Crystalline form of ibrutinib

Priority

[0001] Priority is claimed of Slovenian patent application no. P-2022 00096 that was filed on June 17, 2022.

Technical Field

[0002] The present invention relates to crystalline form of ibrutinib, designated as Form KI, and processes for its preparation.

Background of the invention

[0003] Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK). The chemically name of ibrutinib is l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyr imidin-l-yl]piperidin-l-yl]prop- 2-en-l-one and it has the following formula:

[0004] Ibrutinib was first disclosed in WO 2008/039218.

[0005] Different crystalline forms of ibrutinib are known already.

[0006] WO 2013/184572 discloses amorphous form, crystalline forms and solvates of ibrutinib, designated as Form A, Form B, Form C, Form D, Form E and Form F.

[0007] CN 103694241 discloses crystalline form A of ibrutinib.

[0008] CN 103923084 discloses anhydrous forms, hydrates and solvates of ibrutinib, designated as form II, form III, form IV, form V, form VI, form VII and form VIII.

[0009] WO 2015/081180 discloses a crystalline form of ibrutinib, designated as Form I.

[0010] WO 2015/145415 discloses anhydrous forms, hydrates and solvates of ibrutinib, designated as Form III, Form IV, Form V, Form VI, Form VII, Form VIII and Form IX. [0011] WO 2016/025720 discloses crystalline forms and solvates of ibrutinib designated as Form G, Form J and Form K.

[0012] WO 2016/079216 and WO 2016/160598 disclose solvates of ibrutinib.

[0013] WO 2016/139588 discloses crystalline forms and solvates of ibrutinib designated as Form DI, Form Dla, Form D2, Form D2a, Form D3, Form D4, Form D5, Form D6, Form D7, Form D8, Form D9, Form D10, Form Dl l, Form D12 and Form D13.

[0014] WO 2017/029586 discloses crystalline forms of ibrutinib, designated as Form SI, Form S2, Form S3, Form S4, and an amorphous form, designated as Form Al.

[0015] CN 105646484 discloses a crystalline form B of ibrutinib.

[0016] CN 105646498 discloses a crystalline form F of ibrutinib.

[0017] WO 2016/160604 discloses ibrutinib co-crystals with organic acids.

[0018] Known crystalline forms of ibrutinib show different properties regarding dissolution, stability, processing, etc. However, there is still a need for a new crystalline form of ibrutinib and a process for preparing it. Particularly, there is a need for a new crystalline form of ibrutinib having a good balance between dissolution properties and stability properties. Furthermore, there is a need for a new crystalline form of ibrutinib having good handling and/or processing properties.

Summary of the invention

[0019] The present invention is described by the following items:

(1) A crystalline Form KI of ibrutinib.

(2) The crystalline Form KI of ibrutinib according to item (1) characterized by X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.3±0.1°, 8.8±0.1°, 11.7±0.1°, 13.1±0.1°, 14.9±0.1°, and 16.8±0,l° 2Theta.

(3) The crystalline Form KI of ibrutinib according to item (1) or item (2) characterized by X- ray powder diffraction (XRPD) pattern having additional characteristic peaks at 11.2±0.1°, 15.2±0.1°, 18.5±0.1° 2Theta.

(4) The crystalline Form KI of ibrutinib according to any one of items (1) to (3) characterized by X-ray powder diffraction (XRPD) pattern having additional characteristic peaks at 20.1±0.1°, 21.7±0.1° and 23.8±0.1° 2Theta.

(5) The crystalline Form KI of ibrutinib according to any of items (1) to (4) characterized by X- ray powder diffraction (XRPD) pattern having additional characteristic peaks at 5.7±0.1°, 6.6±0.1°, 8.4±0.1°, 10.8±0.1°, 11.9±0.1°, 13.7±0.1°, 15.9±0.1°, 16.6±0.1°, 17.7±0.1°, 19.0±0.1°, 20.9±0.1°, 22.0±0.1°, 23.0±0.1°, 24.5±0.1°, 25.7±0.1°, 26.8±0.1°, 28.1±0.1°, 29.7±0.1°, 30.6±0.1°, 31.4±0.1°, 32.0±0.1° 2Theta.

(6) The crystalline Form KI of ibrutinib according to any one of items (1) to (5) characterized by a DSC thermogram having an endothermic peak at about 128±3 °C.

(7) The crystalline Form KI of ibrutinib according to any one of items (1) to (6) characterized by mainly spherical agglomerates composed of plate-like primary particles, fused from the center outwards.

(8) A process for preparing the crystalline Form KI of ibrutinib according to any one of items (1) to (7) comprising the following steps: a) obtaining a solution of ibrutinib in alcohol, preferably C1-C5 alcohol, more preferably methanol; b) cooling the solution obtained in step a) to a temperature from 20 °C to 50 °C, preferably from 20 °C to 45 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; c) adding a water having a temperature from 5 °C to 35 °C, preferably from 5 °C to 25 °C, more preferably from 10 °C to 25 °C; d) optionally, adjusting a temperature of the solution obtained in step c) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) optionally, adding the second portion of water having a temperature from 25 °C to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; f) optionally, cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material.

(9) The process for preparing the crystalline Form KI of ibrutinib according to item (8) comprising the following steps: a) obtaining a solution of ibrutinib in alcohol, preferably C1-C5 alcohol, more preferably methanol; b) cooling the solution obtained in step a) to a temperature from 20 °C to 50 °C, preferably from 20 °C to 45 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; c) adding a water having a temperature from 5 °C to 35 °C, preferably from 5 °C to 25 °C, more preferably from 10 °C to 25 °C; d) optionally, adjusting a temperature of the solution obtained in step c) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) adding the second portion of water having a temperature from 25 °C to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; f) optionally, cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material.

(10) The process for preparing the crystalline Form KI of ibrutinib according to item (8) or item (9) comprising the following steps: a) obtaining a solution of ibrutinib in alcohol, preferably C1-C5 alcohol, more preferably methanol; b) cooling the solution obtained in step a) to a temperature from 20 °C to 50 °C, preferably from 20 °C to 45 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C, preferably from 25; c) adding a water having a temperature from 5 °C to 35 °C, preferably from 5 °C to 25 °C, more preferably from 10 °C to 25 °C; d) adjusting a temperature of the solution obtained in step c) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; f) cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material.

