CA3006124A1 - Novel crystalline forms of ibrutinib - Google Patents

Abstract

The present invention provides novel crystalline forms of lbrutinib.
Specific crystalline forms provided by the present invention include lbrutinib Form APO-I, an anhydrous form; APO-II, a methyl benzoate solvate of lbrutinib; and APO-IV, a methyl salicylate solvate of lbrutinib.

Description

NOVEL CRYSTALLINE FORMS OF IBRUTINIB
TECHNICAL FIELD
[0001] The present invention is directed to novel crystalline forms of Ibrutinib and processes for the preparation thereof.
BACKGROUND

[0002] The compound 1-[(3R)-3-[4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-y1]-1-piperidiny1]-2-propen-1-one (1), commonly known as Ibrutinib, is described in WO 2008/039218 A2, for instance, in Example lb.
Ibrutinib is marketed in the United States as IMBRUVICA , and is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.
0_0 N
(1) '--- \
,N
N
/N---C--________________________________________ 0

[0003] Crystalline forms of Ibrutinib are known, and have been disclosed, for example, in WO 2013/184572 Al, which reports non-solvated lbrutinib Forms A, B and C, as well as solvated Forms D, E and F, formed with methyl isobutyl ketone, toluene and methanol, respectively. Further crystalline forms, including anhydrous, solvated and co-crystal forms are reported, for example, in WO
2015/081180 Al, WO 201 5/1 45415 A2, CN 103923084 A, WO 2016/025720 Al, CN 105294696 A, CN 105646498 A, CN 105646499 A, CN105646484 A, WO
2016/079216 Al, WO 2016/139588 Al, ON 106008529 A, WO 2016/150349 Al, WO 2016/170545 Al, WO 2016/156127 Al, WO 2016/160598 Al and WO
2016/160604 Al.

[0004] According to publicly available regulatory approval documents for Ibrutinib, such as the Australian Public Assessment Report (AusPAR), the drug substance Ibrutinib in the approved drug product IMBRUVICAO, is anhydrous Form A. This form of the drug substance is reported to exhibit pH dependent solubility, and to fall within Class II of the Biopharmaceutics Classification System (BCS). Class ll drug substances have high permeability but low solubility, which can present a challenge to achieving good bioavailability. Other anhydrous forms of Ibrutinib, including Form B, are also reported to have low aqueous solubility.

[0005] Known approaches to improving solubility and/or dissolution, and potentially the bioavailability, of a particular crystalline form of a Class II drug substance include, for example, particle size reduction techniques, formulation of the drug substance as the amorphous form, and formulation together with solubilizing excipients. According to the European CHMP Assessment Report (EMA/CHMP/645137/2014), the drug substance Ibrutinib in capsule dosage forms of IMBRUVICAO, is subjected to micronization to facilitate dissolution in the drug product.

[0006] A further consideration related to Ibrutinib drug products is the availability of a high-load tablet formulation of IMBRUVICAO, which delivers more drug substance per dose unit allowing for a reduction in the number of dose units administered to patients daily. High-load tablet formulations of Ibrutinib are described in, for example, US 2016/0256397 Al and WO 2017/125424 Al. Due to the increased amount of lbrutinib compared to the other components of such formulations, the physico-chemical characteristics of the drug substance, such as density, flow properties, compressibility and stability, have a considerable influence on the attributes and acceptability of the formulation. For example, both US 2016/0256397 Al and WO 2017/125424 Al subject Ibrutinib to wet granulation, which is used in the preparation of high-load formulations to provide particles having suitable physical attributes amenable to tabletting. Because wet-granulation involves physical agitation of the solid lbrutinib in the presence of water, the input crystalline form of the drug substance is necessarily stable to moisture, mechanical agitation, and any localized heat generated as a by-product of the agitation to avoid unintended crystalline form transition.

[0007] In some cases, the use of solvated forms of a drug substance can be useful in the development of a low solubility drug substance such as Ibrutinib since incorporation of a solvent molecule into the crystal lattice of a substance can directly alter the solubility and/or dissolution characteristics of the substance.
Depending on the pharmaceutical acceptability and toxicity of the solvent, such a solvate form can be formulated to provide a drug product having enhanced dissolution and potentially improved bioavailability. Furthermore, solvated forms having physico-chemical attributes that are amenable to formulation processes, such as granulation and tabletting, can be formulated to provide drug products having higher dosage strength, allowing for the administration of fewer dose units daily.

[0008] Additionally, solvated crystalline forms of Ibrutinib may be useful as intermediates in the provision of amorphous forms of Ibrutinib. Although amorphous forms of a drug substance typically exhibit more favourable solubility and/or dissolution characteristics than corresponding crystalline forms, achieving the high purity required for the bulk drug substance can be challenging when using amorphous forms owing to the nature of the processes typically employed for their preparation, such as spray drying, evaporation and lyophilisation.
Unlike crystallization procedures, such preparative procedures do not allow for purification of the drug by separation of the drug from impurities that remain dissolved in the crystallization solvent. As a result, when employing these techniques for the preparation of amorphous forms, the purity of the input drug must equal or exceed the expected purity of the final bulk drug substance.
When crystalline forms of a drug are not used as intermediates in the preparation of an amorphous drug substance, it is necessary to purify the drug by non-crystallographic techniques, which can complicate a commercial manufacturing process, or to conduct any necessary purification procedures on an earlier intermediate compound in the synthesis of the drug (with the further requirement that conversion of this intermediate to the drug does not result in the introduction of further impurities). In this way, crystalline solvate forms of Ibrutinib, which may be useful in the provision of amorphous forms of lbrutinib, can contribute to the development of procedures for improving the dissolution properties of this drug substance.

[0009] Although solvates may be sought after, predicting the properties of an as yet undiscovered solvate form of a drug substance is currently not possible.
Further, there is no way to predict whether a drug substance and solvent molecule will co-crystallize in the same crystal lattice, or the conditions under which co-crystallization will occur. Unlike the formation of salts, solvate formation is not aided by the formation of a strong ionic bond between acidic and basic moieties, but instead relies upon weaker non-ionic interactions.

