WO2024164066A1

WO2024164066A1 - Crystalline forms of acalabrutinib maleate

Info

Publication number: WO2024164066A1
Application number: PCT/CA2024/050136
Authority: WO
Inventors: Jeffrey S. PRICE; Fabio E. S. Souza; Allan W. Rey; Uma Kotipalli; Mohammed Abdul Raheem; Yajun Zhao
Original assignee: Apotex Inc
Priority date: 2023-02-09
Filing date: 2024-02-02
Publication date: 2024-08-15

Abstract

The present invention provides novel crystalline forms of acalabrutinib maleate. Specific crystalline forms provided by the present invention include acalabrutinib Form APO-I, Form APO-II, and Form APO-VI, 1,2-propanediol solvates of acalabrutinib maleate; Form APO-III, a crystalline form of acalabrutinib maleate; Form APO-IV and Form APO-V, 1,2-ethanediol solvates of acalabrutinib maleate, and Form APO-VII, a 1,2,3-propanetriol of acalabrutinib maleate. Also provided are pharmaceutical compositions including the acalabrutinib maleate crystalline forms and the use of these forms in the treatment of a Bruton's Tyrosine Kinase (Btk)-mediated disorder.

Description

CRYSTALLINE FORMS OF ACALABRUTINIB MALEATE

TECHNICAL FIELD

[0001] The present invention is directed to novel crystalline forms of acalabrutinib maleate, processes for the preparation thereof, pharmaceutical compositions containing these forms, and their use in the treatment of Bruton’s tyrosine kinase (Btk)- mediated disorders, including certain forms of cancer.

BACKGROUND

[0002] Acalabrutinib (1 ), or 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2- yl]imidazo[1 ,5-a]pyrazin-1-yl}-/V-(pyridin-2-yl)benzamide is the active pharmaceutical ingredient (API) in the form of the maleate salt monohydrate in CALQUENCE® tablets, a prescription medication for use in the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy, chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL).

[0003] WO 2017/002095 A1 , US 10,899,770 B2, WO 2021/255246 A1 , and WO 2022/234602 A1 disclose acalabrutinib maleate and crystalline forms thereof. [0004] Acalabrutinib, in the form of the free base, is the active ingredient in the capsule form of CALQUENCE® which was approved by the U.S. Food & Drug Administration (FDA) on Oct 31 , 2017. According to WO 2021/255246 A1 , administration of CALQUENCE® capsules with gastric reducing agents can decrease acalabrutinib plasma concentrations whereas solid pharmaceutical dosage forms containing acalabrutinib maleate as described therein reportedly provide less variability in acalabrutinib pharmacokinetics over a broader range of stomach pH conditions. A tablet dosage form of CALQUENCE® comprising acalabrutinib maleate monohydrate has since been approved by the FDA on Aug 3, 2022.

[0005] The solubility of crystalline forms of a drug substance in an aqueous environment often correlate to its relative bioavailability, since the manner in which the crystalline form dissolves can correspond to the amount of the drug substance that is available to be absorbed into the body to provide the intended therapeutic effect. One measure of solubility is intrinsic dissolution rate (IDR), which is defined as the dissolution rate of a substance under constant surface area conditions. For low solubility substances, higher IDR values can correlate with higher bioavailability following administration. However, if the goal is to establish bioequivalence to an approved form of a drug, such as acalabrutinib maleate monohydrate, substances with similar IDR values to the approved form are preferred. Alternatively, for the development of extended or sustained release products, forms exhibiting lower IDR values can be preferable since they can provide slower dissolution of the drug independent of the excipients used in the formulation. Prediction of the solubility and IDR of an as yet undiscovered salt or crystalline form of a substance is currently not possible.

[0006] Different crystalline forms of the same compound may have different packing, thermodynamic, spectroscopic, kinetic, surface, and/or 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. Additionally, the particular solubility characteristics of a given crystalline form in relation to undesired impurities can result in differences in the chemical purity of different crystalline forms upon isolation. Differences in stability may result from changes in chemical reactivity, such as differential oxidation. Such properties may provide for more suitable product qualities, such as a dosage form that is more resistant to discolouration when comprised of a specific crystalline form. 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.

[0007] Therefore, there exists a need for novel crystalline forms of acalabrutinib maleate for use in providing improved drug products containing acalabrutinib maleate and their manufacture.

SUMMARY

[0008] The present invention provides, inter alia, acalabrutinib maleate crystalline forms. The acalabrutinib maleate crystalline forms having a combination of properties that differ from known forms of acalabrutinib maleate including packing properties such as molar volume, density, and hygroscopicity; thermodynamic properties such as melting point and solubility; kinetic properties such as dissolution rate and chemical/polymorphic stability; surface properties such as crystal habit/particle morphology; and/or mechanical properties such as hardness, tensile strength, flow, and compactibility.

[0009] Accordingly, in a first aspect of the present invention, there is provided a crystalline form of acalabrutinib maleate that is a solvate of acalabrutinib maleate and a solvent selected from the group consisting of 1 ,2-propanediol, 1 ,2-ethanediol, 1 ,2,3- propanetriol, and mixtures thereof.

[0010] In one embodiment of the first aspect, the crystalline form is a solvate of acalabrutinib maleate and 1 ,2-propanediol. In one embodiment, the molar ratio of acalabrutinib maleate to 1 ,2-propanediol is about 1 :0.5. In one embodiment, the solvate comprises 1 ,2-propanediol in the (S)-configuration. In one embodiment, the solvate comprises 1 ,2-propanediol in the (R)-configuration. In one embodiment, the 1 ,2- propanediol is in the (S)-configuration. In one embodiment, the crystalline form is Form APO-I, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 11.3°, 14.7°, and 16.1 °. In one embodiment, the crystalline form further comprises at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of: 5.2°, 10.4°, 15.6°, 17.3°, 23.4°, and 24.2°. In one embodiment, the crystalline form further comprises peaks, expressed in degrees 26 (± 0.2°), at 5.2°, 10.4°, 15.6°, 17.3°, 23.4°, and 24.2°. In one embodiment, the crystalline form provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 29) as those shown in Figure 1. In one embodiment, the crystalline form is characterized by a DSC thermogram comprising an endothermic peak with a peak onset of about 167 °C and a peak maximum of about 170 °C. In one embodiment, the crystalline form is Form APO- II, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 11.4°, 14.8°, and 16.2°. In one embodiment, the crystalline form further comprises at least three peaks, expressed in degrees 29 (± 0.2°), selected from the group consisting of: 5.2°, 10.5°, 15.7°, 17.3°, 23.4°, and 24.7°. In one embodiment, the crystalline form further comprises peaks, expressed in degrees 29 (± 0.2°), at 5.2°, 10.5°, 15.7°, 17.3°, 23.4°, and 24.7°. In one embodiment, the crystalline form provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 29) as those shown in Figure 2. In one embodiment, the crystalline form is Form APO-VI, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 11.3°, 14.7°, and 16.0°. In one embodiment, the crystalline form further comprises at least three peaks, expressed in degrees 29 (± 0.2°), selected from the group consisting of: 5.2°, 10.4°, 15.5°, 17.3°, 23.4°, and 24.1 °. In one embodiment, the crystalline form further comprises peaks, expressed in degrees 29 (± 0.2°), 5.2°, 10.4°, 15.5°, 17.3°, 23.4°, and 24.1 °. In one embodiment, the crystalline form provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 29) as those shown in Figure 6.

[0011 ] In another embodiment of the first aspect, the crystalline form is a solvate of acalabrutinib maleate and 1 ,2,3-propanetriol. In one embodiment, the molar ratio of acalabrutinib maleate to 1 ,2,3-propanetriol is about 1 :0.5. In one embodiment, the crystalline form is Form APO-VII, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 11 .2°, 14.6°, and 17.2°. In one embodiment, the crystalline form further comprises at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of: 5.2°, 10.1 °, 11 .6°, 15.9°, 23.3°, and 24.0°. In one embodiment, the crystalline form further comprises peaks, expressed in degrees 26 (± 0.2°), 5.2°, 10.1 °, 11.6°, 15.9°, 23.3°, and 24.0°. In one embodiment, the crystalline form provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 29) as those shown in Figure 7.