(11) The process according to any one of items (8) to (10), wherein in step a) 10 to 30 ml of alcohol is used per gram of ibrutinib, preferably 10 to 20 ml of alcohol is used per gram of ibrutinib, more preferably 10 to 15 ml of alcohol is used per gram of ibrutinib.

(12) The process according to any one of items (8) to (11), wherein in step c) a ratio between alcohol and water is from 2: 1 to 1:4, preferably from 1.5: 1 to 1:3, more preferably from 1: 1 to 1:2, most preferably 1: 1.5.

(13) The process for preparing the crystalline Form KI of ibrutinib according to item (8) or items (9) to (12), wherein a volume ratio between alcohol and water in the mixture obtained in step e) is from 2: 1 to 1:3, preferably from 1.5: 1 to 1:2, more preferably from 1: 1 to 1: 1.5. (14) The process according to any one of items (8) to (13), wherein in step c) seed crystals of crystalline Form KI ofibrutinib are added.

(15) The process according to any one of items (8) to (14) comprising the following steps: a) obtaining a solution of ibrutinib in alcohol, preferably C1-C5 alcohol, more preferably methanol; b) cooling the solution obtained in step a) to a temperature from 20 °C to 50 °C, preferably from 20 °C to 45 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; cl) adding the first portion of water having a temperature from 5 °C to 35 °C, preferably from 5 °C to 25 °C, more preferably from 10 °C to 25 °C; c2) optionally, adjusting a temperature of the solution obtained in step cl) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; c3) adding seed crystals of crystalline Form KI of ibrutinib; c4) adding the second portion of water having a temperature from 5 °C to 35 °C, preferably from 5 °C to 25 °C, more preferably from 10 °C to 25 °C; d) optionally, adjusting a temperature of the solution obtained in step c4) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; f) optionally, cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material.

(16) The process according to item (15), wherein a ratio between alcohol and water in the mixture obtained in step c4) is from 2: 1 to 1:4, preferably from 1.5: 1 to 1:3, more preferably from 1 : 1 to 1:2, most preferably 1: 1.5.

(17) A process for preparing the crystalline Form KI of ibrutinib according to any one of items (1) to (7) comprising the following steps: a) obtaining a solution of ibrutinib in a mixture of alcohol, preferably C1-C5 alcohol, more preferably methanol, and water; b) cooling the solution obtained in step a) to a temperature from 0 °C to 40 °C, preferably 15 °C to 35 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 d) optionally, adjusting a temperature of the solution obtained in step b) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) adding the second portion of water having a temperature from 25 to 45 °C, preferably from 30 to 40 °C, more preferably from 30 °C to 35 °C; f) optionally, cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material.

(18) The process according to item (17), comprising the following steps: a) obtaining a solution of ibrutinib in a mixture of alcohol, preferably C1-C5 alcohol, more preferably methanol, and water; b) cooling the solution obtained in step a) to a temperature from 0 °C to 40 °C, preferably 15 °C to 35 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; d) optionally, adjusting a temperature of the solution obtained in step b) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) adding the second portion of water having a temperature from 25 to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; g) optionally, stirring; and h) isolating crystalline material.

(19) The process according to item (17) or item (18), comprising the following steps: a) obtaining a solution of ibrutinib in a mixture of alcohol, preferably C1-C5 alcohol, more preferably methanol, and water; b) cooling the solution obtained in step a) to a temperature from 0 °C to 40 °C, preferably 15 °C to 35 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; c) adding seed crystals of crystalline Form KI of ibrutinib; d) optionally, adjusting a temperature of the solution obtained in step c) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) adding the second portion of water having a temperature from 25 °to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; f) optionally, cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material.

(20) The process according to any one of items (17) to (19), comprising the following steps: a) obtaining a solution of ibrutinib in a mixture of alcohol, preferably C1-C5 alcohol, more preferably methanol, and water; b) cooling the solution obtained in step a) to a temperature from 0 °C to 40 °C, preferably 15 °C to 35 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; c) adding seed crystals of crystalline Form KI of ibrutinib; d) adjusting a temperature of the solution obtained in step c) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) adding the second portion of water having a temperature from 25 °C to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; g) stirring; and h) isolating crystalline material.

(21) The process according to any one of items (17) to (20), wherein in step a) 5 to 30 ml of solvent mixture is used per gram of ibrutinib, preferably 5 to 20 ml of solvent mixture is used per gram of ibrutinib, more preferably 5 to 10 ml of solvent mixture is used per gram of ibrutinib.

(22) The process according to any one of items (17) to (21), wherein in step a) a volume ratio between alcohol and water is from 10: 1 to 1: 1, preferably from 8: 1 to 2: 1, more preferably from 6: 1 to 4: 1, most preferably 5: 1.

(23) The process according to any one of items (8) to (22), wherein in step a) ibrutinib is dissolved at temperature from 45 °C to 70 °C, preferably at temperature from 50 °C to 60 °C, more preferably at temperature from 50 °C to 55 °C.

(24) The process according to any one of items (17) to (23), wherein a volume ratio between alcohol and water in the mixture obtained in step e) is from 2: 1 to 1:3, preferably from 1.5: 1 to 1:2, more preferably from 1 : 1 to 1 : 1.5.

(25) The process according to any one of items (8) to (24), comprising the following additional steps: i) suspending crystalline material obtained in step h) in methanol : water mixture, wherein a volume ratio between alcohol and water is from 9: 1 to 7:3, preferably 6: 1 to 3: 1, more preferably 4: 1; j) stirring; and k) isolating crystalline material.

Brief description of the Figures

[0020] Figure 1 illustrates an X-ray powder diffraction (XRPD) pattern of a crystalline Form KI of ibrutinib.

[0021] Figure 2 illustrates a Differential Scanning Calorimetry (DSC) thermogram of a crystalline Form KI of ibrutinib.

[0022] Figure 3 illustrates SEM of a crystalline Form KI of ibrutinib.