[0010] Known solvated and hydrated crystalline forms of lbrutinib are associated with various problems, such as reproducibility problems associated with the variable incorporation of water/solvent, low onset of dehydration of hydrated forms, the incorporation or use of toxic or questionable solvents for which no adequate safety data is available according to established ICH
(International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines such as Q3C(R5), or preparations that are impractical for commercial use. The tendency of forms to dehydrate limits their usefulness in commercial products since it requires specialized practices to avoid dehydration during drying, handling, storage and formulation activities. Furthermore, the variable and/or undefined nature of some of these forms has regulatory implications, as the characteristics of an active pharmaceutical ingredient must be well-defined and controlled.

[0011] Different crystalline forms of the same compound may have different packing, thermodynamic, spectroscopic, kinetic, surface and mechanical properties. For example, different crystalline forms may have different stability properties. A particular crystalline form may be more sensitive to heat, relative humidity (RH) and/or light. Alternatively or additionally, a particular crystalline form may provide more compressibility and/or density properties thereby providing more desirable characteristics for formulation and/or product manufacturing. Particular crystalline forms may also have different dissolution rates, thereby providing different pharmacokinetic parameters, which allow for specific forms to be used in order to achieve specific pharmacokinetic targets.
Different physical properties of crystalline forms may also affect their processing.
For example, a particular crystalline form may be more resistant to flow, or may be more difficult to filter and/or wash.

[0012] Although general approaches to crystalline form screening of active pharmaceutical ingredients are known, it is well established that the prediction of whether any given compound will exhibit polymorphism is not possible.
Furthermore, prediction of the properties of any unknown crystalline forms, and how they will differ from other crystalline forms of the same compound, remains even more elusive (Joel Bernstein, Polymorphism in Molecular Crystals, Oxford University Press, New York, 2002, page 9).

[0013]
Therefore, there exists a need for novel crystalline forms of Ibrutinib for use in providing improved drug products containing Ibrutinib and their manufacture.
SUMMARY

[0014] The lbrutinib crystalline forms of the present invention exhibit differences in properties when compared to the known crystalline forms of lbrutinib. Depending on the specific crystalline form of the invention used, properties that differ between the invention and known crystalline forms of lbrutinib include:
packing properties such as molar volume, density and hygroscopicity; thermodynamic properties such as melting and solubility;
kinetic properties such as dissolution rate and chemical/polymorphic stability;
surface properties such as crystal habit; or mechanical properties such as hardness, tensile strength, compactibility, tableting, handling, flow, and blending.

[0015] Additionally, the solvated crystalline forms of the present invention incorporate solvents included in the U.S. Food & Drug Administration's (FDA's) Generally Recognized As Safe (GRAS) list or Everything Added to Food in the United States (EAFUS) list. The GRAS list is an inventory of substances generally recognized by the FDA as having been adequately shown to be safe under the conditions of intended use. The EAFUS list contains ingredients added directly to food that the FDA has either approved as food additives, or has listed or affirmed as being GRAS. The solvated crystalline forms of the present invention are also highly stable, having high onsets of desolvation (above 100 C) and fail to desolvate even upon storage for 11 months in humid and high temperature conditions. The solvated crystalline forms of the present invention are well-defined and controllable as evidenced by single crystal X-ray diffraction (SCXRD) data. Furthermore, the crystalline forms of the present invention may be prepared by facile and industrially advantageous processes when compared to known crystalline forms of Ibrutinib in the art.

[0016] Differences in the properties of the crystalline forms of the present invention provide practical advantages that can be exploited to meet specific needs in the manufacture and formulation of Ibrutinib. For example, one or more solvated crystalline forms of the present invention use solvents and reagents which are more pharmaceutically acceptable and environmentally friendly than the solvents used to prepare some of the known forms of Ibrutinib.

[0017] Accordingly, in a first aspect of the present invention, there is provided a crystalline form of Ibrutinib, Form APO-I, characterized by a powder X-ray diffraction (PXRD) diffractogram comprising peaks, expressed in degrees 26 ( 0.2 ), at 5.1 , 7.6 and 12.5 . In a preferred embodiment of the first aspect, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 20 ( 0.2 ), selected from the group consisting of: 10.1 , 11.1 , 14.2 , 15.4 , 16.3 , 17.3 and 18.7 . In a further preferred embodiment of the first aspect, the PXRD diffractogram further comprises peaks, expressed in degrees 20 ( 0.2 ), at 10.1 , 11.1 , 14.2 , 15.4 , 16.3 , 17.3 and 18.7 .

[0018] In a second aspect of the present invention, there is provided a crystalline form of Ibrutinib, comprising Ibrutinib and methyl benzoate.
Preferably, in the crystalline form of the second aspect, the molar ratio of Ibrutinib to methyl benzoate is between approximately 1:0.25 and 1:0.75. Most preferably, the molar ratio of Ibrutinib to methyl benzoate is approximately 1:0.5.

[0019] In a third aspect of the present invention, there is provided a crystalline form of Ibrutinib, FormAP0-11, comprising Ibrutinib and methyl benzoate, characterized by a PXRD diffractogram comprising peaks, expressed in degrees ( 0.2 ), at 6.4 , 10.1 and 12.8 . In a preferred embodiment of the third 15 aspect, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 20 ( 0.2 ), selected from the group consisting of: 13.8 , 17.6 , 18.4 , 19.4 , 20.4 , 21.0 , 21.7 , 23.2 , 24.1 and 24.9 . In a further preferred embodiment of the third aspect, the PXRD diffractogram further comprises peaks, expressed in degrees 20 ( 0.2 ), at 10.3 , 7.6 , 14.1 , 15.3 ,

20 17.8 , 21.1 , 23.4 , 25.7 and 27.2 . Preferably, the crystalline form of the third aspect of the invention provides a PXRD diffractogram that is substantially the same in appearance as the representative PXRD diffractogram of Ibrutinib Form APO-II provided in Figure 3. In a further preferred embodiment of the third aspect, the molar ratio of lbrutinib to methyl benzoate is approximately 1:0.5.
[0020] In a fourth aspect of the present invention, there is provided a crystalline form of Ibrutinib, comprising Ibrutinib and methyl salicylate.
Preferably, in the crystalline form of the fourth aspect, the molar ratio of Ibrutinib to methyl salicylate is between approximately 1:0.25 and 1:0.75.
Most preferably, the molar ratio of Ibrutinib to methyl salicylate is approximately 1:0.5.