[0012] In a further embodiment of the first aspect, the crystalline form is a solvate of acalabrutinib maleate and 1 ,2-ethanediol. In one embodiment, the molar ratio of acalabrutinib maleate to 1 ,2-ethanediol is about 1 :0.5. In one embodiment, the crystalline form is Form APO-IV, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 5.2°, 15.0°, and 21.9°. In one embodiment, the crystalline form further comprises at least three peaks, expressed in degrees 29 (± 0.2°), selected from the group consisting of: 10.4°, 11.6°, 15.7°, 19.2°, 22.3°, and 24.5°. In one embodiment, the crystalline form further comprises peaks, expressed in degrees 29 (± 0.2°), at 10.4°, 11.6°, 15.7°, 19.2°, 22.3°, and 24.5°. In one embodiment, the crystalline form provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 29) as those shown in Figure 4. In another embodiment, the crystalline form is Form APO-V, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 5.2°, 17.4°, and 23.8°. In one embodiment, the crystalline form further comprises at least three peaks, expressed in degrees 29 (± 0.2°), selected from the group consisting of: 10.5°, 11 .6°, 15.8°, 19.2°, 22.2°, and 25.1 °. In one embodiment, the crystalline form further comprises peaks, expressed in degrees 29 (± 0.2°), at 10.5°, 11 .6°, 15.8°, 19.2°, 22.2°, and 25.1 °. In one embodiment, the crystalline form provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 29) as those shown in Figure 5.

[0013] In a second aspect of the present invention, there is provided a crystalline form of acalabrutinib maleate, Form APO-HI, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 5.3°, 15.1 °, and 16.3°. In one embodiment, the crystalline form further comprises at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 10.6°, 11.6°, 15.9°, 17.4°, 18.7°, and 19.2°. In one embodiment, the crystalline form further comprises peaks, expressed in degrees 20 (± 0.2°), at 10.6°, 11.6°, 15.9°, 17.4°, 18.7°, and 19.2°. In one embodiment, the crystalline form provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 20) as those shown in Figure 3. In one embodiment, the crystalline form has a weight percentage of water of less than about 2.0 wt%.

[0014] In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable crystalline form of acalabrutinib according to the first or second aspects of the invention, and one or more pharmaceutically acceptable excipients. In one embodiment, the pharmaceutical composition is in the form of a solid oral dosage form. In one embodiment, the pharmaceutical composition is in the form of a tablet.

[0015] In a fourth aspect of the present invention, there is provided a use of a pharmaceutically acceptable crystalline form of acalabrutinib according to the first or second aspect, or the pharmaceutical composition of the third aspect of the invention, in the treatment of a Bruton’s Tyrosine Kinase (Btk)-mediated disorder. In one embodiment, the Btk-mediated disorder is lymphoma or leukemia. In one embodiment, the lymphoma is mantle cell lymphoma (MCL) or small lymphocytic lymphoma (SLL) and the leukemia is chronic lymphocytic leukemia (CLL).

[0016] In a fifth aspect of the present invention, there is provided a method of treating a Bruton’s Tyrosine Kinase (Btk)-mediated disorder, such as lymphoma or leukemia, comprising administering to a human subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable crystalline form according to the first or second aspects of the invention, or a combination thereof, or the pharmaceutical composition of the third aspect of the invention. [0017] 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

[0018] Embodiments of the present invention are described, by way of example only, with reference to the attached Figures.

[0019] FIG. 1 is a representative PXRD diffractogram of acalabrutinib maleate Form APO-I as prepared in Example 1.

[0020] FIG. 2 is a representative PXRD diffractogram of acalabrutinib maleate Form

APO-II as prepared in Example 2.

[0021 ] FIG. 3 is a representative PXRD diffractogram of acalabrutinib maleate Form APO-I 11 as prepared in Example 4.

[0022] FIG. 4 is a representative PXRD diffractogram of acalabrutinib maleate Form APO-IV as prepared in Example 5.

[0023] FIG. 5 is a representative PXRD diffractogram of acalabrutinib maleate Form APO-V as prepared in Example 6.

[0024] FIG. 6 is a representative PXRD diffractogram of acalabrutinib maleate Form APO-VI as prepared in Example 11 .

[0025] FIG. 7 is a representative PXRD diffractogram of acalabrutinib maleate Form APO-VII as prepared in Example 12.

[0026] FIG. 8 is a DSC thermogram of acalabrutinib maleate Form APO-I as prepared in Example 8.

[0027] FIG. 9 is an illustration of the SCXRD of acalabrutinib Form APO-I as prepared in Example 13.

DETAILED DESCRIPTION [0028] The present invention provides, inter alia, acalabrutinib maleate crystalline forms, including solvate forms comprising solvent(s) selected from the group consisting of 1 ,2-propanediol, 1 ,2-ethanediol, and 1 ,2,3-propanetriol.

[0029] The acalabrutinib maleate crystalline forms of the present invention exhibit differences in properties when compared to the known crystalline forms of acalabrutinib maleate. Depending on the specific crystalline form of the invention used, properties that differ between the invention and known crystalline forms of acalabrutinib maleate include one or more of the following: packing properties such as molar volume, density, and/or hygroscopicity; thermodynamic properties such as melting point and/or solubility; kinetic properties such as dissolution rate and/or chemical/polymorphic stability; surface properties such as crystal habit/particle morphology; and/or mechanical properties such as hardness, tensile strength, flow, and/or compactibility.

[0030] Depending on the manner in which the crystalline forms of the present invention are prepared, and the methodology and instrument used for PXRD analysis, the intensity of a given peak observed in a PXRD diffractogram of a crystalline form may vary when compared to the same peak in the representative PXRD diffractogram provided in Figures 1 to 7. 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 diffractogram of Figures 1 to 7. 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.

[0031 ] In addition to the differences in relative peak intensities that may be observed in comparison to the representative PXRD diffractogram provided in Figures 1 to 7, it is understood that individual peak positions may vary between ±0.2° 29 from the values observed in the representative PXRD d iff ractog rams provided in Figures 1 to 7 for the crystalline form of the invention, or listed in Tables 1 , 3 to 8. 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.

[0032] Further, 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° 29 may be observed when compared to the representative PXRD diffractograms provided in Figures 1 to 7. Thus, PXRD diffractograms of the crystalline form 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 to 7, 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 the PXRD diffractograms of Figures 1 to 7, 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 to 7.

[0033] Depending on the manner in which the crystalline forms are prepared, the methodology and instrument used for DSC analysis, it is understood that peaks corresponding with thermal events in a DSC thermogram may vary between ±2 °C from the values observed in the representative DSC thermogram provided in Figure 8 and described herein. 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.

[0034] 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 comprise single-component and multiple-component crystalline forms of acalabrutinib maleate. Single-component forms of acalabrutinib maleate consist solely of acalabrutinib and maleic acid in the repeating unit of the crystal lattice. Multiplecomponent forms of acalabrutinib comprise solvates and hydrates of acalabrutinib maleate wherein solvent and/or water is also incorporated into the crystal lattice. [0035] Multiple-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 multi-component crystalline form provides a person of skill in the art information as to the general relative quantities of the components of the crystalline form. 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.

[0036] As used herein, the term “weight percentage” (wt%) refers to the ratio of the weight of a subject component to the weight of the subject mixture, using the same weight unit, expressed as a percentage. For example, in reference to water content, the term “weight percentage” (wt%) refers to the ratio: weight water I (weight water + weight acalabrutinib maleate), expressed as a percentage.

[0037] As used herein, the term “acalabrutinib maleate” refers to the maleic acid salt of the compound (1 ) having a molar ratio of acalabrutinib to maleic acid of 1 : 1 .

[0038] As used herein, the term “about” means “close to” and that variation from the exact value that follows the term is within amounts that a person of skill in the art would understand to be reasonable. For example, depending on the context, when the term “about” is used with respect to a numerical value, the value may vary within a reasonable range, such as within +/-10%, +/-5%, or +/-1 % of the stated value.

[0039] As used herein, the term “room temperature” refers to a temperature in the range of 20 °C to 25 °C.