Detailed description of the invention

[0023] As well-known so called 'kinetic' polymorphs shows better dissolution rate that is advantageous during formulation technology and afford several simplification in technology and composition to prepare efficient final dosage formulation. On contrary, it is also known that so called kinetic polymorphs are difficult to produce in polymorphic pure form in robust manner, they often exhibit weak crystallographic and chemical stability and special solvent systems and technologies are required. That is drawback that need to be overcome to make kinetic polymorph useful and profitable for production on industrial scale.

[0024] Surprisingly, new crystalline form of ibrutinib Form KI shows improved dissolution rates compared to thermodynamically more stable forms, like form A, but at the same time it shows good chemical stability and polymorphic stability what is not the case for other kinetic forms of ibrutinib with low crystallinity or even amorphous.

[0025] Regarding processes used for kinetic polymorphs it is well known that they are accompanied with unwanted particle morphology that often lead to slow filtration rates, slow drying process, increased level of residual solvents and water, all that can affect quality, purity, stability and profitability of production of kinetic polymorph.

[0026] Crystalline Form KI of ibrutinib has good filterability that afford good washing of filtered wet cake, good purity and efficient drying resulting in residual organic solvents below limit of detection and very low moisture content. Additionally, crystalline Form KI of ibrutinib shows favorable morphology in view of good handling, particularly good flowability.

[0027] First aspect of the present invention is a crystalline Form KI of ibrutinib. [0028] In one embodiment, the crystalline Form KI of ibrutinib is characterized by X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.3±0.1°, 8.8±0.1°, 11.7±0.1°, 13.1±0.1°, 14.9±0.1°, and 16.8±0.1° 2Theta.

[0029] In another embodiment, the crystalline Form KI of ibrutinib is characterized by X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.3±0.1°, 8.8±0.1°, 11.2±0.1°, 11.7±0.1°, 13.1±0.1°, 14.9±0.1°, I5.2±0.I°, 16.8±0.1°, and 18.5±0.1° 2Theta.

[0030] In another embodiment, the crystalline Form KI of ibrutinib is characterized by X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.3±0.1°, 8.8±0.1°, 11.2±0.1°, 11.7±0.1°, 13.1±0.1°, 14.9±0.1°, I5.2±0,I°, 16.8±0.1°, 18.5±0.1°, 20.1±0.1°, 21.7±0.1°, and 23.8±0.1° 2Theta.

[0031] In another embodiment, the crystalline Form KI of ibrutinib is characterized by X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.3±0.1°, 5.7±0.1°, 6.6±0.1°, 8.4±0.1°, 8.8±0.1°, 10.8±0.1°, 11.2±0.1°, 11.7±0.1°, 11.9±0.1°, 13.1±0.1°, 13.7±0.1°, 14.9±0.1°, 15.2±0.1°, 15.9±0.I°, 16.6±0.1°, 16.8±0.1°, 17.7±0.1°, 18.5±0.1°, 19.0±0.1°, 20.1±0.1°, 20.9±0.1°, 21.7±0.1°, 22.0±0.1°, 23.0±0.1°, 23.8±0.1°, 24.5±0.1°, 25.7±0.1°, 26.8±0.1°, 28.1±0.1°, 29.7±0.1°, 30.6±0.1°, 31.4±0.1°, and 32.0 ± 0.1° 2Theta.

[0032] In another embodiment, the crystalline Form KI of ibrutinib is characterized by X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 1.

[0033] In another embodiment, the crystalline Form KI of ibrutinib is characterized by a DSC thermogram having an endothermic peak at about 128±3 °C, preferably 128±2 °C, more preferably 128±1 °C.

[0034] In another embodiment, the crystalline Form KI of ibrutinib is characterized by a DSC thermogram having an endothermic peak at about 128±3 °C, preferably 128±2 °C, more preferably 128±1 °C, and onset temperature in the range from 113 °C to 119 °C.

[0035] In another embodiment, the crystalline Form KI of ibrutinib is characterized by a DSC thermogram substantially the same as shown in Figure 1.

[0036] In another embodiment, the crystalline Form KI of ibrutinib is characterized by X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.3±0.I°, 8.8±0.1°, 11.7±0.1°, 13.1±0.1°, 14.9±0.1°, 16.8±0.1° 2Theta, and a DSC thermogram having an endothermic peak at about 128±3 °C.

[0037] In another embodiment, the crystalline Form KI of ibrutinib is characterized by X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.3±0.I°, 8.8±0.1°, 11.2±0.1°, 11.7±0.1°, 13.1±0.1°, 14.9±0.1°, 15.2±0.1°, 16.8±0.1°, 18.5±0.1° 2Theta, and a DSC thermogram having an endothermic peak at about 128±3 °C. [0038] In another embodiment, the crystalline Form KI of ibrutinib is characterized by X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.3±0.1°, 8.8±0.1°, 11.2±0.1°, 11.7±0.1°, 13.1±0.1°, 14.9±0.1°, 15.2±0.1°, 16.8±0.1°, 18.5±0.1°, 20.1±0.1°, 21.7±0.1°, 23.8±0.1° 2Theta, and a DSC thermogram having an endothermic peak at about 128±3 °C.

[0039] In another embodiment, particles of the crystalline Form KI of ibrutinib are mainly in the form plate-like primary particles, that optionally form agglomerates.

[0040] In another embodiment, particles of the crystalline Form KI of ibrutinib are mainly in the form of spherical agglomerates composed of plate-like primary particles, fused from the center outwards.

[0041] Although crystalline Form A, Form B and Form DI were obtained from a mixture methanol and water already, we have surprisingly found that from a mixture of alcohol, preferably methanol, and water an additional crystalline form of ibrutinib can be obtained, namely the above described crystalline Form KI. We have found that ibrutinib Form KI is obtained by crystallization from a mixture of methanol and water having an excess of water and by controlling a temperature range.

[0042] The starting material in all processes described below can be obtained by any suitable process for preparing ibrutinib, including processes known in the art. For example, the ibrutinib starting material is obtained as described in WO 2016/115356.

