Process for manufacture of (S)-N-(3-((2-((4-((1-acetylpyrrolidin-3-yl)(methyl)amino)phenyl)amino)-5-methoxypyrimidin-4-yl)oxy)phenyl)acrylamide, and formulations thereof
The invention relates to solid forms of certain N-(pyrimidinyloxy)acrylamide derivatives that are useful in the treatment of proliferation and immunological disorders and other diseases related to the dysregulation of kinases including EGFR (including HER), Alk, PDGFR, BLK, BMX/ETK, BTK, FLT3 (D835Y), ITK, JAK1, JAK2, JAK3, TEC and TXK. The invention provides methods of making these materials and their salts and polymorphs, and intermediates for preparing these materials, as well as pharmaceutical compositions comprising these materials. The solid forms and pharmaceutical compositions comprising them are useful to treat conditions including a proliferation disorder, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eye, rheumatoid arthritis, or lupus.
1. A solid form of a L-(+)-tartrate salt of Compound A:
wherein the solid form is crystalline having an X-ray powder diffraction pattern which comprises at least two peaks selected from: about 5.7°, about 9.8°, about 11.6°, about 14.7°, about 15.4°, about 16.1°, about 17.1°, about 19.3°, about 23.9°, about 24.5°, and about 25.4°, in terms of 2-theta.
2. The solid form of claim 1 , which is a 1:1 salt of Compound A and L-(+)-tartaric acid.
3. The solid form of claim 1 , which is a hydrate of the L-(+)-tartrate salt of Compound A.
4. The solid form of claim 3 , which is a dihydrate.
5. The solid form of claim 1 , wherein the X-ray powder diffraction pattern comprises at least three peaks, wherein the peaks are selected from: about 5.7°, about 9.8°, about 11.6°, about 14.7°, about 15.4°, about 16.1°, about 17.1°, about 19.3°, about 23.9°, about 24.5°, and about 25.4° in terms of 2-theta.
6. The solid form of claim 1 , having a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 74° C. or a thermogravimetric analysis (TGA) substantially as shown in FIG. 7 .
7. A pharmaceutical composition comprising the solid form of a L-(+)-tartrate salt of Compound A according to claim 1 and at least one pharmaceutically acceptable excipient.
8. The pharmaceutical composition of claim 7 , which comprises at least two pharmaceutically acceptable excipients.
9. The pharmaceutical composition of claim 7 , wherein the at least one pharmaceutically acceptable excipient is selected from a filler, a disintegrant, a glidant, an adhesive, a lubricant, and an antioxidant.
10. A dosage unit comprising a solid form of a L-(+)-tartrate salt of Compound A according to claim 1 , in an amount equivalent to a weight of the free base of Compound A, selected from 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, and 400 mg.
11. The dosage unit of claim 10 , which is a tablet or a capsule.
12. The dosage unit of claim 10 , which comprises at least one pharmaceutically acceptable excipient selected from silicified microcrystallinecellulose 50, silicified microcrystallinecellulose 90, pregelatinized starch, mannitol, croscarmellose sodium, povidone, and sodium stearyl fumarate.
13. The dosage unit of claim 10 , which comprises an antioxidant.
14. A packaged pharmaceutical product, which comprises a pharmaceutical composition comprising a solid form of a L-(+)-tartrate salt of Compound A
wherein the solid form is crystalline having an X-ray powder diffraction pattern which comprises at least two peaks selected from: about 5.7°, about 9.8°, about 11.6°, about 14.7°, about 15.4°, about 16.1°, about 17.1°, about 19.3°, about 23.9°, about 24.5°, and about 25.4°, in terms of 2-theta, and a protective agent as two separate materials in a closed container.
15. A method to prepare a pharmaceutical composition according to claim 7 , which comprises combining the solid form of a L-(+)-tartrate salt of Compound A with at least one pharmaceutically acceptable excipient.
16. A pharmaceutical composition comprising a solid form of a L-(+)-tartrate salt of Compound A:
wherein the solid form is crystalline having an X-ray powder diffraction pattern which comprises at least two peaks selected from: about 5.7°, about 9.8°, about 11.6°, about 14.7°, about 15.4°, about 16.1°, about 17.1°, about 19.3°, about 23.9°, about 24.5°, and about 25.4°, in terms of 2-theta, and wherein the solid form is a 1:1 salt of Compound A and L-(+)-tartaric acid, which is prepared by the method of claim 15 .
17. A process for preparation of a solid form of a L-(+)-tartrate salt of Compound A
wherein the solid form is crystalline having an X-ray powder diffraction pattern which comprises at least two peaks selected from: about 5.7°, about 9.8°, about 11.6°, about 14.7°, about 15.4°, about 16.1°, about 17.1°, about 19.3°, about 23.9°, about 24.5°, and about 25.4°, in terms of 2-theta, which comprises contacting Compound A with L-(+)-tartaric acid in the presence of a solvent.
18. A method to treat a condition selected from a proliferation disorder, a proliferative disorder, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eye, rheumatoid arthritis, or lupus in a subject, wherein the method comprises administering to a subject in need thereof a solid form of a L-(+)-tartrate salt of Compound A according to claim 1 or a pharmaceutical composition thereof.