[0040] As used herein, the term “volumes” refers to the parts of solvent of liquids by volume (mL) with respect to the weight of solute (g). For example, when an experiment is conducted using 1 g of starting material and 100 mL of solvent, it is said that 100 volumes of solvent is used.

[0041 ] As used herein, an “immediate-release” (IR) dosage form refers to a dosage form in which no deliberate effort has been made to modify the active pharmaceutical ingredient release rate (wherein a disintegrant is not considered a modification in the context of capsules and tablets). For example, the pharmaceutical compositions of the present invention are preferably provided as immediate-release solid oral tablet dosage forms.

[0042] 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 ±10 minutes when the time is one or two hours, and ±1 hour when longer periods of time are referenced.

[0043] In one embodiment of the present invention, there is provided a new crystalline form of acalabrutinib maleate, acalabrutinib maleate Form APO-I, a solvate comprising acalabrutinib maleate and 1 ,2-propanediol. Preferably, in acalabrutinib maleate Form APO-I, the molar ratio of acalabrutinib maleate to 1 ,2-propanediol is about 1 :0.5. Preferably, in acalabrutinib maleate Form APO-I, both (F?) and (S) isomers of 1 ,2- propanediol are incorporated.

[0044] Acalabrutinib maleate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 11.3°, 14.7°, and 16.1 °. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of 5.2°, 10.4°, 15.6°, 17.3°, 23.4°, and 24.2°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 5.2°, 10.4°, 15.6°, 17.3°, 23.4°, and 24.2°.

[0045] An illustrative PXRD diffractogram of acalabrutinib maleate 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 acalabrutinib maleate 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.

[0046] An illustrative DSC thermogram of acalabrutinib maleate Form APO-I is shown in Figure 8. The DSC thermogram may be further characterized by an endothermic peak with a peak onset at about 167 °C and a peak maximum at about 170 °C.

[0047] As described in Examples 1 , 8, 9, and 10, acalabrutinib maleate Form APO-I can be prepared by combining acalabrutinib and maleic acid in a suitable amount of (RS)- 1 ,2-propanediol (i.e., racemic), preferably from about 2 volumes to about 10 volumes with respect to acalabrutinib, optionally comprising from about 2 wt% to about 4 wt% water, and maintaining the mixture at a suitable temperature, preferably from about 40 °C to about 60 °C, followed by a period of cooling, if necessary. Filtration of the resulting suspension and washing the filter cake with a suitable solvent, preferably methyl f-butyl ether provides acalabrutinib maleate Form APO-I having a PXRD diffractogram consistent with Figure 1. In embodiments, acalabrutinib maleate Form APO-I prepared in the presence of a minute amount of water exhibits more consistent stability at high relative humidity.

[0048] Single crystals of acalabrutinib maleate Form APO-I were grown from a racemic 1 ,2-propanediol/methanol/chloroform solution as described in Example 13 and characterized by single crystal x-ray diffraction (SCXRD). A summary of the SCXRD data is provided in Table 2. An illustration of the asymmetric unit from the SCXRD structure is shown in Figure 9. This illustration depicts a 2:1 acalabrutinib maleate: 1 ,2-propanediol solvate, i.e., the molar ratio of acalabrutinib maleate to 1 ,2-propanediol is 2:1.

[0049] In a second embodiment of the present invention, there is provided a new crystalline form of acalabrutinib maleate, acalabrutinib maleate Form APO-II, a solvate comprising acalabrutinib maleate and (S)-(+)-1 ,2-propanediol. Preferably, in acalabrutinib maleate Form APO-II, the molar ratio of acalabrutinib maleate to (S)-(+)- 1 ,2-propanediol is about 1 :0.5. Preferably, in acalabrutinib maleate Form APO-II, only the (S) isomer of 1 ,2-propanediol is present.

[0050] Acalabrutinib maleate Form APO-II can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 11.4°, 14.8°, and 16.2°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of 5.2°, 10.5°, 15.7°, 17.3°, 23.4°, and 24.7°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 5.2°, 10.5°, 15.7°, 17.3°, 23.4°, and 24.7°.

[0051 ] An illustrative PXRD diffractogram of acalabrutinib maleate Form APO-II, as prepared in Example 2, 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 3. Although illustrative of the PXRD diffractogram that is provided for the acalabrutinib maleate Form APO-II 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.

[0052] A described in Example 2, acalabrutinib maleate Form APO-II can be prepared by combining acalabrutinib and maleic acid in a suitable amount of (S)-(+)-1 ,2- propanediol, preferably from about 2 volumes to about 10 volumes with respect to acalabrutinib, and maintaining the mixture at a suitable temperature, preferably from about 40 °C to about 60 °C, followed by a period of cooling, if necessary. Filtration of the resulting suspension and washing the filter cake with a suitable solvent, preferably methyl f-butyl ether provides acalabrutinib maleate Form APO-II having a PXRD diffractogram consistent with Figure 2.

[0053] In a third embodiment of the present invention, there is provided a new crystalline form of acalabrutinib maleate, acalabrutinib maleate Form APO-HI.

[0054] Acalabrutinib maleate Form APO-II I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 29 (± 0.2°), at 5.3°, 15.1 °, and 16.3°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of 10.6°, 11.6°, 15.9°, 17.4°, 18.7°, and 19.2°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 26 (± 0.2°), at 10.6°, 11 .6°, 15.9°, 17.4°, 18.7°, and 19.2°. Acalabrutinib maleate Form APO-HI can be further characterized based on the amount of water present in the crystalline form. In general, acalabrutinib maleate Form APO-III is typically isolated having a weight percentage of water of less than about 2 wt%, preferably from about 0.5 wt% to about 2 wt%.

[0055] An illustrative PXRD diffractogram of acalabrutinib maleate Form APO-III, as prepared in Example 4, 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 4. Although illustrative of the PXRD diffractogram that is provided for the acalabrutinib maleate Form APO-III 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.

[0056] As described in Example 4, acalabrutinib maleate Form APO-III can be prepared by dissolving amorphous acalabrutinib maleate in a suitable amount of acetone, preferably from about 8 volumes to about 12 volumes with respect to acalabrutinib maleate, preferably seeding the solution with acalabrutinib maleate Form APO-III and allowing the solvent to evaporate to afford a solid. Trituration of the solid with further acetone, preferably from about 8 volumes to about 12 volumes followed by isolation of the solid provides acalabrutinib maleate Form APO-III having a PXRD diffractogram consistent with Figure 3.

[0057] Preferably, seed crystals of acalabrutinib maleate Form APO-III can, in the first instance, be prepared as described in Example 3. Thereafter, seed crystals for future preparations can also be reserved from Form APO-III prepared by any method, for example, as described in Example 4.

[0058] In a fourth embodiment of the present invention, there is provided a new crystalline form of acalabrutinib maleate, acalabrutinib maleate Form APO-IV, a solvate comprising acalabrutinib maleate and 1 ,2-ethanediol. Preferably, in acalabrutinib maleate Form APO-IV, the molar ratio of acalabrutinib maleate to 1 ,2-ethanediol is about 1 :0.5.

[0059] Acalabrutinib maleate Form APO-IV can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 5.2°, 15.0°, and 21.9°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of 10.4°, 11.6°, 15.7°, 19.2°, 22.3°, and 24.5°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 10.4°, 11 .6°, 15.7°, 19.2°, 22.3°, and 24.5°.

[0060] An illustrative PXRD diffractogram of acalabrutinib maleate Form APO-IV, as prepared in Example 4, is shown in Figure 4. A peak listing, comprising peaks from the PXRD diffractogram in Figure 4, and their relative intensities, is provided in Table 5. Although illustrative of the PXRD diffractogram that is provided for the acalabrutinib maleate Form APO-IV 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.

[0061 ] A described in Example 5, acalabrutinib maleate Form APO-IV can be prepared by combining acalabrutinib and maleic acid in a suitable amount of 1 ,2-ethanediol, preferably from about 2 volumes to about 10 volumes with respect to acalabrutinib, and maintaining the mixture at a suitable temperature, preferably from about 40 °C to about 60 °C, followed by a period of cooling, if necessary. Filtration of the resulting suspension and washing the filter cake with a suitable solvent, preferably a mixture of methyl f-butyl ether and acetone provides acalabrutinib maleate Form APO-IV having a PXRD diffractogram consistent with Figure 4.