[0021] In a fifth aspect of the present invention, there is provided a crystalline form of lbrutinib, APO-IV, comprising lbrutinib and methyl salicylate, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 ( 0.2 ), at 6.4 , 10.1 and 12.8 . In a preferred embodiment of the fifth aspect, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 20 ( 0.2 ), selected from the group consisting of: 13.8 , 17.6 , 18.4 , 19.4 , 20.4 , 21.0 , 21.7 , 23.2 , 24.1 and 24.9 . In a further preferred embodiment of the fifth aspect, the PXRD diffractogram further comprises peaks, expressed in degrees 20 ( 0.2 ), at 13.8 , 17.6 , 18.4 , 19.4 , 20.4 , 21.0 , 21.7 , 23.2 , 24.1 and 24.9 . Preferably, the crystalline form of the fifth aspect of the invention provides a PXRD diffractogram that is substantially the same in appearance as the representative PXRD diffractogram of lbrutinib Form APO-IV provided in Figure 6. In a further preferred embodiment of the fifth aspect, the molar ratio of lbrutinib to methyl salicylate is approximately 1:0.5.

[0022] In a sixth aspect of the present invention, there is provided a pharmaceutical composition comprising a crystalline form of lbrutinib according to any one of the first, second, third, fourth or fifth aspects of the invention, and one or more pharmaceutically acceptable excipients.
Preferably, the pharmaceutical composition is in the form of a solid dosage form. Most preferably, the pharmaceutical composition is a capsule or a tablet.

[0023] In a seventh aspect of the present invention, there is provided a use of a crystalline form of Ibrutinib according to any one of the first, second, third, fourth or fifth aspects of the invention, or the pharmaceutical composition of the sixth aspect of the invention, in the treatment of cancer. In a preferred embodiment of the seventh aspect, the cancer is mantle cell lymphoma.

[0024]
Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Embodiments of the present invention are described, by way of example only, with reference to the attached Figures.

[0026] Figure 1 is a PXRD diffractogram of lbrutinib Form APO-I as prepared in Example 1.

[0027] Figure 2 is a PXRD diffractogram of Ibrutinib Form APO-I as prepared in Example 2.

[0028] Figure 3 is a PXRD diffractogram of lbrutinib Form APO-II.

[0029] Figure 4 is an Oak Ridge Thermal Ellipsoid Plot (ORTEP) illustration of the SCXRD of Form APO-II.

[0030] Figure 5 is a calculated PXRD diffractogram of Form APO-II
based on Single Crystal X-Ray Diffraction (SCXRD).

[0031] Figure 6 is a PXRD diffractogram of lbrutinib Form APO-IV.

[0032] Figure 7 is an ORTEP illustration of the SCXRD of Form APO-IV.

[0033] Figure 8 is a calculated PXRD diffractogram of Form APO-IV based on SCXRD.
DETAILED DESCRIPTION

[0034] The present invention provides novel crystalline forms of lbrutinib providing improved properties when compared to known crystalline forms of Ibrutinib. Depending on the specific crystalline form of the invention used, properties that differ between the invention and the known crystalline forms of Ibrutinib include: packing properties such as molar volume, density and hygroscopicity; thermodynamic properties such as melting and solubility;
kinetic properties such as dissolution rate and chemical/polymorphic stability;
surface properties such as crystal habit; and mechanical properties such as hardness, tensile strength, compactibility, tableting, handling, flow, and blending.

[0035] Further, the novel solvated forms of the present invention incorporate solvents found in the U.S. Food & Drug Administration's GRAS and EAFUS lists, and are stable, well-defined and controllable (i.e., the constitution of the solvates have, to date, not shown sensitivity to extrinsic factors such as atmospheric moisture or temperature). Furthermore, the crystalline forms of the present invention may be prepared by facile and industrially advantageous processes when compared to the crystalline forms of lbrutinib known in the art. The improved properties provided by the novel crystalline forms of the present invention provide practical advantages over known forms of lbrutinib that can be exploited to meet specific needs in the manufacture and formulation of Ibrutinib.

[0036] Depending on the manner in which the embodiments of the invention are prepared and the methodology and instrument used for PXRD analysis, the intensity of a given peak observed in a PXRD diffractogram may vary when compared to the same peak in the representative PXRD diffractograms provided in Figures 1, 2, 3 and 6. Thus, differences in relative peak intensities between peaks in a PXRD diffractogram for a given crystalline form may be observed when compared to the relative peak intensities of the peaks in the representative PXRD diffractograms of Figures 1, 2, 3 and 6. Any such differences may be due, in part, to the preferred orientation of the sample and its deviation from the ideal random sample orientation, the preparation of the sample for analysis, and the methodology applied for the analysis. Such variations are known and understood by a person of skill in the art, and any such variations do not depart from the invention disclosed herein.

[0037] In addition to the differences in relative peak intensities that may be observed in comparison to the representative PXRD diffractograms provided in Figures 1, 2, 3 and 6, it is understood that individual peak positions may vary between 0.2 2e from the values observed in the representative PXRD

diffractograms provided in Figures 1, 2, 3 and 6 for the crystalline forms of the invention, or listed in Tables 1, 2, 3 and 5. Such variations are known and understood by a person of skill in the art, and any such variations do not depart from the invention disclosed herein.