[0043] Another aspect of the present invention is a process for preparing the crystalline Form KI of ibrutinib comprising the following steps: a) obtaining a solution of ibrutinib in alcohol, preferably C1-C5 alcohol, more preferably methanol; b) cooling the solution obtained in step a) to a temperature from 20 °C to 50 °C, preferably from 25 °C to 45 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; c) adding a water having a temperature from 5 °C to 35 °C, preferably from 5 °C to 25 °C, more preferably from 10 °C to 25 °C; d) optionally, adjusting a temperature of the solution obtained in step c) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) optionally, adding the second portion of water having a temperature from 25 °C to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; f) optionally, cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material.

[0044] In one embodiment, a process for preparing the crystalline Form KI of ibrutinib comprises the following steps: a) obtaining a solution of ibrutinib in alcohol, preferably C1-C5 alcohol, more preferably methanol; b) cooling the solution obtained in step a) to a temperature from 20 °C to 50 °C, preferably from 25 °C to 45 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; c) adding a water having a temperature from 5 °C to 35 °C, preferably from 5 °C to 25 °C, more preferably from 10 °C to 25 °C; d) optionally, adjusting a temperature of the solution obtained in step c) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; f) cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material.

[0045] In one embodiment, a process for preparing the crystalline Form KI of ibrutinib comprising the following steps: a) obtaining a solution of ibrutinib in alcohol, preferably C1-C5 alcohol, more preferably methanol; b) cooling the solution obtained in step a) to a temperature from 20 °C to 50 °C, preferably from 25 °C to 45 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; c) adding a water having a temperature from 5 °C to 35 °C, preferably from 5 °C to 25 °C, more preferably from 10 °C to 25 °C; d) optionally, adjusting a temperature of the solution obtained in step c) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) adding the second portion of water having a temperature from 25 °C to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; f) optionally, cooling a suspension to a temperature from 0 to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material.

[0046] In one embodiment, in step a) 10 to 30 ml of alcohol is used per gram of ibrutinib, preferably 10 to 20 ml of alcohol is used per gram of ibrutinib, more preferably 10 to 15 ml of alcohol is used per gram of ibrutinib.

[0047] In one embodiment, in step a) ibrutinib is dissolved at temperature from 45 °C to 70 °C, preferably at temperature from 50 °C to 60 °C, more preferably at temperature from 50 °C to 55 °C.

[0048] In one embodiment, in step c) a volume ratio between alcohol and water is from 2: 1 to 1:4, preferably from 1.5: 1 to 1:3, more preferably from 1: 1 to 1:2, most preferably 1: 1.5. [0049] In one embodiment, a volume ratio between alcohol and water in the mixture obtained in step e) is from 2: 1 to 1:3, preferably from 1.5: 1 to 1:2, more preferably from 1: 1 to 1: 1.5.

[0050] In one preferred embodiment, a process for preparing the crystalline Form KI of ibrutinib comprising the following steps: a) obtaining a solution of ibrutinib in alcohol, preferably C1-C5 alcohol, more preferably methanol; b) cooling the solution obtained in step a) to a temperature from 20 °C to 50 °C, preferably from 25 °C to 45 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; c) adding a water having a temperature from 5 to 35 °C, preferably from 5 °C to 25 °C, more preferably from 10 °C to 25 °C; d) optionally, adjusting a temperature of the solution obtained in step c) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) adding the second portion of water having a temperature from 25 °C to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; f) optionally, cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) stirring; and h) isolating crystalline material; wherein, in step c) a volume ratio between alcohol and water is from 2: 1 to 1 :4, preferably from 1.5: 1 to 1:3, more preferably from 1 : 1 to 1:2, most preferably 1 : 1.5, and wherein, a volume ratio between alcohol and water in the mixture obtained in step e) is from 2: 1 to 1:3, preferably from 1.5: 1 to 1:2, more preferably from 1: 1 to 1: 1.5.

[0051] In one preferred embodiment, a process for preparing the crystalline Form KI of ibrutinib comprising the following steps: a) obtaining a solution of ibrutinib methanol; b) cooling the solution obtained in step a) to a temperature from 20 °C to 50 °C, preferably from 25 °C to 45 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; c) adding a water having a temperature from 5 °C to 35 °C, preferably from 5 °C to 25 °C, more preferably from 10 °C to 25 °C; d) optionally, adjusting a temperature of the solution obtained in step c) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; f) cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) stirring; and h) isolating crystalline material; wherein, in step c) a volume ratio between methanol and water is from 2: 1 to 1:4, preferably from 1.5: 1 to 1:3, more preferably from 1: 1 to 1:2, most preferably 1: 1.5, and wherein, a volume ratio between alcohol and water in the mixture obtained in step e) is from 2: 1 to 1:3, preferably from 1.5: 1 to 1:2, more preferably from 1: 1 to 1: 1.5.

[0052] The process for preparing the crystalline Form KI of ibrutinib is even more efficient if the seed crystals of crystalline Form KI of ibrutinib are used in the process.

[0053] The seed crystals are typically added in an amount of 0.1 wt% to 10 wt%, preferably in an amount of 0.5 wt% to 7.0 wt%, most preferably 1 .0 wt.% 5.0 wt%, on the basis of the total amount of ibrutinib dissolved in step a).

[0054] The seed crystals of crystalline Form KI of ibrutinib may be obtained by the processes for preparing the crystalline Form KI of ibrutinib as described in any of the above embodiments.

[0055] In one preferred embodiment, step c) comprises the following sub-steps: cl) adding the first portion of water having a temperature from 5 °C to 35 °C, preferably from 5 °C to 25 °C, more preferably from 10 °C to 25 °C; c2) optionally, adjusting a temperature of the solution obtained in step cl) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; c3) adding seed crystals of the crystalline Form KI of ibrutinib; and c4) adding the second portion of water having a temperature from 5 °C to 35 °C, preferably from 5 °C to 25 °C, more preferably from 10 °C to 25 °C.

[0056] In one embodiment, the first portion of water added in step cl) represents from 10 to 30%, preferably from 10 to 20%, of the amount of water added in step cl) and step c4) together.