[0062] In a fifth embodiment of the present invention, there is provided a new crystalline form of acalabrutinib maleate, acalabrutinib maleate Form APO-V, a solvate comprising acalabrutinib maleate and 1 ,2-ethanediol. Preferably, in acalabrutinib maleate Form APO-V, the molar ratio of acalabrutinib maleate to 1 ,2-ethanediol is about 1 :0.5.

[0063] Acalabrutinib maleate Form APO-V can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 5.2°, 17.4°, and 23.8°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of 10.5°, 11.6°, 15.8°, 19.2°, 22.2°, and 25.1 °. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 10.5°, 11 .6°, 15.8°, 19.2°, 22.2°, and 25.1 °.

[0064] An illustrative PXRD diffractogram of acalabrutinib maleate Form APO-V, as prepared in Example 6, is shown in Figure 5. A peak listing, comprising representative peaks from the PXRD diffractogram in Figure 5, and their relative intensities, is provided in Table 6. Although illustrative of the PXRD diffractogram that is provided for the acalabrutinib maleate Form APO-V 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.

[0065] As described in Example 6, acalabrutinib maleate Form APO-V can be prepared by exposing acalabrutinib maleate Form APO-IV to water vapour, preferably humidified air having a suitable relative humidity (RH), at a suitable temperature, preferably from about 30 °C to about 50 °C, for a suitable time. Preferably, the relative humidity of the humidified air is greater than about 50% RH, more preferably from about 70% RH to about 100% RH. The conversion provides acalabrutinib maleate Form APO- V having a PXRD diffractogram consistent with Figure 5.

[0066] In a sixth embodiment of the present invention, there is provided a new crystalline form of acalabrutinib maleate, acalabrutinib maleate Form APO-VI, a solvate comprising acalabrutinib maleate and (F?)-1 ,2-propanediol. Preferably, in acalabrutinib maleate Form APO-VI, the molar ratio of acalabrutinib maleate to (F?)-1 ,2-propanediol is about 1 :0.5. Preferably, in acalabrutinib maleate Form APO-VI, only the (F?) isomer of 1 ,2- propanediol is incorporated.

[0067] Acalabrutinib maleate Form APO-VI can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 11.3°, 14.7°, and 16.0°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of 5.2°, 10.4°, 15.5°, 17.3°, 23.4°, and 24.1°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 29 (± 0.2°), at 5.2°, 10.4°, 15.5°, 17.3°, 23.4°, and 24.1 °.

[0068] An illustrative PXRD diffractogram of acalabrutinib maleate Form APO-VI, as prepared in Example 11 , 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 7. Although illustrative of the PXRD diffractogram that is provided for the acalabrutinib maleate Form APO-VI 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.

[0069] A described in Example 11 , acalabrutinib maleate Form APO-VI can be prepared by combining acalabrutinib and maleic acid in a suitable amount of (F?)-1 ,2- propanediol, preferably from about 2 volumes to about 10 volumes with respect to acalabrutinib, and maintaining the mixture at a suitable temperature, preferably from about 40 °C to about 60 °C, followed by a period of cooling, if necessary. Filtration of the resulting suspension and washing the filter cake with a suitable solvent, preferably methyl f-butyl ether provides acalabrutinib maleate Form APO-VI having a PXRD diffractogram consistent with Figure 6.

[0070] In a seventh embodiment of the present invention, there is provided a new crystalline form of acalabrutinib maleate, acalabrutinib maleate Form APO-VII, a solvate comprising acalabrutinib maleate and 1 ,2,3-propanetriol (glycerol). Preferably, in acalabrutinib maleate Form APO-VII, the molar ratio of acalabrutinib maleate to 1 ,2,3- propanetriol is about 1 :0.5.

[0071 ] Acalabrutinib maleate Form APO-VII can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 11.2°, 14.6°, and 17.2°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of 5.2°, 10.1 °, 11.6°, 15.9°, 23.3°, and 24.0°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 5.2°, 10.1 °, 11.6°, 15.9°, 23.3°, and 24.0°.

[0072] An illustrative PXRD diffractogram of acalabrutinib maleate Form APO-VII, as prepared in Example 12, is shown in Figure 7. A peak listing, comprising representative peaks from the PXRD diffractogram in Figure 7, and their relative intensities, is provided in Table 8. Although illustrative of the PXRD diffractogram that is provided for the acalabrutinib maleate Form APO-VII 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.

[0073] A described in Example 12, acalabrutinib maleate Form APO-VII can be prepared by combining acalabrutinib and maleic acid in a suitable amount of 1 ,2,3- propanetriol, preferably from about 2 volumes to about 10 volumes with respect to acalabrutinib, and maintaining the mixture at a suitable temperature, preferably from about 5 °C to about 60 °C, followed by a period of cooling, if necessary. Preferably, maintaining the mixture at a suitable temperature comprises one or more cycles of altering the temperature down and then up again from about 50 °C to about 5 °C in about 5 °C or 10 °C increments with hold periods at each interval of about 1 hour. The resulting solid can be collected by filtration of the resulting suspension, preferably with the aid of a suitable solvent such as an alcohol or ketone, which is also useful for washing the filter cake. Excess 1 ,2,3-propanetriol can be displaced from the solid, if necessary, by stirring and/or sonicating the solid in a suitable solvent, preferably an alcohol such as 2-propanol, filtering, and washing to provide acalabrutinib maleate Form APO-VII having a PXRD diffractogram consistent with Figure 7.

[0074] In an eighth embodiment of the invention, there is provided a pharmaceutical composition of a pharmaceutically acceptable crystalline form of acalabrutinib maleate selected from the group consisting of Form APO-I, Form APO-II, Form APO-III, Form APO-V, Form APO-VI, Form APO-VII, and mixtures thereof, with one or more pharmaceutically acceptable excipients. Preferably, the crystalline form of acalabrutinib maleate in the composition is Form APO-I. The amount of crystalline form(s) present in the composition, expressed as the equivalent acalabrutinib free base, is preferably from about 15 % w/w to about 55 % w/w, preferably from about 30 % w/w to about 35 % w/w, the remainder comprising pharmaceutically acceptable excipients. Preferably, the pharmaceutical composition is provided as a solid dosage form suitable for oral administration, such as a capsule, tablet, pill, powder, or granulate. Most preferably, the pharmaceutical composition is provided as an immediate-release tablet. Preferably, the amount of acalabrutinib maleate crystalline form(s) present in the dosage form is equivalent to from about 75 mg to about 125 mg, or about 75 mg, or about 80 mg, or about 85 mg, or about 90 mg, or about 95 mg, or about 100 mg, or about 105 mg, or about 110 mg, or about 115 mg, or about 120 mg, or about 125 mg of acalabrutinib free base. Preferably, the pharmaceutical composition provides a dose of acalabrutinib maleate that is equivalent to the 100 mg of acalabrutinib found in CALQUENCE® drug products. As used herein, the phrase “therapeutically effective amount” means that amount of crystalline form of acalabrutinib maleate that will elicit a biological or medical response of a tissue, system, or patient that is being sought by the administrator (such as a researcher, doctor, or veterinarian) which includes alleviation of the symptoms of the condition or disease being treated and the prevention, slowing or halting of progression of the condition or disease, including but not limited to a Bruton’s Tyrosine Kinase (Btk)- mediated disorder, such as lymphoma or leukemia. In some examples, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. For convenience, the total daily dosage may be divided and administered in portions during the day as required. In some examples, the dosage can range from about 0.1 mg/kg to about 10 mg/kg of body weight/day of crystalline form of acalabrutinib maleate. It should be understood that any numerical range recited herein is intended to include all sub-ranges subsumed therein.

