Crystalline Lorlatinib : fumaric acid and solid state form thereof
The present disclosure relates to crystalline Lorlatinib:Fumaric acid, solid state forms thereof, processes for preparation thereof, pharmaceutical compositions and methods of use thereof.
1. Anhydrous Crystalline Lorlatinib:Fumaric acid which is a co-crystal.
2. Crystalline Lorlatinib:Fumaric acid according to claim 1 , wherein the molar ratio between Lorlatinib and fumaric acid is between 2:1.5 and 1.5:1.
3. A crystalline product according to claim 1 , designated Form A, which is characterized by data selected from one or more of the following:
(a) an XRPD pattern having peaks at 8.0, 11.6, 13.5, 17.1 and 18.2 degrees 2-theta±0.2 degrees 2-theta;
(b) an XRPD pattern as depicted in FIG. 1 ;
(c) a solid-state 13C NMR spectrum with signals at 170.4, 152.0, 141.3, 119.0 and 74.1 ppm±0.2 ppm;
(d) a solid state 13C NMR spectrum having the following chemical shift absolute differences from a peak at 23.6 ppm±2 ppm of 146.8, 128.4, 117.7, 95.4 and 50.5 ppm±0.1 ppm;
(e) a solid-state 13C NMR spectrum as depicted in FIG. 3 or 4 or 5 ; or
(f) combinations of these data.
4. A crystalline product according to claim 1 , designated Form A, characterized by an XRPD pattern having peaks at 8.0, 11.6, 13.5, 17.1 and 18.2 degrees 2-theta±0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks selected from 13.1, 14.4, 15.7, 19.6 and 24.1 degrees two theta±0.2 degrees two theta.
5. A crystalline product according to claim 1 , designated Form A, characterized by an XRPD pattern having peaks at 8.0, 11.6, 13.1, 13.5, 14.4, 15.7, 17.1 18.2, 19.6 and 24.1 degrees 2-theta±0.2 degrees 2-theta.
6. A crystalline product according to claim 1 containing not more than about 1% (w/w) or not more than about 0.5% (w/w) of water or organic solvent.
7. A crystalline product according to claim 1 , which contains: no more than about 20% (w/w) of any other crystalline forms of Lorlatinib:Fumaric acid.
8. A crystalline product according to claim 1 , which contains no more than about 20% (w/w) of amorphous Lorlatinib:Fumaric acid.
9. A medicament comprising the crystalline product according to claim 1 .
10. A pharmaceutical composition comprising a crystalline product according to claim 1 , and at least one pharmaceutically acceptable excipient.
11. A process for preparing a pharmaceutical composition, comprising combining a crystalline product according to claim 1 with at least one pharmaceutically acceptable excipient.
12. A process for the preparation of a crystalline product according to claim 1 comprising:
(a) preparing a mixture comprising Lorlatinib and fumaric acid in water;
(b) optionally stirring;
(c) optionally cooling;
(d) optionally isolating crystalline Lorlatinib:Fumaric acid from the mixture;
(e) optionally washing and drying; and
(f) obtaining a crystalline product according to claim 1 .
13. A process according to claim 12 , wherein step (a) comprises providing a mixture containing Lorlatinib Form 2 and fumaric acid in water, under heating.
14. A process according to claim 13 , wherein the mixture in step (a) has a mol ratio of Lorlatinib to fumaric acid of: 1:1.4 to about 1:0.5.
15. A process according to claim 12 , wherein the crystalline product obtained is crystalline Lorlatinib:Fumaric acid Form A and the process further comprises a step of combining the crystalline Lorlatinib:Fumaric acid Form A with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.
16. A method of treating cancer comprising administering a therapeutically effective amount of a crystalline product according to claim 1 , to a subject in need of the treatment.