[0057] In one preferred embodiment, a process for preparing the crystalline Form KI of ibrutinib comprises the following steps: a) obtaining a solution of in alcohol, preferably C1-C5 alcohol, more preferably methanol; b) cooling the solution obtained in step a) to a temperature from 20 °C to 50 °C, preferably from 25 °C to 45 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; cl) adding the first portion of water having a temperature from 5 to 35 °C, preferably from 5 to 25 °C, more preferably from 10 to 25 °C; c2) optionally, adjusting a temperature of the solution obtained in step cl) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; c3) adding seed crystals of crystalline Form KI of ibrutinib; c4) adding the second portion of water having a temperature from 5 °C to 35 °C, preferably from 5 °C to 25 °C, more preferably from 10 °C to 25 °C; d) optionally, adjusting a temperature of the solution obtained in step c4) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, most preferably from 20 °C to 35 °C; f) optionally, cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material.

[0058] In one embodiment, a ratio between alcohol and water added in step cl) and in step c4) together is from 2: 1 to 1:4, preferably from 1.5: 1 to 1:3, more preferably from 1: 1 to 1:2, most preferably 1: 1.5.

[0059] In one preferred embodiment, a process for preparing the crystalline Form KI of ibrutinib comprises the following steps: a) obtaining a solution of ibrutinib in alcohol, preferably C1-C5 alcohol, more preferably methanol; b) cooling the solution obtained in step a) to a temperature from 20 °C to 50 °C, preferably from 25 °C to 45 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; cl) adding the first portion of water having a temperature from 5 to 35 °C, preferably from 5 °C to 25 °C, more preferably from 10 °C to 25 °C; c2) optionally, adjusting a temperature of the solution obtained in step cl) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, most preferably from 20 °C to 35 °C; c3) adding seed crystals of crystalline Form KI of ibrutinib; c4) adding the second portion of water having a temperature from 5 °C to 35 °C, preferably from 5 °C to 25 °C, more preferably from 10 °C to 25 °C; d) optionally, adjusting a temperature of the solution obtained in step c4) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, most preferably from 20 °C to 35 °C; f) optionally, cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material; wherein a ratio between alcohol and water in the mixture obtained in step c4) is from 2: 1 to 1:4, preferably from 1.5: 1 to 1:3, more preferably from 1: 1 to 1:2, most preferably 1: 1.5.

[0060] In one preferred embodiment, a process for preparing the crystalline Form KI of ibrutinib comprises the following steps: a) obtaining a solution of ibrutinib in alcohol, preferably C1-C5 alcohol, more preferably methanol; b) cooling the solution obtained in step a) to a temperature from 20 °C to 50 °C, preferably from 25 °C to 45 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; cl) adding the first portion of water having a temperature from 5 °C to 35 °C, preferably from 5 °C to 25 °C, more preferably from 10 °C to 25 °C; c2) adjusting a temperature of the solution obtained in step cl) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, most preferably from 20 °C to 35 °C; c3) adding seed crystals of crystalline Form KI of ibrutinib; c4) adding the second portion of water having a temperature from 5 °C to 35 °C, preferably from 5 °C to 25 °C, more preferably from 10 °C to 25 °C; d) optionally, adjusting a temperature of the solution obtained in step c4) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, most preferably from 20 °C to 35 °C; f) optionally, cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material; wherein a ratio between alcohol and water in the mixture obtained in step c4) is from 1: 1 to 1:2, preferably 1: 1.5.

[0061] In one preferred embodiment, a process for preparing the crystalline Form KI of ibrutinib comprises the following steps: a) obtaining a solution of ibrutinib in alcohol, preferably C1-C5 alcohol, more preferably methanol; b) cooling the solution obtained in step a) to a temperature from 25 °C to 35 °C; cl) adding the first portion of water having a temperature from 10 °C to 25 °C; c2) adjusting a temperature of the solution obtained in step cl) to a temperature from 20 °C to 35 °C; c3) adding seed crystals of crystalline Form KI of ibrutinib; c4) adding the second portion of water having a temperature from 10 °C to 25 °C; d) adjusting a temperature of the solution obtained in step c4) to a temperature from 20 °C to 35 °C; g) stirring; and h) isolating crystalline material; wherein a ratio between alcohol and water in the mixture obtained in step c4) is from 2: 1 to 1:4, preferably from 1.5: 1 to 1:3, more preferably from 1: 1 to 1:2, most preferably 1: 1.5.

[0062] In one preferred embodiment, a process for preparing the crystalline Form KI of ibrutinib comprises the following steps: a) obtaining a solution of ibrutinib in alcohol, preferably C1-C5 alcohol, more preferably methanol; b) cooling the solution obtained in step a) to a temperature from 25 °C to 35 °C; cl) adding the first portion of water having a temperature from 10 °C to 25 °C; c2) adjusting a temperature of the solution obtained in step cl) to a temperature from 20 °C to 35 °C; c3) adding seed crystals of crystalline Form KI of ibrutinib; c4) adding the second portion of water having a temperature from 10 °C to 25 °C; d) optionally, adjusting a temperature of the solution obtained in step c4) to a temperature from 20 °C to 35 °C; g) stirring; and h) isolating crystalline material; wherein a ratio between alcohol and water in the mixture obtained in step c4) is from 1: 1 to 1:2, preferably 1: 1.5.

[0063] In preferred embodiments, in step j) suspension is stirred preferably for 1 to 24 hours, more preferably 2 to 12 hours, most preferably 3 to 8 hours.

[0064] In alternative embodiment, the process for preparing the crystalline Form KI of ibrutinib according to any one of embodiments above comprises the following additional steps: i) suspending crystalline material obtained in step h) in methanol : water mixture, wherein a volume ratio between alcohol and water is from 9: 1 to 7:3, preferably 6: 1 to 3: 1, more preferably 4: 1; j) stirring; and k) isolating crystalline material.

[0065] Isolation in step h) or step k) may be performed by any method known in the art, such as fdtration, centrifugation, or evaporation of solvent. Moreover, the isolated crystals may optionally be dried, e.g. under reduced pressure, typically at a temperature between 20 °C and 30 °C or the crystals may directly be used in further processes.