[0075] Suitable pharmaceutically acceptable excipients are preferably inert with respect to the crystalline form of acalabrutinib maleate 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, carboxymethylcellulose, 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, calcium hydrogen phosphate, dixylitol and lactitol; disintegrants such as croscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycollate, com starch, microcrystalline cellulose, hydroxypropyl methylcellulose and low-substituted 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, poloxamers, polyethylene glycol and talc; and dispersants or solubility enhancing agents, such cyclodextrins, glyceryl monostearate, 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. Other suitable excipients and the preparation of solid oral dosage forms is well known to person of skill in the art, and is described generally, for example, in Remington The Science and Practice of Pharmacy 21^st Edition (Lippincott Williams & Wilkins: Philadelphia; 2006; Chapter 45). [0076] In a tablet dosage form, a preferable pharmaceutical composition comprises acalabrutinib maleate (e.g. from about 10 wt% to about 60 wt%); at least one diluent such as microcrystalline cellulose or mannitol (e.g. from about 10 wt% to about 70 wt%); at least one disintegrant such as low-substituted hydroxypropyl cellulose (e.g. from about 1 wt% to about 10 wt%); and at least one lubricant such as sodium stearyl fumarate or magnesium stearate (e.g. from about 0.25 wt% to about 3 wt%).

[0077] 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 21^st Edition (Lippincott Williams & Wilkins: Philadelphia; 2006; Chapter 46).

[0078] In a ninth embodiment of the invention, there is provided a method of treating a Bruton’s Tyrosine Kinase (Btk)-mediated disorder comprising administering to a human subject in need thereof one or more pharmaceutically acceptable acalabrutinib maleate crystalline forms selected from the group consisting of Form APO-I, Form APO-II, Form APO-HI, Form APO-V, Form APO-VI, or Form APO-VII and combinations thereof, and a pharmaceutically acceptable excipient. The Btk-mediated disorder may be selected from the group consisting of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and/or small lymphocytic leukemia (SLL). Methods of treatment comprising administering a therapeutically effective amount of acalabrutinib maleate in the treatment of a Btk- mediated disorder have been disclosed in, for example, WO 2021/255246 A2.

EXAMPLES

[0079] The following non-limiting examples are illustrative of some of the aspects and embodiments of the invention described herein.

[0080] Unless otherwise noted, the acalabrutinib used as a starting material in the following examples was consistent with acalabrutinib Form 3, which is reported in US 10,899,767 B2.

[0081 ] PXRD diffractograms were recorded on a Broker D8 Discover powder X-ray diffractometer (Bruker-AXS, Karlsruhe, Germany). The sample holder was oscillated along X and Y axes during the measurement. The generator was a Micro-focus X-ray source (IMSTube: Cu tube with 1 .5406 A) with a voltage of 50 kV and current of 1 .00 mA, using a divergence slit of 0.3 mm and collimator of 0.3 mm. For each sample, one frame was collected using a still scan with a Pilatus 3R-100 kA detector at the distance of 154.72 mm from the sample. Raw data were evaluated using the program EVA (Bruker-AXS, Karlsruhe, Germany).

Differential Scanning Calorimetry Analysis:

[0082] The DSC thermogram was collected on a TA Instruments Q2000 DSC instrument. A sample (3.6850 mg) was weighed into a T-zero pan and was crimped closed. The sample was analyzed under a flow of nitrogen (50 ± 5 mL/min) at a scan rate of 10 °C/m inute between 25 °C and 250 °C.

Single Crystal Data Collection and Processing

[0083] The sample for SCXRD analysis was coated with a small amount of Paratone oil. All X-ray measurements were made on a Broker VENTURE Dual Source (Cu Ips/Mo IpS) single crystal diffractometer at a temperature of 100 K. From the initial indexing it was evident that the sample crystal was non-merohedrally twinned (vide infra). The unit cell dimensions were determined from 9974 reflections with 2.26° < 9 < 23.45°. The data collection strategy was a number of co and <p scans which collected data up to 54.21 ° (26). The frame integration was performed using SAINT (Bruker-AXS, SAINT Version V8.40B, 2016) within Apex4 (v2022.10-0). The resulting raw data was scaled and absorption corrected using a multi-scan averaging of symmetry eguivalent data using TWINABS (Bruker-AXS, TWINABS Version 2012.1 , 2012).

Single Crystal Structure Solution and Refinement

[0084] The crystal structure was solved by using an intrinsic phasing methodology with the SHELXT program (Sheldrick, G. M., Acta Cryst. 2015, A71, 3-8). All non-hydrogen atoms were obtained from the initial solution and refined anisotropically, with hydrogen atoms (with the exceptions of those listed below) being introduced at idealized positions and allowed to ride on the parent atom. The position of the hydrogen atoms bound to most nitrogen and oxygen atoms (with the exception of those on 08, O7A, and O8A) were obtained from the difference Fourier map and allowed to refine isotropically. The twin fraction was refined and converged to a value of 0.2558. In the asymmetric unit, the entire PG solvent and one carbon atom (C6/C6D and C6A/C6B) in both acalabrutinib molecules were disordered over two orientations. The occupancy of the major orientations were refined to values of 0.577(7), 0.858(10), and 0.71 (3), respectively. The Flack parameter was calculated to be -0.2(5) using Parson quotients (Parsons, S.; Flack, H. D. and Wagner, T. Acta Cryst. 2013, B69, 249-259). The structural model was fit to the data using full matrix least-squares based on F². The calculated structure factors included corrections for anomalous dispersion from the usual tabulation. The structure was refined using the SHELXL program from the SHELX suite of crystallographic software (Sheldrick, G. M., Acta Cryst. 2015, C71, 3-8) within 0lex2 (Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H., J. Appt. Crystallogr. 2009, 42, 339-341 ). Graphic plots were produced using the Mercury program suite (Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edington, P. R.; McCabe, P.; Pidcock, E.; Rodriguez- Monge, L.; Taylor, R.; van de Streek, J. and Wood, P. A. J. Appt. Cryst., 2008, 41, 466- 470) with anisotropic atoms displayed to 50% probability.

Example 1 : Preparation of Acalabrutinib Maleate Form APO-I

[0085] A solution of maleic acid (25.6 mg) in racemic 1 ,2-propanediol (0.8 mL) was added to acalabrutinib (101.0 mg), and the resulting suspension was heated with stirring at 50 °C for 8 hours. After this, the suspension was cooled to 10 °C in 10 °C increments with holding at each temperature for one hour (i.e. 40 °C, 30 °C, 20 °C, 10 °C). Finally, the suspension was cooled to 5 °C and stirred for 3 hours. Stirring was then discontinued and the suspension was allowed to sit at 5 °C overnight. Methyl f-butyl ether (0.8 mL) was then added, and the suspension briefly mixed. The solid was collected by filtration, washed with methyl f-butyl ether (4 x 1 mL), and allowed to air dry to afford acalabrutinib maleate Form APO-I (93.5 mg) as a white solid. The PXRD diffractogram of a sample prepared by this method is shown in Figure 1 . The PXRD diffractogram of a sample of Form APO-I was unchanged following storage at room temperature and 60% RH for 4 days.

[0086] ¹H NMR (300 MHz, DMSO-d₆): 10.89 (s, 1 H), 8.42 (d, J = 4.7 Hz, 1 H), 8.21 (m, 3H), 7.98, 7.95 (2 overlapping doublets, J = 5.6 Hz, total 1 H), 7.87 (t, J = 7.9 Hz, 1 H), 7.77 (m, 2H), 7.41 (br. s, 1 ,2H), 7.18 (m, 2.6H), 6.14 (s, 2H), 5.76 (d of d, J = 3.3 Hz, 8.0 Hz, 0.3H), 5.51 (m, 0.7H), 3.83 (m, 1.5H), 3.59 (m, 1.7H), 3.26 (d of d, J = 6.1 Hz, 10.6 Hz, 0.8H), 3.15 (d of d, J = 5.7 Hz, 10.5 Hz, 0.7H), 1 .9-2.4 (overlapping m and s, 6.4H), 1 .68 (s, 1 H), 0.99 (d, J = 6.3 Hz, 1 ,5H).

Example 2: Preparation of Acalabrutinib Maleate Form APO-

[0087] A solution of maleic acid (38.9 mg) in (S)-(+)-1 ,2-propanediol (1 mL) was added to acalabrutinib (154.3 mg), and the resulting suspension was heated with stirring at 50 °C for 8 hours. After this, the suspension was cooled to 10 °C in 10 °C increments with holding at each temperature for one hour (i.e. 40 °C, 30 °C, 20 °C, 10 °C). Finally, the suspension was cooled to 5 °C and stirred for 3 hours. Stirring was then discontinued and the suspension was allowed to sit at 5 °C overnight. Methyl f-butyl ether (1 mL) was then added, and the suspension briefly mixed. The solid was collected by filtration, washed with methyl f-butyl ether (5 x 1 mL), and allowed to air dry to afford acalabrutinib maleate Form APO-II (134.0 mg) as a white solid. The PXRD diffractogram of a sample prepared by this method is shown in Figure 2. The PXRD diffractogram of a sample of Form APO- II was unchanged following storage at room temperature and 60% RH for 3 days. Furthermore, PXRD of an uncapped sample was unchanged following storage at room temperature/75% RH and 40 °C/60% RH for at least 54 and 29 days, respectively.

[0088] ¹H NMR (300 MHz, DMSO-d₆): 10.89 (s, 1 H), 8.42 (d, J = 4.7 Hz, 1 H), 8.21 (m, 3H), 7.98, 7.95 (2 overlapping doublets, J = 5.6 Hz, total 1 H), 7.87 (t, J = 7.9 Hz, 1 H), 7.77 (m, 2H), 7.43 (br. s, 1.1 H), 7.18 (m, 2.5H), 6.14 (s, 2H), 5.76 (d of d, J = 3.3 Hz, 8.0 Hz, 0.3H), 5.51 (m, 0.7H), 3.83 (m, 1.5H), 3.59 (m, 1.5H), 3.26 (d of d, J = 6.1 Hz, 10.6 Hz, 0.7H), 3.15 (d of d, J = 5.7 Hz, 10.5 Hz, 0.7H), 1.9-2.4 (overlapping m and s, 6.3H), 1 .68 (s, 1 H), 0.99 (d, J = 6.3 Hz, 1 ,6H).

of Acalabrutinib Maleate Form APO-III Seeds

[0089] Amorphous acalabrutinib maleate (329.8 mg), as prepared in Example 7, was dissolved in acetone (5.5 mL) and the solution was repeatedly perturbed by removing 50 pL aliquots with a pipette until white crystallites began precipitating. After leaving the mixture overnight at room temperature in a closed environment, methyl f-butyl ether (2 mL) was added, the mother liquor was decanted, and the resulting solid was allowed to air dry to afford acalabrutinib maleate Form APO-III seed crystals.

4: Preparation of Acalabrutinib Maleate Form APO-III

[0090] Amorphous acalabrutinib maleate (163.8 mg) was dissolved in acetone (1.7 mL) to afford a solution. The solution was then seeded with a few of the seed crystals obtained in Example 3 and a white solid began crystallizing. The solution was allowed to evaporate over 4 hours to afford a mixture of brown and white solids. Addition of acetone (1.7 mL) followed by sonication (10 sec) dissolved the brown solid and the resulting mixture was allowed to sit for 2.5 hours in a sealed environment. The solid was isolated by decanting the mother liquor and allowed to air dry over 3 days to afford acalabrutinib maleate Form APO-III (68.9 mg) as an off-white powder. The PXRD diffractogram of a sample prepared by this method is shown in Figure 3. The water content of the solid by Karl Fischer (KF) analysis was 1.8 wt%. The PXRD diffractogram of a sample of Form APO-III was unchanged following storage at room temperature and ambient humidity for 30 days.

[0091 ] ¹H NMR (300 MHz, DMSO-d₆): 10.89 (s, 1 H), 8.42 (d, J = 4.7 Hz, 1 H), 8.21 (m, 3H), 7.98, 7.95 (2 overlapping doublets, J = 5.6 Hz, total 1 H), 7.87 (t, J = 7.9 Hz, 1 H), 7.77 (m, 2H), 7.40 (br. s, 1.2H), 7.18 (m, 2.6H), 6.15 (s, 2H), 5.76 (d of d, J = 3.3 Hz, 8.0 Hz, 0.3H), 5.51 (m, 0.7H), 3.83 (m, 1.6H), 3.61 (m, 1.3H), 1.9-2.4 (overlapping m and s, 6.4H), 1.68 (s, 1 H).

Example 5: Preparation of Acalabrutinib Maleate Form APO-IV

[0092] A solution of maleic acid (24.9 mg) in 1 ,2-ethanediol (0.8 mL) was added to acalabrutinib (99.6 mg), and the resulting suspension was heated with stirring at 50 °C for 8 hours. After this, the suspension was cooled to 10 °C in 10 °C increments with holding at each temperature for one hour (i.e. 40 °C, 30 °C, 20 °C, 10 °C). Finally, the suspension was cooled to 5 °C and stirred for 3 hours. Stirring was then discontinued and the suspension was allowed to sit at 5 °C overnight. Methyl f-butyl ether (0.8 mL) was then added, and the suspension briefly mixed. The solid was collected by filtration, washed with methyl f-butyl ether (4 x 1 mL), and allowed to air dry to afford crude acalabrutinib maleate Form APO-IV (89.1 mg). Excess 1 ,2-ethanediol was removed by suspending the solid in a mixture (1 :1 ) of methyl f-butyl ether/acetone (1 mL) and sonicating for 30 seconds. The solid was collected by filtration, washed with the same solvent mixture (4 x 1 mL), and allowed to air dry for one hour to afford acalabrutinib maleate Form APO-IV (66.1 mg) as a white solid. The PXRD diffractogram of a sample prepared by this method is shown in Figure 4. The water content of the solid by Karl Fischer (KF) analysis was 0.64 wt%.

[0093] ¹H NMR (300 MHz, methanol-^): 8.38 (d, J = 4.9 Hz, 1 H), 8.25 (d, J = 8.4 Hz, 1 H), 8.16 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 5.8 Hz, 1 H), 7.85 (m, 3H), 7.19 (d of d, J = 5.0 Hz, 6.7 Hz, 1 H), 7.14 (d, J = 5.7 Hz, 0.3H), 7.06 (d, J = 5.7 Hz, 0.8H), 6.27 (s, 2H), 5.76 (d of d, J = 3.9 Hz, 7.6 Hz, 0.3H), 5.48 (d of d, J = 5.1 Hz, 7.6 Hz, 0.8H), 3.96 (m, 1 ,6H), 3.77 (m, 0.6H), 3.60 (s, 2H), 2.0-2.6 (overlapping m and s, 6.8H), 1.74 (s, 0.7H).

Example 6: Preparation of Acalabrutinib Maleate Form APO-V

[0094] A sample (10 mg) of acalabrutinib maleate Form APO-IV was exposed to 75 % RH at 40 °C for 4 days to afford acalabrutinib maleate Form APO-V as a white solid. The PXRD diffractogram of a sample prepared by this method is shown in FIG. 5. The PXRD diffractogram of an uncapped sample of Form APO-V was substantially unchanged (peaks within +/-0.2 2-theta) following storage at 40 °C/75% RH for at least 72 days.

Acalabrutinib Maleate

[0095] A solution of maleic acid (0.59 g) in water (3 mL) was added to a heated (50 °C) suspension of acalabrutinib (2.38 g) in a mixture of acetone/water (50 mL/20 mL) to afford a solution. The solution was then allowed to cool slowly to room temperature with stirring for about 2 hours, after which the solvent was removed in vacuo to afford a brown solid which was further dried in vacuo (1 Torr) for 3 days. PXRD analysis of the resulting flaky brown solid (2.43 g) indicated an amorphous material. ¹ H NMR analysis was consistent with acalabrutinib maleate.

8: Preparation of Acalabrutinib Maleate Form APO-I

[0096] A suspension of acalabrutinib (1.1296 g) and maleic acid (282.0 mg) in racemic 1 ,2-propanediol (anhydrous, 8 mL) was heated with stirring at 50 °C for 8 hours. After this, the suspension was cooled to 40 °C and stirred for an additional hour, then cooled to 30 °C and stirred for an additional hour, then cooled to 20 °C and stirred for an additional hour, then cooled to 10 °C and stirred for an additional hour, then cooled to 5 °C and stirred for 3 hours. Stirring was then discontinued and the suspension was allowed to sit at 5 °C overnight. The suspension was diluted with methyl f-butyl ether (10 mL), filtered, washed with methyl f-butyl ether (3 x 10 mL, 1 x 20 mL), and dried under vacuum aspiration for 1 hour to afford acalabrutinib Form APO-I (0.9924 g) as a white solid. The PXRD diffractogram and ¹H NMR spectrum of the solid were consistent with the sample characterized in Example 1 . The DSC thermogram of the solid is shown in Figure 8. The water content of the solid by Karl Fischer (KF) analysis was 0.12 wt%. The PXRD diffractogram of an uncapped sample of the Form APO-I solid was substantially unchanged (peaks within +/-0.2 2-theta) following storage at 40 °C/75% RH for at least 48 days.