[0038] Further, it is understood that, depending on the instrument used for X-ray analysis and its calibration, uniform offsets in the peak position of each peak in a PXRD diffractogram of greater that 0.2 28 may be observed when compared to the representative PXRD diffractograms provided in Figures 1, 2, 3 and 6. Thus, PXRD diffractograms of the crystalline forms of the present invention may, in some circumstances, display the same relative peak positions as observed in the representative PXRD diffractograms provided in Figures 1, 2, 3 and 6, with the exception that each peak is offset in the same direction, and by approximately the same amount, such that the overall PXRD diffractogram is substantially the same in appearance as a PXRD diffractogram of Figures 1, 2, and 6, with the exception of the uniform offset in peak positions. The observation of any such uniform peak shift in a PXRD diffractogram does not depart from the invention disclosed herein given that the relative peak positions of the individual peaks within the PXRD diffractogram remain consistent with the relative peak positions observed in the PXRD diffractograms of Figures 1, 2, 3 and 6 for the crystalline forms of the invention.

[0039] As used herein, the term 'crystalline form' refers to a substance with a particular arrangement of molecular components in its crystal lattice, and which may be identified by physical characterization methods such as PXRD. As used herein, the term crystalline form is intended to include single-component and multiple-component crystalline forms of Ibrutinib. Single-component forms of Ibrutinib consist solely of Ibrutinib in the repeating unit of the crystal lattice.
Multiple-component forms of lbrutinib include solvates of Ibrutinib wherein a solvent is also incorporated into the crystal lattice.

[0040] As used herein, the term 'solvate' refers to a multiple-component crystalline form as defined above containing both lbrutinib and a co-former which is liquid under ambient conditions.

[0041] Multi-component crystalline forms comprising more than one type of molecule, such as solvates, may have some variability in the exact molar ratio of their components depending on a variety of conditions used. For example, a molar ratio of components within a solvate provides a person of skill in the art information as to the general relative quantities of the components of the solvate.
In many cases, the molar ratio may vary by 20% from a stated range. For example, with respect to the present invention, a molar ratio of 1:0.5 should be understood to include the ratios 1:0.4 and 1:0.6, as well as all of the individual ratios in between.

[0042] As used herein, when referring to a solvent content, the term "weight percentage" (wt %) refers to the ratio: weight solvent/ (weight solvent +
weight lbrutinib), expressed as a percentage.

[0043] As used herein, the term "room temperature" refers to a temperature in the range of 20 C to 25 C.

[0044] As used herein, the term "overnight" refers to a time of 16 to 24 hours.

[0045] Unless defined otherwise herein, the term "approximately", when used in reference to a weight percentage, allows for a variance of plus or minus 10 %.

[0046] When describing the embodiments of the present invention there may be a common variance to a given temperature or time that would be understood or expected by the person skilled in the art to provide substantially the same result. For example, when reference is made to a particular temperature, it is to be understood by the person skilled in the art that there is an allowable variance of 5 C associated with that temperature. When reference is made to a particular time, it is to be understood that there is an allowable variance of minutes when the time is one or two hours, and 1 hour when longer periods of time are referenced.

[0047] In a first embodiment of the present invention, there is provided a new crystalline form of lbrutinib, lbrutinib Form APO-I. Preferably, Form APO-I is unsolvated. More preferably, Form APO-I is anhydrous and unsolvated.

[0048]
lbrutinib Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 ( 0.2 ), at 5.1 , 7.6 and 12.5 . Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 20 ( 0.2 ), selected from the group consisting of: 10.1 , 11.1 , 14.2 , 15.4 , 16.3 , 17.3 and 18.7 .
More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 20 ( 0.2 ), at 10.1 , 11.1 , 14.2 , 15.4 , 16.3 , 17.3 and 18.7 .
PXRD
studies of capped and uncapped samples of lbrutinib Form APO-I have shown that this crystal form is stable following storage in stability chambers maintained at 27 C/60 % RH for at least 31 days and 40 C/75 % RH for at least 21 days.

[0049] A
first illustrative PXRD diffractogram of lbrutinib Form APO-I, as prepared in Example 1, is shown in Figure 1. A peak listing, comprising representative peaks from the PXRD diffractogram in Figure 1, and their relative intensities, is provided in Table 1.
Although illustrative of the PXRD
diffractogram that is provided for the lbrutinib Form APO-I of the present invention, the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.
Table 1: Relative peak intensities of lbrutinib Form APO-1 from Figure 1 Angle ( 20) Relative intensity (%) 5.11 100.00 7.60 9.26 10.09 8.79 11.05 7.57 12.50 20.70 14.20 10.71 15.40 5.08 16.26 2.64 17.30 ______________________________________ 6.92 _ 18.65 6.47

[0050] A
second illustrative PXRD diffractogram of Ibrutinib Form APO-I, as prepared in Example 2, which utilizes an extended drying time, is shown in Figure 2. A peak listing, comprising representative peaks from the PXRD
diffractogram in Figure 2, and their relative intensities, is provided in Table 2.
This illustrates how minor inter-batch variations in peak positions and peak intensities can be observed in the PXRD diffractogram for a given crystalline form. Thus, depending on a particular sample, the position and prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractograms and peak listings provided.
Table 2: Relative peak intensities of Ibrutinib Form APO-1 from Figure 2 Angle ( 20) Relative intensity (%) 5.18 100.00 7.66 4.69 10.07 6.65 11.05 6.45 12.48 16.92 14.29 8.31 15.51 4.56 16.37 3.35 17.37 6.34 18.65 3.32

[0051] As described in Examples 1 and 2, lbrutinib Form APO-I can be prepared by the drop-wise addition of water to a heated solution of Ibrutinib in 2,2,2-trifluoroethanol while it is allowed to cool.
Filtration of the resulting suspension provides Ibrutinib Form APO-I having a PXRD diffractogram consistent with that of Figure 1 and Figure 2.

[0052] In a second embodiment of the present invention, there is provided a new crystalline form of Ibrutinib, Ibrutinib Form APO-II, which is a solvate of Ibrutinib and methyl benzoate. Preferably, in Ibrutinib Form APO-II, the molar ratio of Ibrutinib to methyl benzoate is approximately 1:0.5.

[0053] Ibrutinib Form APO-II can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 ( 0.2 ), at 6.4 , 10.1 and 12.8 . Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 20 ( 0.2 ), selected from the group consisting of: 13.8 , 17.6 , 18.4 , 19.4 , 20.4 , 21.0 , 21.7 , 23.2 , 24.1 and 24.9 . More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 28 ( 0.2 ), at 13.8 , 17.6 , 18.4 , 19.4 , 20.4 , 21.0 , 21.7 , 23.2 , 24.1 and 24.9 . PXRD studies of capped and uncapped samples of Ibrutinib Form APO-II have shown that this crystal form is stable following storage in stability chambers maintained at 27 C/60 % RH and 40 C/75 c'/0 RH for at least 25 days.

