Pharmaceutical forms of acalabrutinib maleate

Abstract

This disclosure relates, in general, to: (a) solid dosage forms comprising acalabrutinib maleate; (b) methods of using such dosage forms to treat B-cell neoplasms and / or other conditions; (c) kits comprising such dosage forms and, optionally, a second dosage form comprising another therapeutic agent; (d) methods of preparing such dosage forms; and (e) dosage forms prepared by such methods.

Description

The present disclosure relates generally to: (a) solid dosage forms comprising acalabrutinib maleate; (b) methods of using said dosage forms to treat B cell neoplasms and / or other conditions; (c) kits comprising said dosage forms and, optionally, a second dosage form comprising another therapeutic agent; (d) methods of preparation of said pharmaceutical forms; and (e) dosage forms prepared by such methods. BACKGROUND OF THE INVENTION Acalabrutinib is a selective and covalent inhibitor of Bruton's tyrosine kinase (BTK). It is the active pharmaceutical ingredient in the drug CALQUENCE®, which has been approved in several countries (including the United States, Canada, and Australia) for the treatment of chronic lymphocytic leukemia, small cell lymphocytic leukemia, and mantle cell lymphoma. CALQUENCE® is marketed as capsules containing 100 mg of acalabrutinib crystalline free base (specifically, anhydrous form A). International publication WO2017 / 002095 reports anhydrous form A, additional free base crystal forms of acalabrutinib and salt crystal forms of acalabrutinib including, for example, salts of citrate, fumarate, gentisate, maleate, oxalate, phosphate, sulfate and Acalabrutinib L-tartrate. The CALQUENCE® SmPC recommends avoiding coadministration with gastric acid-lowering agents because such agents may decrease plasma concentrations of acalabrutinib. Therefore, acalabrutinib dosage forms are needed that reduce the potential impact of gastric acid-lowering agents on acalabrutinib plasma concentrations when administered concomitantly with the acalabrutinib dosage form. BRIEF DESCRIPTION OF THE INVENTION In one aspect, the disclosure relates to solid dosage forms comprising about 75 mg to about 125 mg (free base equivalent weight) of acalabrutinib maleate and at least one pharmaceutically acceptable excipient for oral administration to a human, in where the pharmaceutical form satisfies the following conditions: At least about 75% of the acalabrutinib maleate dissolves in about 30 minutes, as determined in an in vitro dissolution test performed with a USP 2 dissolution apparatus (paddle apparatus), a solution volume of 900 ml, a 0.1 N hydrochloric acid dissolution medium and a paddle rotation of 50 rpm; and at least about 75% of the acalabrutinib maleate is dissolved in about 60 minutes, as determined in an in vitro dissolution test performed with a USP 2 dissolution apparatus (paddle apparatus), a solution volume of 900 ml, a 5 mM phosphate dissolution medium at pH 6.8 and a paddle rotation of 75 rpm. In other aspects, solid dosage forms comprise about 75 mg to about 100 mg (free base equivalent weight) of acalabrutinib maleate. In other aspects, acalabrutinib maleate is present as acalabrutinib maleate monohydrate, such as crystalline form A of acalabrutinib maleate. In another aspect, the present disclosure relates to the solid dosage forms described above, wherein the dissolution rate of acalabrutinib maleate in the 5 mM phosphate dissolution medium at pH 6.8 does not decrease by more than 20% with respect to its initial dissolution rate after storing the dosage form in a suitable container for six months at 40 °C and a relative humidity of 75%. In another aspect, the present disclosure relates to one or more of the solid dosage forms described above, wherein no more than about 5% (w / w) of the acalabrutinib maleate present in the dosage form is degraded after retaining the form. pharmaceutical in a suitable container for six months at 40 °C and 75% relative humidity. In another aspect, the present disclosure relates to one or more of the solid dosage forms described above, wherein the dosage form is bioequivalent to a 100 mg Calquence® capsule when administered orally to a fasted human subject at who has not been administered a gastric acid-lowering agent, wherein the dosage form is bioequivalent when the confidence interval of the relative mean of the Cmax, the AUC(o t) and the AUC(o~) of the dosage form with Compared to the 100 mg Calquence® capsule, it is between 80% and 125%. In another aspect, the present disclosure relates to one or more of the solid dosage forms described above, wherein the dosage form, when administered twice daily to a population of fasted human subjects, satisfies one or more of the following: Pharmacokinetic conditions for acalabrutinib: the mean Cmax value in the human subject population is about 400 ng / ml to about 900 ng / ml; the average value of the ABC <o-24>in the human subject population it is approximately 350 ng«h / ml to approximately 1900 ng*h / ml; and / or the mean AUC(o-~) value in the human subject population is about 350 ng*h / ml to about 1900 ng*h / ml. In another aspect, the present disclosure relates to one or more of the solid dosage forms described above, wherein the dosage form, when administered twice daily to a human subject, provides an average occupancy of Bruton's tyrosine kinase in steady state of at least approximately 90% in peripheral blood mononuclear cells. In another aspect, the present disclosure relates to one or more of the solid dosage forms described above, wherein the dosage form comprises: acalabrutinib maleate in an amount of about 15% to about 55% by weight of the dosage form ; at least one diluent in an amount of about 10% to about 70% by weight of the dosage form; at least one disintegrant in an amount of about 0.5% to about 15% by weight of the dosage form; and at least one lubricant in an amount of about 0.25% to about 4% by weight of the dosage form; and where the sum of the individual quantities is equal to 100% of the total weight of the pharmaceutical form. In another aspect, the present disclosure relates to one or more of the solid dosage forms described above, wherein the dosage form comprises: acalabrutinib maleate monohydrate in an amount of about 30% to about 35% by weight (equivalent weight free base) of the pharmaceutical form; mannitol in an amount of about 30% to about 35% by weight of the dosage form; microcrystalline cellulose in an amount of about 25% to about 30% by weight of the dosage form; hydroxypropylcellulose in an amount of about 3% to about 7% by weight of the dosage form; and sodium stearyl fumarate in an amount of about 1% to about 4% by weight of the dosage form; and where the sum of the individual quantities is equal to 100% of the total weight of the pharmaceutical form. BRIEF DESCRIPTION OF THE DRAWINGS The fig. 1 is a representative XRPD diffractogram of crystalline form A of acalabrutinib maleate monohydrate. The fig. 2 shows the dissolution profiles of the phosphate, oxalate and maleate salts of acalabrutinib in simulated gastric juice / FaSSIF-V2 medium. The fig. 3 shows the dissolution profiles of the phosphate, oxalate and maleate salts of acalabrutinib in deionized water / FaSSIF-V2 medium. IVIA / a / ZUZZ / U I 004 I The fig. 4 is a dynamic vapor sorption plot for a phosphate salt of acalabrutinib. The fig. 5 is a thermogravimetric analysis graph for a phosphate salt of acalabrutinib. The fig. 6 is an XRPD diffractogram for a phosphate salt of acalabrutinib. The fig. 7 is a thermogravimetric analysis graph for an oxalate salt of acalabrutinib. The fig. 8 is a dynamic vapor sorption plot for an oxalate salt of acalabrutinib. The fig. 9A is a thermogravimetric analysis graph for a maleate salt of acalabrutinib. The fig. 9B is a graph of thermogravimetric analysis of a maleate salt of acalabrutinib performed under an alternative set of conditions. The fig. 10A is a dynamic vapor sorption plot of a first sample of acalabrutinib maleate salt. The fig. 10B is a dynamic vapor sorption plot of a second, higher quality sample of acalabrutinib maleate salt. The fig. 11 shows the dissolution profiles of micronized and unground acalabrutinib maleate salts in simulated gastric juice / FaSSIF-V2 medium. The fig. 12 shows the dissolution profiles of micronized and unground acalabrutinib maleate salts in deionized water / FaSSIF-V2 medium. The fig. 13 shows the solubility versus final pH values ​​for acalabrutinib maleate and acalabrutinib free base in various buffered solutions. The fig. 14 shows the dissolution profiles obtained in a low pH test under immersion conditions for acalabrutinib maleate tablets T16, T17 and T18, and acalabrutinib free base capsule C1. The fig. 15 shows the dissolution profiles obtained in a neutral pH and low ionic strength test under immersion conditions for acalabrutinib maleate tablets T16, T17 and T18. The fig. 16 shows the dissolution profiles obtained from a neutral pH and high ionic strength test for acalabrutinib T13 maleate tablet and acalabrutinib C2 free base capsule. The fig. 17 shows the dissolution profiles obtained in a neutral medium without buffering capacity (i.e., conditions similar to those of a stomach treated with a proton pump inhibitor) for the acalabrutinib T1 maleate tablet and the acalabrutinib T1 freebase capsule. acalabrutinib C1. IVIA / a / ZUZZ / U I 004 I The fig. 18 shows the dissolution profiles obtained in a neutral medium without buffer capacity for the acalabrutinib maleate tablet T13 and the acalabrutinib C1 free