Example 9: Preparation of Acalabrutinib Maleate Form APO-I

[0097] A suspension of acalabrutinib (1.1369 g) and maleic acid (283.7 mg) in a mixture of racemic 1 ,2-propanediol (anhydrous, 8 mL) and water (0.28 mL) was heated with stirring at 50 °C for 8 hours. After this, the suspension was cooled to 40 °C and stirred for an additional hour, then cooled to 30 °C and stirred for an additional hour, then cooled to 20 °C and stirred for an additional hour, then cooled to 10 °C and stirred for an additional hour, then cooled to 5 °C and stirred for 3 hours. Stirring was then discontinued and the suspension was allowed to sit at 5 °C overnight. The suspension was diluted with methyl f-butyl ether (10 mL), filtered, washed with methyl f-butyl ether (3 x 10 mL, 1 x 20 mL), and dried under vacuum aspiration for 1 hour to afford acalabrutinib Form APO-I (0.9714 g) as a white solid. The PXRD diffractogram and ¹H NMR spectrum of the solid were consistent with the sample characterized in Example 1. The water content of the solid by Karl Fischer (KF) analysis was 0.42 wt%. The PXRD diffractogram of an uncapped sample of the Form APO-I solid was substantially unchanged (peaks within +/- 0.2 2-theta) following storage at 40 °C/75% RH for at least 48 days.

Example 10: Preparation of Acalabrutinib Maleate Form APO-I

[0098] A mixture of acalabrutinib (15 g, 32.2 mmol), maleic acid (3.74 g, 32.2 mmol) and racemic 1 ,2-propanediol (anhydrous, 45 mL) was heated to 50 °C with stirring under nitrogen for 8 hours, then cooled to room temperature and maintained for 6 hours. The mixture was further cooled to 0 to 5 °C, diluted with methyl f-butyl ether (75 mL), and stirred for 2 hours. The suspension was then filtered, and the resulting damp solid was slurried in methyl f-butyl ether (90 mL) at room temperature for 1 hour, filtered, and dried in vacuo to afford acalabrutinib maleate Form APO-I (17.9 g) as a white solid. The PXRD diffractogram and ¹H NMR spectrum of the solid were consistent with the sample characterized in Example 1 . A sample of the solid subjected to heating in a vacuum oven (ca. 10-15 Torr) at about 85-90 °C overnight did not exhibit loss of 1 ,2-propanediol.

Example 11 : Preparation of Acalabrutinib Maleate Form APO-VI

[0099] A suspension of acalabrutinib (108.6 mg) and maleic acid (38.5 mg) in (F?)-1 ,2- propanediol (0.6 mL) was heated with stirring at 50 °C for 8 hours. After this, the suspension was cooled to 40 °C and stirred for an additional hour, then cooled to 30 °C and stirred for an additional hour, then cooled to 20 °C and stirred for an additional hour, then cooled to 10 °C and stirred for an additional hour, then cooled to 5 °C and stirred for 3 hours. Stirring was then discontinued and the suspension was allowed to sit at 5 °C overnight. The suspension was diluted with methyl f-butyl ether (1 mL), filtered, washed with methyl f-butyl ether (5 x 1 mL), and dried in vacuo overnight to afford acalabrutinib Form APO-VI (101 .2 mg) as a white solid. The PXRD diffractogram of the solid is shown in Figure 6. The water content of the solid by Karl Fischer (KF) analysis was 0.72 wt%. The PXRD diffractogram of a capped sample of the Form APO-VI solid was substantially unchanged (peaks within +/-0.2 2-theta) following storage at room temperature and ambient RH for 25 days.

[0100] ¹H NMR (300 MHz, DMSO- de) 10.89 (s, 1 H), 8.42 (d, J = 4.1 Hz, 1 H), 8.21 (m, 3H), 7.98, 7.95 (2 overlapping doublets, J = 5.6 Hz, total 1 H), 7.87 (t, J = 7.9 Hz, 1 H), 7.76 (m, 2H), 7.44 (br. s, 1.2H), 7.18 (m, 2.4H), 6.14 (s, 2H), 5.77 (d of d, J = 3.1 Hz, 7.1 Hz, 0.5H), 5.51 (m, 0.9H), 3.83 (m, 1.5H), 3.59 (m, 1.5H), 3.26 (d of d, J = 5.7 Hz, 10.3 Hz, 0.7H), 3.15 (d of d, J = 5.8 Hz, 10.7 Hz, 0.7H), 1.9-2.4 (overlapping m and s, 6.5H), 1 .68 (s, 1 H), 0.99 (d, J = 6.2 Hz, 1 ,5H).

Example 12: Preparation of Acalabrutinib Maleate Form APO-VII

[0101 ] A suspension of acalabrutinib (1 .1354 g) and maleic acid (285.1 mg) in 1 ,2,3- propanetriol (anhydrous glycerol, 5 mL) was stirred and subjected to the following temperature regime: 50 °C, 2h (an additional 3 mL of anhydrous glycerol was added after 45 minutes at this temperature); 40 °C, 1 h; 30 °C, 1 h; 20 °C, 1 h; 10 °C, 1 h; 5 °C, 1 h; 40 °C, 1 h; 30 °C, 1 h; 20 °C, 1 h; 10 °C, 1 h; 5 °C, 1 h; 30 °C, 1 h; 20 °C, 1 h; 10 °C, 1 h; 5 °C, 1 h. At this point, the sample was composed of a solution containingclumps of solid. It was then heated with stirring at 50 °C for 8 hours (significant precipitate was observed after 1 hour at this temperature). After this, the suspension was cooled to 40 °C and stirred for an additional hour, then cooled to 30 °C and stirred for an additional hour, then cooled to 20 °C and stirred for an additional hour, then cooled to 10 °C and stirred for an additional hour, then cooled to 5 °C and stirred for 3 hours. Stirring was then discontinued and the suspension was allowed to sit at 5 °C overnight. The extremely viscous suspension was transferred to a filter under vacuum and filtration was facilitated by the addition of 2- propanol (6 mL) to the suspension. The solid was washed with 2-propanol (6 mL) and acetone (5 mL), then dried in vacuo (ca. 1 Torr) for 3 days to afford a white solid (1 .1002 g). ¹H NMR analysis showed the molar ratio of acalabrutinib to 1 ,2,3-propanetriol in the solid was about 1 :1 (the solid contained excess 1 ,2,3-propanetriol). A portion (120.4 mg) of the solid was treated with 2-propanol (1 mL) to afford a suspension which was sonicated for 30 seconds and left undisturbed for 40 minutes. The solid was then isolated by vacuum filtration, washed with 2-propanol (1 mL) and acetone (2 x 1 mL), and dried in vacuo (ca. 1 Torr) overnight to afford acalabrutinib maleate Form APO-VII (77.4 mg) exhibiting a molar ratio of acalabrutinib:1 ,2,3-propanetriol of about 1 :0.5 as a white powder. The PXRD diffractogram of the sample is shown in Figure 7. The PXRD diffractogram of a capped sample of the Form APO-VII solid was substantially unchanged (peaks within +/-0.2 2-theta) following storage at room temperature and ambient humidity for at least 18 days.

[0102] ¹ H NMR (300 MHz, methanol-^): 8.38 (d, J = 4.9 Hz, 1 H), 8.25 (d, J = 8.4 Hz,

1 H), 8.16 (d, J = 8.1 Hz, 2H), 7.96 (d, J = 5.8 Hz, 1 H), 7.86 (m, 3H), 7.19 (m, 1 H), 7.14 (d, J = 5.7 Hz, 0.2H), 7.06 (d, J = 5.8 Hz, 0.7H), 6.27 (s, 2H), 5.76 (m, 0.2H), 5.48 (m, 0.8H), 3.96 (m, 1 ,6H), 3.77 (m, 0.5H), 3.56 (m, 2.9H), 2.0-2.6 (overlapping m and s, 6.6H), 1.74 (s, 0.7H).