[0054] An illustrative PXRD diffractogram of Ibrutinib Form APO-II is shown in Figure 3. A peak listing, comprising representative peaks from the PXRD
diffractogram in Figure 3, and their relative intensities, is provided in Table 3.
Although illustrative of the PXRD diffractogram that is provided for the Ibrutinib Form APO-II of the present invention, the relative intensities of the peaks are variable. Thus, depending on a particular sample, the position and prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.
Table 3: Relative peak intensities of Ibrutinib Form APO-II from Figure 3 Angle ( 20) Relative intensity (%) 6.37 40.93 9.66 27.93 10.14 46.99 12.44 19.12 12.79 48.88 13.77 23.17 17.65 47.17 17.94 27.04 18.39 70.72 19.45 100.00 20.40 77.71 21.03 22.00 21.72 50.30 22.13 30.15 23.15 44.36 24.06 11.75 24.93 16.96

[0055] As described in Examples 3 and 4, Ibrutinib Form APO-II can be prepared from a solution of Ibrutinib in methyl benzoate by heating the solution to approximately 100 C, allowing the solution to cool and then adding excess hydrocarbon anti-solvent, preferably heptane or cyclohexane, drop-wise, to promote crystallization. Filtration and drying of the resulting material provides Ibrutinib Form APO-II having a PXRD diffractogram consistent with that of Figure 3.

[0056] Single crystals of Ibrutinib were grown from a layered solution of methyl benzoate and heptanes as described in Example 5, and characterized by SCXRD. A summary of the SCXRD data is provided in Table 4. An ORTEP
illustration of the unit cell from the SCXRD structure is shown in Figure 4.
This illustration depicts a 2:1 lbrutinib:methyl benzoate solvate, i.e., the molar ratio of Ibrutinib to methyl benzoate is 1:0.5.
Table 4: Single Crystal X-Ray Diffraction Parameters of the 2:1 Ibrutinib:methyl benzoate solvate (Form APO-II) Formula C25H24N602.1/2C8H802 Formula Weight (g/mol) 508.57 Crystal System triclinic Space Group P1 Temperature, K 110 a, A 10.1282(16) b, A 10.2383(16) c, A 14.246(3) 95.523(7) 102.506(5) 115.706(4) v,A3 1268.8(4) p (g/cm3) 1.331 xõ A, (CuKa) 1.54178 Measured fraction of data 0.969 Unique reflections measured/

reflections included in refinement R1 0.0453 wR2 0.1159 R1 (all data) 0.0489 wR2 (all data) 0.1194 Goodness of Fit 1.037 Min & Max peak heights on final AF
-0.276, 0.590 Map (OA)

[0057] A calculated PXRD diffractogram based on the SCXRD data is shown in Figure 5. This calculated PXRD diffractogram shows that the single crystal analyzed provides a PXRD pattern that is consistent with the PXRD
diffractogram provided by lbrutinib Form APO-II.

[0058] In a third embodiment of the present invention, there is provided a new crystalline form of lbrutinib, lbrutinib Form APO-IV, a solvate of Ibrutinib and methyl salicylate. Preferably, in lbrutinib Form APO-IV, the molar ratio of lbrutinib to methyl salicylate is approximately 1:0.5.

[0059] lbrutinib Form APO-IV can be characterized by a PXRD
diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 ( 0.2 ), at 6.4 , 10.2 and 12.9 . Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 28 ( 0.2 ), selected from the group consisting of: 13.9 , 17.7 , 18.4 , 19.4 , 20.5 , 21.3 , 21.8 , 23.2 , 24.2 and 24.9 . More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 20 ( 0.2 ), at 13.9 , 17.7 , 18.4 , 19.4 , 20.5 , 21.3 , 21.8 , 23.2 , 24.2 and 24.9 . PXRD studies of uncapped samples of Ibrutinib Form APO-IV have shown that this crystal form is stable following storage in a stability chambers maintained at 40 C/75 % RH for at least 11 months.

[0060] An illustrative PXRD diffractogram of Ibrutinib Form APO-IV is shown in Figure 6. A peak listing, comprising representative peaks from the PXRD
diffractogram in Figure 6, and their relative intensities, is provided in Table 5.
Although illustrative of the PXRD diffractogram that is provided for the Ibrutinib Form APO-IV of the present invention, the relative intensities of the peaks are variable. Thus, depending on a particular sample, the position and prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.
Table 5: Relative peak intensities of Ibrutinib Form APO-IV from Figure 6 Angle ( 26) Relative intensity (%) 6.45 31.36 9.63 15.52 10.22 44.46 12.29 20.84 12.92 48.01 13.92 23.64 17.40 37.75 17.74 59.99 18.44 66.29 19.58 100.00 20.51 79.27 21.27 14.28 21.63 32.82 22.21 36.02 23.11 13.64 24.23 6.11 24.95 10.51

[0061] As described in Example 6, lbrutinib Form APO-IV can be prepared from a solution of lbrutinib in methyl salicylate by heating the solution to approximately 100 C, allowing the solution to cool, and then adding excess heptane anti-solvent drop-wise, during which time crystallization occurs.
Filtration and drying of the resulting material provides lbrutinib Form APO-IV
having a PXRD diffractogram consistent with that of Figure 6.