[0066] Another aspect of the present invention is a process for preparing the crystalline Form KI of ibrutinib comprising the following steps: a) obtaining a solution of ibrutinib in a mixture of alcohol, preferably C1-C5 alcohol, more preferably methanol, and water; b) cooling the solution obtained in step a) to a temperature 0 °C to 40 °C, preferably from 15 °C to 35 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; d) optionally, adjusting a temperature of the solution obtained in step b) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) optionally, adding the second portion of water having a temperature from 25 °C to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; f) optionally, cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material. [0067] According to this aspect water mixed with alcohol in step a) is considered as the first portion of water.

[0068] In one embodiment, a process for preparing the crystalline Form KI of ibrutinib comprises the following steps: a) obtaining a solution of ibrutinib in a mixture of alcohol, preferably C1-C5 alcohol, more preferably methanol, and water; b) cooling the solution obtained in step a) to a temperature from 0 °C to 40 °C, preferably from 15 °C to 35 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; d) adjusting a temperature of the solution obtained in step b) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; f) cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material.

[0069] In one embodiment, a process for preparing the crystalline Form KI of ibrutinib comprising the following steps: a) obtaining a solution of ibrutinib in a mixture of alcohol, preferably C1-C5 alcohol, more preferably methanol, and water; b) cooling the solution obtained in step a) to a temperature from 0 °C to 40 °C, preferably 15 °C to 35 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; d) optionally, adjusting a temperature of the solution obtained in step b) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) adding the second portion of water having a temperature from 25 °C to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; f) optionally, cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material.

[0070] In one embodiment, a process for preparing the crystalline Form KI of ibrutinib comprising the following steps: a) obtaining a solution of ibrutinib in a mixture of alcohol, preferably C1-C5 alcohol, more preferably methanol, and water; b) cooling the solution obtained in step a) to a temperature from 0 °C to 40 °C, preferably 15 °C to 35 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; d) optionally, adjusting a temperature of the solution obtained in step b) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) adding the second portion of water having a temperature from 25 °C to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; g) optionally, stirring; and h) isolating crystalline material.

[0071] In one embodiment, in step a) 5 to 30 ml of solvent mixture is used per gram of ibrutinib, preferably 5 to 20 ml of solvent mixture is used per gram of ibrutinib, more preferably 5 to 10 ml of solvent mixture is used per gram of ibrutinib.

[0072] In one embodiment, in step a) a volume ratio between alcohol and water is from 10: 1 to 1: 1, preferably from 8: 1 to 2: 1, more preferably from 6: 1 to 4: 1, most preferably 5: 1.

[0073] In one embodiment, in step a) ibrutinib is dissolved at temperature from 45 °C to 70 °C, preferably at temperature from 50 °C to 60 °C, more preferably at temperature from 50 °C to 55 °C.

[0074] In one embodiment, a volume ratio between alcohol and water in the mixture obtained in step e) is from 2: 1 to 1:3, preferably from 1.5: 1 to 1:2, more preferably from 1: 1 to 1: 1.5.

[0075] In one preferred embodiment, a process for preparing the crystalline Form KI of ibrutinib comprising the following steps: a) obtaining a solution of ibrutinib in a mixture of alcohol, preferably C1-C5 alcohol, more preferably methanol, and water; b) cooling the solution obtained in step a) to a temperature from 0 °C to 40 °C, preferably from 15 °C to 35 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; d) adjusting a temperature of the solution obtained in step b) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) adding the second portion of water having a temperature from 25 °C to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; f) optionally, cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) stirring; and h) isolating crystalline material; wherein, in step a) a volume ratio between alcohol and water is from 10: 1 to 1: 1, preferably from 8: 1 to 2: 1, more preferably from 6: 1 to 4: 1, most preferably 5: 1, and wherein, a volume ratio between alcohol and water in the mixture obtained in step e) is from 2: 1 to 1:3, preferably from 1.5: 1 to 1:2, more preferably from 1: 1 to 1: 1.5. [0076] In one preferred embodiment, a process for preparing the crystalline Form KI of ibrutinib comprising the following steps: a) obtaining a solution of ibrutinib in a mixture of methanol and water; b) cooling the solution obtained in step a) to a temperature from 0 °C to 40 °C, preferably from 15 °C to 35 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; d) adjusting a temperature of the solution obtained in step b) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) adding the second portion of water having a temperature from 25 °C to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; g) stirring; and h) isolating crystalline material; wherein, in step a) a volume ratio between alcohol and water is from 10: 1 to 1: 1, preferably from 8: 1 to 2: 1, more preferably from 6: 1 to 4: 1, most preferably 5: 1, and wherein, a volume ratio between alcohol and water in the mixture obtained in step e) is from 2: 1 to 1:3, preferably from 1.5: 1 to 1:2, more preferably from 1: 1 to 1: 1.5.

The process for preparing the crystalline Form KI of ibrutinib is even more efficient if the seed crystals of crystalline Form KI of ibrutinib are used in the process.

[0077] The seed crystals are typically added in an amount of 0.1 wt% to 10 wt%, preferably in an amount of 0.5 wt% to 7.0 wt%, most preferably 1 .0 wt.% 5.0 wt%, on the basis of the total amount of ibrutinib dissolved in step a).

[0078] The seed crystals of crystalline Form KI of ibrutinib may be obtained by the processes for preparing the crystalline Form KI of ibrutinib as described in any of the above embodiments.

[0079] In one preferred embodiment, a process for preparing the crystalline Form KI of ibrutinib comprising the following steps: a) obtaining a solution of ibrutinib in a mixture of alcohol, preferably C1-C5 alcohol, more preferably methanol, and water; b) cooling the solution obtained in step a) to a temperature from 0 °C to 40 °C, preferably from 15 °C to 35 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; c) adding seed crystals of crystalline Form KI of ibrutinib; d) optionally, adjusting a temperature of the solution obtained in step c) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) optionally, adding the second portion of water having a temperature from 25 °C to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; f) optionally, cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material.

[0080] In one preferred embodiment, a process for preparing the crystalline Form KI of ibrutinib comprising the following steps: a) obtaining a solution of ibrutinib in a mixture of alcohol, preferably C1-C5 alcohol, more preferably methanol, and water; b) cooling the solution obtained in step a) to a temperature from 0 °C to 40 °C, preferably 15 °C to 35 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; c) adding seed crystals of crystalline Form KI of ibrutinib; d) optionally, adjusting a temperature of the solution obtained in step c) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) adding the second portion of water having a temperature from 25 °C to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; f) optionally, cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material.