base capsule. The fig. 19 shows a dissolution profile under changing pH conditions for acalabrutinib maleate tablet T19. The fig. 20 shows the dissolution profiles under changing pH conditions for acalabrutinib T19 maleate tablet and acalabrutinib C3 free base capsule. The fig. 21 is a plot of the cumulative fraction available of acalabrutinib (%) versus time (minutes) for acalabrutinib maleate T19 tablet and acalabrutinib C2 freebase capsule when evaluated on a TIM-1 system in associated gastric conditions to an acidic gastric compartment and also in gastric conditions associated with dosing in combination with a proton pump inhibitor or an acid-reducing agent. The fig. 22 shows the particle size distributions of acalabrutinib maleate tablets T10 (D(v, 0.9) ~ 150 pm), T11 (D(v, 0.9) « 16 pm), T13 (D(v, 0.9) ~ 500 pm) and T15 (D(v, 0.9) » 70 pm). The fig. 23 shows the dissolution profiles in 5 mM sodium phosphate buffer medium for acalabrutinib maleate tablets T10, T11,T13 and T15 (drug loading 26% by weight). The fig. 24 shows the dissolution profiles in 5 mM sodium phosphate buffer medium for acalabrutinib maleate tablets T9, T2 and T14 (43% drug loading by weight). The fig. 25 shows the results of an in vivo study in a canine model to measure the free base AUC(0-24) values ​​of acalabrutinib and acalabrutinib maleate when co-administered with omeprazole. The fig. 26 shows the dissolution profiles in a deionized water medium for various binary mixtures of disintegrants and acalabrutinib maleate (1:5 ratio). The fig. 27 shows the dissolution profiles in a deionized water medium for various binary mixtures of lubricants and acalabrutinib maleate (1:15). The fig. 28 shows the dissolution profiles in a deionized water medium for tablet cores T2 and T3. The fig. 29 shows the dissolution profiles in a deionized water medium for the T6 and T8 tablet cores. The fig. 30 shows the dissolution profiles in a deionized water medium for the T4 and T5 tablet cores. The fig. 31 provides a schematic overview of a process for preparing the acalabrutinib T21 maleate tablet of Example 4. DETAILED DESCRIPTION OF THE INVENTION I. Definitions Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly interpreted by one skilled in the art to which this invention pertains. When ranges are used to describe, for example, quantities, they are intended to include all combinations and subcombinations of specific ranges and embodiments. The singular forms an, an, and the include plural references, unless the context clearly indicates otherwise. The use of the term approximately when referring to a number or numerical interval means that the number or numerical interval referred to is an approximation within the experimental variability (or within the statistical experimental error), and therefore the number or the numerical range may vary. The variation is typically 0% to 15%, preferably 0% to 10%, more preferably 0% to 5% of the indicated number or numerical range. In many cases, the term approximately may include numbers that are rounded to the nearest significant figure. The term acalabrutinib refers to the International Nonproprietary Name (INN) of the compound 4-{8-amino-3-[(2S)-1 -(but-2-inoyl)pyrrolidin-2-¡l]¡m idazo[1,5-a]pyrazin-1 -i l}-N(pyrídin-2-yl)benzamide having the chemical structure shown below: International publication WO2013 / 010868 discloses acalabrutinib (Example 6) and describes the synthesis of acalabrutinib. International publication WO2020 / 043787 further describes the synthesis of acalabrutinib. International publication WO2013 / 010868 and international publication WO2020 / 043787 are incorporated by reference in their entirety. The term "acalabrutinib maleate monohydrate" refers to crystalline acalabrutinib maleate monohydrate, including the crystalline A form of acalabrutinib maleate monohydrate. Example 6.2 of international publication n.sWO2017 / 002095 describes the preparation of crystalline form A of acalabrutinib maleate monohydrate. International publication n.eWO2017 / 002095 is incorporated by reference in its entirety. Acalabrutinib maleate form A may also be named by the alternative nomenclature of acalabrutinib maleate monohydrate form 1. Unless otherwise indicated, any reference in the present disclosure to an amount of acalabrutinib, acalabrutinib maleate or acalabrutinib maleate monohydrate is based on the free base equivalent weight of acalabrutinib. For example, 100 mg refers to 100 mg of acalabrutinib free base or an equivalent amount of acalabrutinib maleate or acalabrutinib maleate monohydrate. The term ACP-5862 refers to the compound 4-[8-amino-3-[4-(but-2ino¡lamino)butanoyl]¡m¡dazo[1,5-a]pyrazin-1-yl]- N-pyridín-2-ílbenzamide which has the chemical structure shown below: ACP-5862 is an active metabolite of