[0062] Single crystals of lbrutinib were grown from a layered solution of lbrutinib in methyl salicylate and heptane as described in Example 7, and characterized by SCXRD. A summary of the SCXRD data is provided in Table 6.
An ORTEP illustration of the unit cell from the SCXRD structure is shown in Figure 7. This illustration depicts a 2:1 lbrutinib:methyl salicylate solvate, i.e., the molar ratio of lbrutinib to methyl salicylate is 1:0.5.
Table 6: Single Crystal X-Ray Diffraction Parameters of the 2:1 Ibrutinib:methyl salicylate solvate (Form APO-IV) Formula C25H241\1602.%C8H803 Formula Weight (g/mol) 516.57 Crystal System triclinic Space Group P 1 Temperature, K 110 a, A 10.172(2) b, A 10.354(2) c, A 14.125(3) 96.053(11) p,. 101.675(13) 116.200(10) V, A' 1274.6(5) p (g/cm3) 1.346 k, A, (CuKoc) 1.54178 Measured fraction of data 0.969 Unique reflections measured 6218 R1 0.0659 wR2 0.1682 R1 (all data) 0.0882 wR2 (all data) 0.1935 Goodness of Fit 1.027 Min & Max peak heights on final AF
-0.285, 0.439 Map (OA)

[0063] A
calculated PXRD diffractogram based on the SCXRD data is shown in Figure 8. This calculated PXRD diffractogram shows that the single crystal analyzed provides a PXRD pattern that is consistent with the PXRD
diffractogram provided by lbrutinib Form APO-IV.

[0064] In a further embodiment of the invention, there is provided a pharmaceutical composition of Ibrutinib Form APO-I, a crystalline form of Ibrutinib comprising lbrutinib and methyl benzoate or a crystalline form of Ibrutinib and methyl salicylate, with one or more pharmaceutically acceptable excipients. Preferably, the pharmaceutical composition is a solid dosage form suitable for oral administration, such as a capsule, tablet, pill, powder or granulate. Most preferably, the pharmaceutical composition is a capsule or a tablet. Preferably, the pharmaceutical composition provides a dose of Ibrutinib that is equivalent to the 70 mg, 140 mg, 280 mg, 420 mg or 560 mg of Ibrutinib found in IMBRUVICA drug products.

[0065] Suitable pharmaceutically acceptable excipients are preferably inert with respect to the crystalline forms of Ibrutinib of the present invention, and may include, for example, one or more excipients selected from binders such as lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymethylcellu lose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatine, polyvinylpyrollidone (PVP) and sodium alginate; fillers or diluents such as lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g., microcrystalline cellulose, cellulose), calcium sulphate, xylitol and lactitol;
disintegrants such as croscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycollate, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose;
lubricants such as magnesium stearate, magnesium lauryl stearate, sodium stearyl fumarate, stearic acid, calcium stearate, zinc stearate, potassium benzoate, sodium benzoate, myristic acid, palmitic acid, mineral oil, hydrogenated castor oil, medium-chain triglycerides, poloxamer, polyethylene glycol and talc; and dispersants or solubility enhancing agents, such cyclodextrins, glyceryl monostea rate, hypromellose, meglumine, Poloxamer, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, polyoxylglycerides, povidone, and stearic acid. Other excipients including preservatives, stabilisers, anti-oxidants, silica flow conditioners, antiadherents or glidants may be added as required.
Suitable excipients and the preparation of solid oral dosage forms are well known to person of skill in the art, and are described generally, for example, in Remington The Science and Practice of Pharmacy 21st Edition (Lippincott Williams &
Wilkins: Philadelphia; 2006; Chapter 45).

[0066] Optionally, when the pharmaceutical compositions are solid dosage forms, the solid dosage forms may be prepared with coatings, such as enteric coatings and extended release coatings, using standard pharmaceutical coatings. Such coatings, and their application, are well known to persons skilled in the art, and are described, for example, in Remington The Science and Practice of Pharmacy 21st Edition (Lippincott Williams & Wilkins:
Philadelphia;
2006; Chapter 47).

EXAMPLES

[0067] The following non-limiting examples are illustrative of some of the aspects and embodiments of the invention described herein.

[0068]. The Ibrutinib used as a starting material in the following examples was consistent with either lbrutinib Form A (Example 1-3, 4-7) or lbrutinib Form C
(Example 4), which are reported in WO 2013/184572 Al. Other polymorphic forms are equally suitable as starting material when preparing the novel crystalline forms of lbrutinib of the present invention.
Powder X-Ray Diffraction Analysis

[0069] Data were acquired on a PANanalytical X-Pert Pro MPD diffractometer with fixed divergence slits and an X'Celerator RTMS detector. The diffractometer was configured in Bragg-Brentano geometry; data was collected over a 2-theta range of 30 to 40 using CuKa radiation at a power of 40 mA and 45 kV. CuK13 radiation was removed using a divergent beam nickel filter. A step size of 0.0170 was used. Samples were rotated to reduce preferred orientation effects.
Samples were lightly ground prior to analysis.
Single Crystal Data Collection and Processing

[0070] Samples for SCXRD analysis were mounted on a Mitegen polyimide micromount with a small amount of Paratone N oil. All X-ray measurements were made on a Bruker-Nonius KappaCCD Apex2 diffractometer at a temperature of 110 K. In the case of Form APO-II, the unit cell dimensions were determined from a symmetry constrained fit of 9826 reflections with 6.5 < 2q <
130.42 and the data collection strategy was a number of w and j scans which collected data up to 132.544 (2q). In the case of Form APO-IV, the unit cell dimensions were determined from a symmetry constrained fit of 4980 reflections with 6.56 <20 < 128.88 and the data collection strategy was a number of co and cp scans which collected data up to 132.158 (20). Frame integration was performed using SAINT (Bruker-AXS, SAINT Version 2013.8, 2013). The resulting raw data was scaled and absorption corrected using a multi-scan averaging of symmetry equivalent data using SADABS (Bruker-AXS, SADABS
Version 2012.1, 2012).
Single Crystal Structure Solution and Refinement

[0071] Single crystal structures were solved by using a dual space methodology with the SHELXT program (Sheldrick, G. M., Acta Cryst. 2015, A71, 3-8). All non-hydrogen atoms were obtained from the initial solution, with hydrogen atoms being introduced at idealized positions and allowed to ride on the parent atom. The structural model was fit to the data using full matrix least-squares based on F2. Calculated structure factors include corrections for anomalous dispersion from the usual tabulation. The absolute configuration was determined by the calculation of Parsons quotients (Parsons, S.; Flack, H. D.
and Wagner, T. Acta Cryst. 2013, 869, 249-259). Structure refinement was conducted using the SHELXL-2014 program from the SHELX suite of crystallographic software (Sheldrick, G. M., Acta Cryst. 2015, C71, 3-8).
Graphic plots were produced using the NRCVAX program suite (Gabe, E. J.; Le Page, Y.;
Charland, J. P.; Lee, F. L. and White, P. S. J. App!. Cryst. 1989, 22, 384-387).
Calculated PXRD Diffractograms

