Crystalline form of lorlatinib free base hydrate
This invention relates to 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]benzoxadiazacyclo-tetradecine-3-carbonitrile (lorlatinib) free base hydrate (Form 24 ). This invention also relates to pharmaceutical compositions comprising Form 24 , and to methods of using Form 24 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 hydrate, having a powder X-ray diffraction (PXRD) pattern comprising peaks at 2θ values of: 8.8, 9.7, 17.6 and 18.8 °2θ±0.2 °2θ.
2. The crystalline form of claim 1 , having a PXRD pattern further comprising a peak at the 2θ value of: 10.9 °20±0.2 °2θ.
3. The crystalline form of claim 1 , having a 13 C solid state NMR spectrum comprising resonance (ppm) values of: 40.2, 41.2 and 136.2 ppm±0.2 ppm.
4. The crystalline form of claim 1 , having a 19 F solid state NMR spectrum comprising a resonance (ppm) value of: −104.0 ppm±0.2 ppm.
5. The crystalline form of lorlatinib free base hydrate of claim 1 , for use as a medicament for treating cancer in a mammal, wherein the cancer is selected from the group consisting of ALK-positive non-small cell lung cancer (NSCLC) mediated by anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 receptor tyrosine kinase (ROS1), ALK-positive anaplastic large cell lymphoma (ALCL), and ALK-positive neuroblastoma.
6. The crystalline form of lorlatinib free base hydrate of claim 1 , for use in the treatment of cancer in a mammal, wherein the cancer is selected from the group consisting of ALK-positive non-small cell lung cancer (NSCLC) mediated by anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 receptor tyrosine kinase (ROS1), ALK-positive anaplastic large cell lymphoma (ALCL), and ALK-positive neuroblastoma.
7. A pharmaceutical composition comprising the crystalline form of lorlatinib free base hydrate of claim 1 , and a pharmaceutically acceptable carrier or excipient.
8. A method of treating cancer in a mammal comprising administering to the mammal a therapeutically effective amount of the crystalline form of lorlatinib free base hydrate of claim 1 , wherein the cancer is selected from the group consisting of ALK-positive non-small cell lung cancer (NSCLC) mediated by anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 receptor tyrosine kinase (ROS1), ALK-positive anaplastic large cell lymphoma (ALCL), and ALK-positive neuroblastoma.
9. A crystalline form of lorlatinib free base hydrate, having a 13 C solid state NMR spectrum comprising two or more resonance (ppm) values of: 40.2, 41.2 and 136.2 ppm±0.2 ppm.
10. The crystalline form of claim 9 , having a 13 C solid state NMR spectrum further comprising the resonance (ppm) value of: 128.1 ppm±0.2 ppm.
11. The crystalline form of claim 9 , having a 13 C solid state NMR spectrum further comprising the resonance (ppm) value of: 145.3 ppm±0.2 ppm.
12. The crystalline form of claim 9 , having a 19 F solid state NMR spectrum comprising a resonance (ppm) value of: −104.0 ppm±0.2 ppm.
13. A crystalline form of lorlatinib free base hydrate, having a 19 F solid state NMR spectrum comprising a resonance (ppm) value of: −104.0 ppm±0.2 ppm.