[0081] In one preferred embodiment, a process for preparing the crystalline Form KI of ibrutinib comprising the following steps: a) obtaining a solution of ibrutinib in a mixture of alcohol, preferably C1-C5 alcohol, more preferably methanol, and water; b) cooling the solution obtained in step a) to a temperature from 0 °C to 40 °C, preferably 15 °C to 35 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; c) adding seed crystals of crystalline Form KI of ibrutinib; d) adjusting a temperature of the solution obtained in step c) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) adding the second portion of water having a temperature from 25 °C to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; g) stirring; and h) isolating crystalline material. [0082] In one embodiment, in step a) 5 to 30 ml of solvent mixture is used per gram of ibrutinib, preferably 5 to 20 ml of solvent mixture is used per gram of ibrutinib, more preferably 5 to 10 ml of solvent mixture is used per gram of ibrutinib.

[0083] In one embodiment, in step a) a volume ratio between alcohol and water is from 10: 1 to 1: 1, preferably from 8: 1 to 2: 1, more preferably from 6: 1 to 4: 1, most preferably 5: 1.

[0084] In one embodiment, in step a) ibrutinib is dissolved at temperature from 45 °C to 70 °C, preferably at temperature from 50 °C to 60 °C, more preferably at temperature from 50 °C to 55 °C.

[0085] In one embodiment, a volume ratio between alcohol and water in the mixture obtained in step e) is from 2: 1 to 1:3, preferably from 1.5: 1 to 1:2, more preferably from 1: 1 to 1: 1.5.

[0086] In one preferred embodiment, a process for preparing the crystalline Form KI of ibrutinib comprising the following steps: a) obtaining a solution of ibrutinib in a mixture of alcohol, preferably C1-C5 alcohol, more preferably methanol, and water; b) cooling the solution obtained in step a) to a temperature from 0 °C to 40 °C, preferably from 15 °C to 35 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; c) adding seed crystals of crystalline Form KI of ibrutinib; d) adjusting a temperature of the solution obtained in step c) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) adding the second portion of water having a temperature from 25 °C to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; f) optionally, cooling a suspension to a temperature from 0 °C to 15 °C, preferably to a temperature from 5 °C to 10 °C; g) optionally, stirring; and h) isolating crystalline material; wherein, in step a) a volume ratio between alcohol and water is from 10: 1 to 1: 1, preferably from 8: 1 to 2: 1, more preferably from 6: 1 to 4: 1, most preferably 5: 1, and wherein, a volume ratio between alcohol and water in the mixture obtained in step e) is from 2: 1 to 1:3, preferably from 1.5: 1 to 1:2, more preferably from 1: 1 to 1: 1.5.

[0087] In one preferred embodiment, a process for preparing the crystalline Form KI of ibrutinib comprising the following steps: a) obtaining a solution of ibrutinib in a mixture of alcohol, preferably C1-C5 alcohol, more preferably methanol, and water; b) cooling the solution obtained in step a) to a temperature from 0 °C to 40 °C, preferably from 15 °C to 35 °C, more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; c) adding seed crystals of crystalline Form KI of ibrutinib; d) adjusting a temperature of the solution obtained in step c) to a temperature from 15 °C to 45 °C, more preferably from 15 °C to 40 °C, even more preferably from 20 °C to 35 °C, even more preferably from 25 °C to 35 °C, most preferably from 25 °C to 30 °C; e) adding the second portion of water having a temperature from 25 °C to 45 °C, preferably from 30 °C to 40 °C, more preferably from 30 °C to 35 °C; g) stirring; and h) isolating crystalline material; wherein, in step a) a volume ratio between alcohol and water is from 10: 1 to 1: 1, preferably from 8: 1 to 2: 1, more preferably from 6: 1 to 4: 1, most preferably 5: 1, and wherein, a volume ratio between alcohol and water in the mixture obtained in step e) is from 2: 1 to 1:3, preferably from 1.5: 1 to 1:2, more preferably from 1: 1 to 1: 1.5.

[0088] In alternative embodiment, the process for preparing the crystalline Form KI of ibrutinib according to any one of embodiments above comprises the following additional steps: i) suspending crystalline material obtained in step h) in methanol : water mixture, wherein a volume ratio between alcohol and water is from 9: 1 to 7:3, preferably 6: 1 to 3: 1, more preferably 4: 1; j) stirring; and k) isolating crystalline material.

[0089] In some preferred embodiments, after step d) suspension is stirred preferably for 1 to 24 hours, more preferably 2 to 12 hours, most preferably 3 to 8 hours, before the second portion of water is added in step e).

[0090] In preferred embodiments, in step j) suspension is stirred preferably for 1 to 24 hours, more preferably 2 to 12 hours, most preferably 3 to 8 hours.

[0091] Isolation in step h) or step k) may be performed by any method known in the art, such as filtration, centrifugation, or evaporation of solvent. Moreover, the isolated crystals may optionally be dried, e.g. under reduced pressure, typically at a temperature between 20 °C and 30 °C or the crystals may directly be used in further processes.

[0092] Another aspect of the present invention is a pharmaceutical composition comprising the crystalline Form KI of ibrutinib and at least one pharmaceutically acceptable excipient. Preferably, the pharmaceutical composition is an oral solid dosage form, such as, but not limited to, capsules, tablet, lozenge, pastille, pill, dragee, powder, granules, pellets. Pharmaceutical compositions may be manufactured by a conventional methods, such as, but not limited to, mixing, dry granulation, wet granulation, encapsulation, or compression. [0093] In one embodiment, the pharmaceutically acceptable excipient is selected, but not limited to, from the group consisting of diluents, fdlers, binders, disintegrants, glidants, lubricants, colorants, surfactants. Examples of suitable excipients are microcrystalline cellulose, lactose, mannitol, sorbitol, calcium carbonate, silicified microcrystalline cellulose, pregelatinized starch, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxypropylethycellulose, croscarmel- lose, croscarmellose sodium, sodium starch glycolate, povidone, crospovidone, sodium lauryl sulfate, polyvinyl alcohol, macrogol, magnesium stearate, talc, colloidal anhydrous silica, ferric oxides, titanium dioxide.

