Ibrutinib solid forms and production process therefor
View Patent ↗Provided are ibrutinib polymorphs, e.g., crystalline ibrutinib Forms III, IV, V, VI, VII, VIII and Form IX and processes for producing these crystalline forms, stable amorphous ibrutinib and processes for preparing stable amorphous ibrutinib, pharmaceutical compositions comprising these forms and methods of using these crystalline and amorphous forms.
1. Crystalline ibrutinib Form VII characterized by an X-ray powder diffraction pattern exhibiting strong diffraction peaks at 6.5, 13.0, 17.7, 18.3, 20.0, 21.0, 21.5, and 23.9±0.2 degrees 2θ.
2. The crystalline ibrutinib Form VII of claim 1 further characterized by an infrared spectrum exhibiting characteristic absorption bands at 3433, 1587, 1491, 1437, 1238, 986, 862, and 692 cm −1 .
3. The crystalline solid ibrutinib Form VII of claim 1 further characterized by DSC curve exhibiting peak onset at 116.7° C.
4. A pharmaceutical composition comprising crystalline ibrutinib Form VII and one or more pharmaceutically acceptable additives or excipients.
5. A process for preparing crystalline ibrutinib polymorph VII, the process comprising:
dissolving or slurrying ibrutinib in anisole or in a mixture of anisole with another solvent or anti-solvent; optionally heating;
optionally adding an anti-solvent;
optionally cooling;
optionally seeding with crystalline ibrutinib Form VII; and
isolating the solid and, optionally, drying the solid.
6. The process of claim 5 , wherein said other solvent or anti-solvent is selected from acetone, cyclohexane, petroleum ether, isooctane, and xylene.
7. The process of claim 5 , wherein said crystalline ibrutinib Form VII has a purity of at least 98%.
8. The process of claim 5 , wherein the mixture is heated to a temperature of between 40° C. and 90° C.
9. The process of claim 5 , wherein cooling is carried out gradually.
10. A process for preparing ibrutinib Form VII, comprising:
dissolving ibrutinib in a first solvent;
exposing the solution to the vapors of a second solvent for a period of at least one day to produce crystals;
isolating the crystals; and
optionally drying the crystals to afford dry ibrutinib Form VII.
11. The process of claim 10 , wherein the first solvent comprises anisole.
12. The process of claim 10 , wherein the second solvent is selected from acetone, cyclohexane, isooctane, petroleum ether, toluene, xylene and mixtures thereof.
13. A method for treating mantle cell lymphoma and chronic lymphoid leukemia comprising administering to a subject in need a therapeutically effective dose of ibrutinib Form VII.