[0072] PXRD diffractograms were calculated from SCXRD data using the Mercury software package (CCDC, version 3.9) with A=1.54056 as the source.
Differential Scanning Calorimetry Analysis

[0073] The DSC thermograms were collected on a Mettler-Toledo 821e instrument. Samples (1 ¨ 5 mg) were weighed into a 40 pL aluminum pan and were crimped closed with an aluminum lid. The samples were analyzed under a flow of nitrogen (ca. 50 mL/min) at a scan rate of 10 C/minute.

Example 1: Preparation of Ibrutinib Form APO-I

[0074] A magnetically stirred suspension of Ibrutinib (500 mg) in 2,2,2-trifluroethanol (5 mL) was warmed to 50 C for approximately 1 hour to afford a solution. The solution was removed from the heat source and water (40 mL) was added drop-wise over one hour over which time the mixture turned to a milky suspension. After stirring overnight, the solid was collected by filtration and washed with water (5 mL) to afford Ibrutinib Form APO-I as a white solid (420 mg, 84 % yield). The PXRD diffractogram of a sample prepared by this method is shown in Figure 1.
Example 2: Preparation of Ibrutinib Form APO-I

[0075] A magnetically stirred suspension of Ibrutinib (500 mg) in 2,2,2-trifluroethanol (5 mL) was warmed to 50 C for approximately 1 hour to afford a solution. The solution was removed from the heat source and water (40 mL) was added drop-wise over one hour over which time the mixture turned to a milky suspension. After stirring overnight, the solid was collected by filtration and washed with water (4 mL). Drying overnight under high vacuum at room temperature afforded Ibrutinib Form APO-I as a white solid (400 mg, 80 %
yield).
The PXRD diffractogram of a sample prepared by this method is shown in Figure 2.
Example 3: Preparation of Ibrutinib Form APO-II

[0076] A
stirred suspension of Ibrutinib (400 mg) in methyl benzoate (10 mL) was heated to 100 C for approximately 1 hour to afford a solution. The solution was allowed to cool to room temperature prior to drop-wise addition of heptane (50 mL) over approximately 1 hour. The resulting turbid suspension was stirred overnight. The solid was collected by filtration, washed with heptane (10 mL) and dried under high vacuum at room temperature to afford lbrutinib Form APO-II as a white solid (400 mg, 78 % yield). The PXRD diffractogram of a sample prepared by this method is shown in Figure 3. DSC analysis of this sample showed an endothermic peak corresponding with desolvation having an onset at about 141 C and a peak maximum at about 143 C.

[0077] 1H-NMR (d6-DMS0) 6 = 8.26 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.62-7.72 (m, 2.5H), 7.53 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.9 Hz, 2H), 7.09-7.24 (m, 5H), 6.66-6.95 (m, 1H), 6.10 (t, J = 17.9 Hz, 1H), 5.71 (d, J = 9.9 Hz, 0.5H), 5.59 (d, J = 11.2 Hz, 0.5H), 4.61-4.80 (m, 1H), 4.56 (d, J = 12.3 Hz, 0.5H), 4.15-4.28 (br m, 1H), 4.08 (d, J = 12.8 Hz, 0.5H), 3.86 (s, 1.5H) 3.62-3.80 (m, 0.5H), 3.07-3.15 (m, 1H), 3.01 (br t, J = 12.1 Hz, 0.5H), 2.19-2.36 (m, 1H), 2.06-2.19 (m, 1H), 1.87-2.00 (m, 1H), 1.47-1.70 (m, 1H).
Example 4: Preparation of lbrutinib Form APO-II

[0078] A stirred suspension of lbrutinib (5 g) in methyl benzoate (22.5 mL) was heated to 100 C for approximately 1 hour to afford a solution. The solution was allowed to cool to room temperature to afford a suspension to which was added heptane (22.5 mL) drop-wise. The resulting suspension was stirred for 30 minutes prior to collection of the solid by filtration. The filter cake was washed with heptane (2 x 3 mL) and dried under high vacuum at 30 C for 2 hours to afford lbrutinib Form APO-II as a white solid (4.8 g, 96 % yield). The PXRD
diffractogram of a sample prepared by this method was consistent with that shown in Figure 3.
Example 5: Preparation of Single Crystals of lbrutinib Form APO-II

[0079] A stirred suspension of lbrutinib (100 mg) in methyl benzoate (4 mL) was heated to 100 C for approximately 2 hours to afford a clear solution, with a clarification filtration being performed before cooling the solution to room temperature. To the cooled solution was slowly layered heptane (15 mL). The flask was left undisturbed at room temperature for several days, with crystal growth beginning after one day. Crystals were collected after gently decanting off the solvent, with one crystal being selected for SCXRD analysis. Figure 4 depicts an ORTEP illustration of the SCXRD of the Form APO-II crystals prepared by this method. Figure 5 depicts a calculated PXRD based on the SCXRD of this sample acquired according to the conditions given above.
Example 6: Preparation of lbrutinib Form APO-IV

[0080] A
stirred suspension of lbrutinib (413 mg) in methyl salicylate (8 mL) was heated to 100 C for approximately 1 hour to afford a clear solution, which was then clarified by filtration before being cooled to room temperature.
Heptane (80 mL) was added to the solution drop-wise over approximately 2.5 hours. The resulting turbid suspension was stirred overnight, and the solid was collected by filtration, washed with heptane (2 x 10 mL), and dried under high vacuum at room temperature to afford lbrutinib Form APO-IV as a white solid (438 mg, 90 %
yield). The PXRD diffractogram of a sample prepared by this method is shown in Figure 6.

