2θ values of: 9.6, 10.1 and 16.2 °2θ±0.2 °2θ.
2. The crystalline form of claim 1 , having a PXRD pattern further comprising a peak at the 2θ value of: 17.3 °2θ±0.2 °2θ.
3. The crystalline form of claim 2 , having a PXRD pattern further comprising a peak at the 2θ value of: 14.3 °2θ±0.2 °2θ.
4. The crystalline form of claim 1 , having a Raman spectrum comprising wavenumber (cm −1 ) values of: 2229 and 2240 cm −1 ±2 cm −1 .
5. The crystalline form of claim 1 , having a 13 C solid state NMR spectrum comprising resonance (ppm) values of: 39.1 and 142.1 ppm±0.2 ppm.
6. The crystalline form of claim 1 , having a 19 F solid state NMR spectrum comprising resonance (ppm) values of: −108.2 and −115.2 ppm±0.2 ppm.
7. A crystalline form of lorlatinib free base, having a Raman spectrum comprising wavenumber (cm −1 ) values of: 2229 and 2240 cm −1 ±2 cm −1 .
8. The crystalline form of claim 7 , having a Raman spectrum further comprising the wavenumber (cm −1 ) value of: 1619 cm −1 ±2 cm −1 .
9. The crystalline form of claim 8 , having a Raman spectrum further comprising the wavenumber (cm −1 ) value of: 1553 cm −1 ±2 cm −1 .
10. The crystalline form of claim 9 , having a Raman spectrum further comprising the wavenumber (cm −1 ) value of: 774 cm −1 ±2 cm −1 .
11. The crystalline form of claim 7 , having a 13 C solid state NMR spectrum comprising resonance (ppm) values of: 39.1 and 142.1 ppm±0.2 ppm.
12. The crystalline form of claim 7 , having a 19 F solid state NMR spectrum comprising resonance (ppm) values of: −108.2 and −115.2 ppm±0.2 ppm.
13. A crystalline form of lorlatinib free base, having a 13 C solid state NMR spectrum comprising two or more resonance (ppm) values of: 39.1 and 142.1 ppm±0.2 ppm.
14. The crystalline form of claim 13 , having a 13 C solid state NMR spectrum further comprising the resonance (ppm) value of: 112.3 ppm±0.2 ppm.
15. The crystalline form of claim 14 , having a 13 C solid state NMR spectrum further comprising the resonance (ppm) value of: 25.8 ppm±0.2 ppm.
16. The crystalline form of claim 15 , having a 13 C solid state NMR spectrum further comprising the resonance (ppm) value of: 117.7 ppm±0.2 ppm.
17. A crystalline form of lorlatinib free base, having a 19 F solid state NMR spectrum comprising a resonance (ppm) value selected from the group consisting of: −108.2 and −115.2 ppm±0.2 ppm.
18. A pharmaceutical composition comprising the crystalline form of lorlatinib free base according to claim 1 , and a pharmaceutically acceptable carrier or excipient.
19. A method of treating abnormal cell growth in a mammal comprising administering to the mammal a therapeutically effective amount of the crystalline form of lorlatinib free base according to claim 1 , wherein the abnormal cell growth is cancer mediated by anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 receptor tyrosine kinase (ROS1).
20. The method of claim 19 , wherein the cancer is non-small cell lung cancer (NSCLC).