Crystalline forms of lorlatinib maleate
This invention relates to new crystalline forms 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) maleate. The invention also relates to pharmaceutical compositions comprising lorlatinib maleate, and to methods of using lorlatinib maleate and compositions comprising it in the treatment of abnormal cell growth, such as cancer, in mammals.
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) maleate hydrate, having a powder X-ray diffraction (PXRD) pattern comprising two or more peaks at 2θ values selected from the group consisting of: 10.6, 12.7, 16.2, 18.5 and 27.8 °2θ±0.2 °2θ.
2. The crystalline form of claim 1 , having a PXRD pattern comprising peaks at 2θ values of: 10.6, 18.5 and 27.8 °2θ±0.2 °2θ.
3. The crystalline form of claim 2 , having a PXRD pattern further comprising a peak at the 2θ value of: 12.7 °2θ±0.2 °2θ.
4. The crystalline form of claim 2 , having a PXRD pattern further comprising a peak at the 2θ value of: 16.2 °2θ±0.2 °2θ.
5. The crystalline form of claim 1 , having a Raman spectrum comprising wavenumber (cm −1 ) values of: 808, 1553, 1672 and 2233 cm −1 ±2 cm −1 .
6. The crystalline form of claim 1 , having a 13 C solid state NMR spectrum comprising resonance (ppm) value of: 136.1 ppm±0.2 ppm.
7. The crystalline form of claim 1 , having a 19 F solid state NMR spectrum comprising resonance (ppm) value of: −110.1 ppm±0.2 ppm.
8. A crystalline form of lorlatinib maleate hydrate, having a Raman spectrum comprising two or more wavenumber (cm −1 ) values selected from the group consisting of: 808, 1307, 1553, 1571, 1672 and 2233 cm −1 ±2 cm −1 .
9. The crystalline form of claim 8 , having a Raman spectrum comprising wavenumber (cm −1 ) values of: 808, 1553, 1672 and 2233 cm −1 ±2 cm −1 .
10. The crystalline form of claim 9 , having a Raman spectrum further comprising the wavenumber (cm −1 ) value of: 1307 cm −1 ±2 cm −1 .
11. The crystalline form of claim 9 or 10 , having a Raman spectrum further comprising the wavenumber (cm −1 ) value of: 1571 cm −1 ±2 cm −1 .
12. The crystalline form of claim 8 , having a 13 C solid state NMR spectrum comprising resonance (ppm) value of: 136.1 ppm±0.2 ppm.
13. The crystalline form of claim 8 , having a 19 F solid state NMR spectrum comprising a resonance (ppm) value of: −110.1 ppm±0.2 ppm.
14. A crystalline form of lorlatinib maleate hydrate, having a 13 C solid state NMR spectrum comprising two or more resonance (ppm) values selected from the group consisting of: 48.7, 116.0, 131.3 and 136.1 ppm±0.2 ppm.
15. The crystalline form of claim 14 , having a 13 C solid state NMR spectrum comprising resonance (ppm) values of: 131.3 and 136.1 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: 48.7 ppm±0.2 ppm.
17. The crystalline form of claim 15 , having a 13 C solid state NMR spectrum further comprising the resonance (ppm) value of: 116.0 ppm±0.2 ppm.
18. A crystalline form of lorlatinib maleate hydrate, having a 19 F solid state NMR spectrum comprising a resonance (ppm) value of: −110.1 ppm±0.2 ppm.
19. The crystalline form of claim 18 , having a PXRD pattern comprising peaks at 2θ values of: 10.6, 18.5 and 27.8 °2θ±0.2 °2θ.
20. The crystalline form of claim 18 , having a Raman spectrum comprising wavenumber (cm −1 ) values of: 808, 1553, 1672 and 2233 cm −1 ±2 cm −1 .
21. A pharmaceutical composition comprising the crystalline form of lorlatinib maleate hydrate according to claim 1 , and a pharmaceutically acceptable carrier or excipient.