[0081] 1H-NMR (d5-DMS0) 6 = 10.50 (s, 0.5H), 8.26 (s, 1H), 7.79 (dd, 0.5H), 7.65 (d, 2H), 7.53 (t, 0.5H), 7.44 (t, 2H), 7.09-7.24 (m, 5H), 6.66-6.99 (m, 1H), 6.83 (m, 05H), 6.72 (m, 0.5), 6.10 (t, 1H), 5.71 (d, 0.5H), 5.60 (d, 0.5H), 4.61-4.80 (m, 1H), 4.56 (d, 0.5H), 4.15-4.28 (m, 1H), 4.08 (d, 0.5H), 3.89 (s, 1.5H) 3.62-3.80 (m, 0.5H), 3.07-3.25 (m, 1H), 3.01 (br t, 0.5H), 2.19-2.36 (m, 1H), 2.06-2.19 (m, 1H), 1.87-2.00 (m, 1H), 1.47-1.70 (m, 1H).
Example 7: Preparation of Single Crystals of Ibrutinib Form APO-IV

[0082] A stirred suspension of lbrutinib (36 mg) in methyl salicylate (2 mL) was heated to 100 C for approximately 2 hours to afford a clear solution, which was then subjected to a clarification filtration before being cooled to room temperature. To the cooled solution was slowly layered heptane (10 mL). The flask was left undisturbed at room temperature for several days. Single crystal growth began after 1 day. Crystals were collected after gently decanting off the solvent, with one crystal being selected for SCXRD analysis. Figure 7 depicts an ORTEP illustration of the SCXRD of the Form APO-II crystals prepared by this method. Figure 8 depicts a calculated PXRD based on the SCXRD of this sample acquired according to the conditions given above.

Claims (24)

What is claimed is:

1. A crystalline form of lbrutinib characterized by a powder X-ray diffraction (PXRD) diffractogram comprising peaks, expressed in degrees 2.theta. ( 0.2°), at 5.1°, 7.6° and 12.5°.

2. The crystalline form of lbrutinib of claim 1, characterized by a PXRD
diffractogram further comprising at least three peaks, expressed in degrees 2.theta. ( 0.2°), selected from the group consisting of: 10.1°, 11.1°, 14.2°, 15.4°, 16.3°, 17.3° and 18.7°.

3. The crystalline form of lbrutinib of claim 1, characterized by a PXRD
diffractogram further comprising peaks, expressed in degrees 2.theta. ( 0.2°), at 10.10, 11.1°, 14.2°, 15.4°, 16.3°, 17.3°
and 18.7°.

4. The crystalline form of any one of claims 1 to 3, providing a PXRD
diffractogram substantially the same in appearance as the PXRD diffractogram provided in Figure 1 or 2.

5. A crystalline form of lbrutinib comprising lbrutinib and methyl benzoate.

6. The crystalline form of claim 5, wherein the molar ratio of lbrutinib to methyl benzoate is between approximately 1:0.25 and 1:0.75.

7. The crystalline form of claim 5, wherein the molar ratio of lbrutinib to methyl benzoate is approximately 1:0.5.

8. A crystalline form of lbrutinib that comprises lbrutinib and methyl benzoate characterized by a powder X-ray diffraction (PXRD) diffractogram comprising peaks, expressed in degrees 2.theta. ( 0.2°), at 6.4°, 10.1° and 12.8°.

9. The crystalline form of claim 8, further comprising at least three peaks, expressed in degrees 2.theta. ( 0.2°), selected from the group consisting of: 13.8°, 17.6°, 18.4°, 19.4°, 2.theta..4°, 21.0°, 21.7°, 23.2°, 24.1° and 24.9°.

10. The crystalline form of claim 8, further comprising peaks, expressed in degrees 2.theta. (~ 0.2°), at 13.8°, 17.6°, 18.4°, 19.4°, 20.4°, 21.0°, 21.7°, 23.2°, 24.1°
and 24.9°.

11. The crystalline form of any one of claims 8 to 10, providing a PXRD
diffractogram substantially the same in appearance as the PXRD diffractogram provided in Figure 3.

12. A crystalline form of lbrutinib comprising lbrutinib and methyl salicylate.

13. The crystalline form of claim 12, wherein the molar ratio of lbrutinib to methyl salicylate is approximately 1:0.25 and 1:0.75.

14. The crystalline form of claim 12, wherein the molar ratio of lbrutinib to methyl salicylate is approximately 1:0.5.

15. A crystalline form of lbrutinib that comprises lbrutinib and methyl benzoate characterized by a powder X-ray diffraction (PXRD) diffractogram comprising peaks, expressed in degrees 2.theta. (~ 0.2°), at 6.4°, 10.2° and 12.9°.

16. The crystalline form of claim 15, further comprising at least three peaks, expressed in degrees 2.theta. (~ 0.2°), selected from the group consisting of: 13.9°, 17.7°, 18.4°, 19.4°, 20.5°, 21.3°, 21.8°, 23.2°, 24.2° and 24.9°.

17. The crystalline form of claim 15, further comprising peaks, expressed in degrees 2.theta. (~ 0.2°), at 13.9°, 17.7°, 18.4', 19.4°, 20.5°, 21.3°, 21.8°, 23.2°, 24.2°
and 24.9°.

18. The crystalline form of any one of claims 15 to 17, providing a PXRD
diffractogram substantially the same in appearance as the PXRD diffractogram provided in Figure 6.

19. A pharmaceutical composition comprising the crystalline form of lbrutinib according to any one of claims 1 to 18, and one or more pharmaceutically acceptable excipients.

20. The pharmaceutical composition of claim 19, wherein the the crystalline form of lbrutinib is a crystalline form according to any one of claims 5 to 11.

21. The pharmaceutical composition of claim 19 or 20, wherein the pharmaceutical composition is a capsule or a tablet.

22. The use of the crystalline form of lbrutinib according to any one of claims 1 to 18 in the treatment of cancer.

23. The use of claim 22, wherein the crystalline form of lbrutinib is a crystalline form according to any one of claims 5 to 11.

24. The use of claim 22 or 23, wherein the cancer is mantle cell lymphoma.