[0094] In one embodiment, the crystalline Form KI of ibrutinib is administrated in the amount from 300 mg/day to 1000 mg/day, preferably from 420 mg/day to 840 mg/day, more preferably from 420 mg/day to 840 mg/day 560 mg/day, most preferably in the amount 420 mg/day.

[0095] Another aspect of the present invention is use of the crystalline Form KI of ibrutinib or a pharmaceutical composition comprising the crystalline Form KI of ibrutinib for inhibiting Bruton's tyrosine kinase activity or for the treatment of a disease, disorder, or condition, which would benefit from inhibition of Bruton's tyrosine kinase activity.

[0096] In one embodiment, the crystalline Form KI of ibrutinib or a pharmaceutical composition comprising the crystalline Form KI of ibrutinib are used for the treatment of cancer, autoimmune diseases or conditions, heteroimmune diseases or conditions, and inflammatory diseases or conditions.

[0097] In one embodiment, the cancer is a B cell malignancy selected from chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B Cell lymphoma (DLBCL), and multiple myeloma.

[0098] In one embodiment, the cancer is diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, nodal marginal zone B cell lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.

[0099] In one embodiment, the autoimmune disease is inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic throm- bocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, autoimmune hemolytic anemia, warm autoimmune hemolytic anemia, cold hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, or vulvodynia.

[0100] In one embodiment, the inflammatory disease is asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacry- oadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0101] The following examples further illustrate the invention but are not to be construed as limiting its scope.

Examples:

[0102] Methods of Measurement and Analyses

[0103] X-Ray Powder Diffraction (XRPD):

[0104] Powder diffractograms were collected using X-ray powder diffractometer (PANalytical X’Pert PRO MPD, Almelo, NL) with Cu Ka radiation (X = 1.5418 A) at 45 kV and 40 mA and X' Celerator detector. Measurement was performed in the 2Theta range from 3 to 32.5°, with step size 0.033° and integration time 500 s.

[0105] Differential Scanning Calorimetry (DSC):

[0106] DSC measurements were performed on DSC 1 Mettler Toledo. 3 mg of sample was weighted in 40 pL aluminum crucibles with perforated lid. Sample was heated with linear heating rate 10 K/min up to 190 °C in the flow of nitrogen, 40 mL/min.

[0107] Scanning electron microscope (SEM):

[0108] Particle morphology images were collected by FEG Carl Zeiss ULTRA plus scanning electron microscope using Evemhart-Thomley secondary electron detector at 3. 1 mm working distance, 1 kV EHT and 30 pm aperture size.

[0109] Intrinsic dissolution rate (IDR):

[0110] The analyses were performed using USP Dissolution Apparatus 2 (paddles) with fixed-disk system. The compressed API (200 mg/1 min/1 ton) was exposed to acidic media for one hour under constant conditions (surface area 0.5 cm ² , 10 mM HC1, 900 ml, 37 °C, 100 rpm). The samples were withdrawn after 5, 10, 15, 20, 30, 45, 60 minutes and analyzed with HPLC system. IDR was calculated using zero-order linear fit through the experimental data.

Example 1:

[0111] Ibrutinib (50g) was dissolved in methanol (750 m ) at 55 °C. Solution was filtered and cooled to 25 to 30 °C. During stirring cold water (1125 m ) at 15-20 °C was added in 2 hours. After addition, temperature was below 29 °C and crystallization occurred. Suspension was cooled to 5-10 °C and stirred for 4 hours. Material vas filtered and rinsed with chilled water. Wet material was suspended in methanol : water mixture (8V:2V) and stirred for 4 hours. Suspension was filtered and so obtained material was dried in vacuum dryer at 30 °C. Dried product (36 g) moisture content was 0.26% and content of residual methanol was below limit of detection.

Example 2:

[0112] Ibrutinib (50g) was dissolved in methanol (500 mb) at 55 °C. Solution was filtered and cooled to 30-35 °C. During stirring water (150 mb) at 20°C and seeding crystals (1500 mg), obtained by the Example 1, were added into the mixture at temperature 33 °C. East lot of water (600 mb) at 20 °C was added in 2 hours. After addition temperature was below 30 °C. Suspension was cooled to 5-10 °C and stirred for 4 hours. Material was filtered and rinsed with chilled water. Wet material was suspended in methanol : water mixture (8V:2V) and stirred for 4 hours. Suspension was filtered and so obtained material was dried in vacuum dryer at 30 °C. Dried product (37 g) moisture content was 0.27% and content of residual methanol was below limit of detection.

Example 3:

[0113] Ibrutinib (35g) was dissolved in methanol (350 mb) at 55 °C. Solution was filtered and cooled to 30-35 °C. During stirring water (70 mb) at 5-10°C and seeding crystals (350 mg) were added into the mixture at temperature 32 °C. East lot of water (455 mb) at 20 °C was added in 1 hour. After addition temperature was 30 °C. Suspension was cooled to 5-10 °C and stirred for 4 hours. Material was filtered and rinsed with chilled water and so obtained material was dried in vacuum dryer at 30 °C. Dried product (29.5 g grams) moisture content was 0.46% and content of residual methanol was below limit of detection.

Example 4:

[0114] Ibrutinib (50g) was dissolved in mixture of methanol (500 mb) and water (100 mb) at 52 °C. Clear solution was filtered through 0.5 urn filter, cooled to 30 °C and seeding crystals of form KI (500 mg) were added. After seeding suspension was left to crystallize for 30 minutes followed by heating of suspension to 35 °C over 2 hours. After 35 °C was reached suspension was stirred for additional 2 hours. Preheated water at 33 °C (650 mb) was gradually added into the suspension over 1 hour. Suspension was stirred for 2 hour at 35 °C and material was filtered and dried in vacuum try dryer at 30 °C under vacuum of 100 mbar and nitrogen flow. Dried product (44.3 g) moisture content was 0.31% and content of residual methanol was below limit of detection.

Example 5:

[0115] Results of intrinsic dissolution rate (IDR) analysis for the crystalline Form KI of ibrutinib and the crystalline Form A of ibrutinib are presented in the Table here below: