Crystalline form I of ibrutinib
Crystalline Form I of ibrutinib, processes for its preparation, pharmaceutical compositions comprising the new Form, and use of Form I of ibrutinib for treating or delaying diseases or disorders related to activity of Bruton's tyrosine kinase (BTK) proteins are disclosed. The novel Form was characterized by X-ray powder diffraction, differential scanning calorimetry, and other techniques. It can be readily prepared and is suitable for use in the preparation of solid dosage forms.
1. A crystalline form of ibrutinib, designated as Form I, having an X-ray powder diffraction pattern comprising the following 2θ values measured using CuKα radiation: 5.2°±0.2°, 17.6°±0.2°, and 22.1°±0.2°.
2. The crystalline form of claim 1 , wherein the X-ray powder diffraction pattern further comprises the following 2θ values measured using CuKα radiation: 19.3°±0.2°, 20.8°±0.2°, and 22.4°±0.2°.
3. The crystalline form of claim 1 , wherein the X-ray powder diffraction pattern further comprises the following 2θ values measured using CuKα radiation: 16.2°±0.2°, 18.1°±0.2°, 18.9°±0.2°, and 23.0°±0.2°.
4. The crystalline form of claim 1 , having an X-ray powder diffraction pattern substantially as depicted in FIG. 1 .
5. The crystalline form of claim 1 , having a differential scanning calorimetric thermogram substantially as depicted in FIG. 2 .
6. The crystalline form of claim 1 , having a thermal gravimetric analysis thermogram substantially as depicted in FIG. 3 .
7. A process for the preparation of ibrutinib Form I, comprising: dissolving ibrutinib in a solvent system selected from the group consisting of alcohol having three or more carbon atoms, ether, ketone, a mixture of alcohol with alkane, a mixture of ether and alkane, and a mixture of ketone with alkane to form a solution; and crystallizing said Form I by cooling the solution under ambient conditions or in a controlled manner.
8. The process according to claim 7 , wherein said solvent system is a mixture of an alcohol or ketone and an alkane.
9. The process according to claim 8 , wherein said alcohol is a lower alcohol, and said alkane is a C 4 -C 10 alkane.
10. The process according to claim 8 , wherein the solvent system is a mixture of 2-propanol and n-heptane.
11. The process according to claim 8 , wherein said ketone is a C 3 -C 6 ketone, and said alkane is a C 4 -C 10 alkane.
12. The process according to claim 8 , wherein the solvent system is a mixture of acetone and n-heptane.
13. A pharmaceutical composition comprising crystalline Form I of ibrutinib and a pharmaceutically acceptable carrier, wherein said crystalline Form I has an X-ray powder diffraction pattern comprising the following 2θ values measured using CuKα radiation: 5.2°±0.2°, 17.6°±0.2°, and 22.1°±0.2°.
14. The pharmaceutical composition of claim 13 , wherein the X-ray powder diffraction pattern of said crystalline Form I further comprises the following 2θ values measured using CuKα radiation: 19.3°±0.2°, 20.8°±0.2°, and 22.4°±0.2°.
15. The pharmaceutical composition of claim 13 , wherein the X-ray powder diffraction pattern further comprises the following 2θ values measured using CuKα radiation: 16.2°±0.2°, 18.1°±0.2°, 18.9°±0.2°, and 23.0°±0.2°.
16. The pharmaceutical composition of claim 13 , wherein said crystalline Form I has a melting point at about 135.1° C. as measured by differential scanning calorimetry (DSC).
17. The pharmaceutical composition of claim 13 , wherein the X-ray powder diffraction pattern of said crystalline Form I has an X-ray powder diffraction pattern substantially as depicted in FIG. 1 .
18. A method of treating or delaying the progression or onset of a disease or disorder in connection with activity of a Bruton's tyrosine kinase (BTK), comprising administering to a subject in need thereof a pharmaceutical composition comprising crystalline Form I of ibrutinib.
19. The method of claim 18 , wherein said disease or disorder is a B cell malignancy selected from the group consisting of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B Cell lymphoma (DLBCL), and multiple myeloma.