Example 13: Preparation of Single Crystals of Acalabrutinib Maleate Form APO-I

[0103] A solution of acalabrutinib (103.0 mg) in a mixture (4:1 :1 ) of racemic 1 ,2- propanediol/methanol/chloroform (1.2 mL) was added to maleic acid (25.8 mg), which dissolved upon gentle stirring. The solution was left undisturbed in an uncapped vial for several months. The resulting block-shaped crystals were collected after gently decanting the solvent, with one crystal being selected for SCXRD analysis. FIG. 9 depicts an illustration of the SCXRD of the Form APO-I crystals prepared by this method. For atoms which were disordered, only the dominant positions are shown.

Example 14: Comparative intrinsic dissolution testing

[0104] Intrinsic dissolution rate (IDR) measurements were performed using a Wood’s apparatus. Samples were prepared by compressing an amount of sample at 1.5 metric tons for 1 minute. A dissolution medium consisting of 9000.1 N HCI, 0.05M acetate buffer (pH 4.5) or 0.05 M phosphate buffer (pH 6.8) and rotation speed of 50 rpm, was used for each experiment. The wavelengths used for measurement were 304 nm (0.1 N HCI), 281 nm (pH 4.5) and 230 nm (pH 6.8). The results are provided in Table 9.

Claims

What is claimed is:

1 . A crystalline form of acalabrutinib maleate that is a solvate of acalabrutinib maleate and a solvent(s) selected from the group consisting of 1 ,2-propanediol, 1 ,2-ethanediol, and 1 ,2,3-propanetriol.

2. The crystalline form of claim 1 , that is a solvate of acalabrutinib maleate and 1 ,2- propanediol.

3. The crystalline form of claim 2, wherein the molar ratio of acalabrutinib maleate to 1 ,2-propanediol is about 1 :0.5.

4. The crystalline form of claim 2 or 3, wherein the solvate comprises 1 ,2-propanediol in the (S)-configuration.

5. The crystalline form of claim 4, wherein the solvate comprises 1 ,2-propanediol in the (R)-configuration.

6. The crystalline form of claim 2 or 3, wherein the 1 ,2-propanediol is in the (S)- configuration.

7. The crystalline form of claim 2 or 3, wherein the 1 ,2-propanediol is in the (R)- configuration.

8. The crystalline form of claim 5, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 11.3°, 14.7°, and 16.1 °.

9. The crystalline form of claim 8, further comprising at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of: 5.2°, 10.4°, 15.6°, 17.3°, 23.4°, and 24.2°.

10. The crystalline form of claim 8, further comprising peaks, expressed in degrees 26 (± 0.2°), at 5.2°, 10.4°, 15.6°, 17.3°, 23.4°, and 24.2°.

11 . The crystalline form of any one of claims 8 to 10, providing a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 29) as those shown in Figure

1.

12. The crystalline form of any one of claims 8 to 11 , characterized by a DSC thermogram comprising an endothermic peak with a peak onset of about 167 °C and a peak maximum of about 170 °C.

13. The crystalline form of claim 6, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 26 (± 0.2°), at 11.4°, 14.8°, and 16.2°.

14. The crystalline form of claim 13, further comprising at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of: 5.2°, 10.5°, 15.7°, 17.3°, 23.4°, and 24.7°.

15. The crystalline form of claim 13, further comprising peaks, expressed in degrees 29 (± 0.2°), at 5.2°, 10.5°, 15.7°, 17.3°, 23.4°, and 24.7°.

16. The crystalline form of any one of claims 13 to 15, providing a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 29) as those shown in Figure

2.

17. The crystalline form of claim 7, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 11.3°, 14.7°, and 16.0°.

18. The crystalline form of claim 17, further comprising at least three peaks, expressed in degrees 29 (± 0.2°), selected from the group consisting of: 5.2°, 10.4°, 15.5°, 17.3°, 23.4°, and 24.1 °.

19. The crystalline form of claim 17, further comprising peaks, expressed in degrees 29 (± 0.2°), at 5.2°, 10.4°, 15.5°, 17.3°, 23.4°, and 24.1 °.

20. The crystalline form of any one of claims 17 to 19, providing a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 29) as those shown in Figure 6.

21 . The crystalline form of claim 1 , that is a solvate of acalabrutinib maleate and 1 ,2- ethanediol.

22. The crystalline form of claim 21 , wherein the molar ratio of acalabrutinib maleate to 1 ,2-ethanediol is about 1 :0.5.

23. The crystalline form of claim 22, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 5.2°, 15.0°, and 21.9°.

24. The crystalline form of claim 23, further comprising at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of: 10.4°, 11.6°, 15.7°, 19.2°, 22.3°, and 24.5°.

25. The crystalline form of claim 23, further comprising peaks, expressed in degrees 26 (± 0.2°), at 10.4°, 11 .6°, 15.7°, 19.2°, 22.3°, and 24.5°.

26. The crystalline form of any one of claims 22 to 25, providing a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 29) as those shown in Figure

4.

27. The crystalline form of claim 22, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 5.2°, 17.4°, and 23.8°.

28. The crystalline form of claim 27, further comprising at least three peaks, expressed in degrees 29 (± 0.2°), selected from the group consisting of: 10.5°, 11.6°, 15.8°, 19.2°, 22.2°, and 25.1 °.

29. The crystalline form of claim 27, further comprising peaks, expressed in degrees 29 (± 0.2°), at 10.5°, 11.6°, 15.8°, 19.2°, 22.2°, and 25.1 °.

30. The crystalline form of any one of claims 27 to 29, providing a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 29) as those shown in Figure

5.

31 . The crystalline form of claim 1 , that is a solvate of acalabrutinib maleate and 1 ,2,3- propanetriol.

32. The crystalline form of claim 31 , wherein the molar ratio of acalabrutinib maleate to 1 ,2,3-propanetriol is about 1 :0.5.

33. The crystalline form of claim 32, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 11.2°, 14.6°, and 17.2°.

34. The crystalline form of claim 33, further comprising at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of: 5.2°, 10.1 °, 11.6°, 15.9°, 23.3°, and 24.0°.

35. The crystalline form of claim 33, further comprising peaks, expressed in degrees 26 (± 0.2°), at 5.2°, 10.1 °, 11.6°, 15.9°, 23.3°, and 24.0°.

36. The crystalline form of any one of claims 33 to 35, providing a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 29) as those shown in Figure 7.

37. A crystalline form of acalabrutinib maleate characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 5.3°, 15.1 °, and 16.3°.

38. The crystalline form of claim 37, further comprising at least three peaks, expressed in degrees 29 (± 0.2°), selected from the group consisting of: 10.6°, 11.6°, 15.9°, 17.4°, 18.7°, and 19.2°.

39. The crystalline form of claim 37, further comprising peaks, expressed in degrees 29 (± 0.2°), at 10.6°, 11.6°, 15.9°, 17.4°, 18.7°, and 19.2°.

40. The crystalline form of any one of claims 37 to 39, providing a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 29) as those shown in Figure 3.

41 . The crystalline form of any one of claims 37 to 40, having a weight percentage of water of less than about 2.0 wt%.

42. A pharmaceutical composition comprising the crystalline form of acalabrutinib maleate according to any one of claims 1 to 41 , and one or more pharmaceutically acceptable excipients.

43. The pharmaceutical composition of claim 42, wherein the pharmaceutical composition is provided in the form of a tablet.

44. A method of treating a Bruton’s Tyrosine Kinase (Btk)-mediated disorder comprising administering to a human subject in need thereof a therapeutically effective amount of a crystalline form of acalabrutinib according to any one of claims 1 to 41 , or a pharmaceutical composition of claim 42 or claim 43.

45. The method of treatment of claim 44, wherein the Bruton’s Tyrosine Kinase (Btk)- mediated disorder is lymphoma or leukemia.

46. The method of treatment of claim 45, wherein the lymphoma is mantle cell lymphoma (MCL) or small lymphocytic lymphoma (SLL).

47. The method of treatment of claim 45, wherein the leukemia is chronic lymphocytic leukemia (CLL).