acalabrutinib. The term AUC(o-24| refers to the area under the plasma concentration-time curve from time 0 (time of dosing) to 24 hours after dosing, calculated using the linear trapezoidal method. The term AUC(o-oo) refers to the area under the plasma concentration-time curve from time 0 (time of dosing) to infinity (°°), calculated using the linear trapezoidal method. The term BID means bis in die or twice a day. The term Cmax refers to the maximum plasma concentration observed during the entire sampling period. The terms coadministration, in combination with and combination may refer to the administration of two or more therapeutic agents. In one aspect, combination may refer to simultaneous administration (e.g., administration of both agents in separate dosage forms but substantially at the same time). In a further aspect of the invention combination may refer to a sequential administration (e.g., where a first agent is administered, followed by time spacing, followed by the administration of a second additional agent). When administration is sequential, the delay in administration of the subsequent component should be neither too long nor too short, so as not to lose the benefit of the combination. Unless the context otherwise requires, the terms understand, understands, and understands are used on the basis and with the clear understanding that they are to be interpreted inclusively, and not exclusively, and that the applicant intends each of those words to be interpreted accordingly. this way in interpreting this patent, including the claims below. The term crystalline as applied to acalabrutinib, acalabrutinib maleate or acalabrutinib maleate monohydrate refers to a solid state form, where the molecules are distributed forming a distinguishable crystal lattice (i) comprising distinguishable unit cells, and (i ) that produces diffraction peaks when subjected to X-ray radiation. The term "crystalline purity" refers to the crystalline purity of acalabrutinib, acalabrutinib maleate or acalabrutinib maleate monohydrate with respect to a particular crystalline form, determined by analytical X-ray powder diffraction methods. The term crystallization, as used throughout the present application, may refer to crystallization and / or recrystallization, depending on the applicable circumstances relating to the preparation of acalabrutinib, acalabrutinib maleate or acalabrutinib maleate monohydrate. The terms “D(o.i) and D<v, o.i), as used in the present application, mean that 10% of the total volume of sample material has a particle size diameter less than the specified value, determined by laser diffraction. The terms D(0.5) and D(V, 0.5), as used in this application, mean that 50% of the total volume of sample material has a particle size diameter less than the specified value, determined by laser diffraction. IVIA / a / ZUZZ / U I OΟ4Ί The terms D(o.9) and D<v, o.9), as used in the present application, mean that 90% of the total volume of sample material has a particle size diameter less than the value specified, determined by laser diffraction. The term pharmaceutically acceptable (as in the reference to a pharmaceutically acceptable diluent or a pharmaceutically acceptable disintegrant) refers to a material that is compatible with administration to a subject, for example, the material does not cause an undesirable biological effect. Examples of pharmaceutically acceptable excipients are described in the Handbook of Pharmaceutical Excipients, Rowe et al, Ed. (Pharmaceutical Press, 7th Ed., 2012). Pharmaceutically acceptable carrier or pharmaceutically acceptable excipient means any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption retarding agents and inert ingredients. Except to the extent that any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with acalabrutinib, acalabrutinib maleate or acalabrutinib maleate monohydrate, its use is contemplated in the therapeutic compositions of the invention. The term Q means the amount (Q) of an active substance in a sample that dissolves in a given time, expressed as a percentage of the total amount of the active substance present in the sample. The term QD means quaque dieo once a day. The term Tmax refers to the time of the maximum observed plasma concentration (Cmax) The terms treat and treatment refer to improving, suppressing, eradicating, reducing the severity, decreasing the frequency of incidence, reducing the risk or delaying the onset of the disease. The abbreviations listed in Table 1 have the meaning indicated in that table. TABLE 1 ABBREVIATION MEANING DC Direct compression LDLBG Diffuse large B-cell lymphoma DVS Dynamic vapor sorption FaSSIF Simulated fasting intestinal juice g grams g / mol Grams / mol h hour HDPE High-density polyethylene HPLC High-performance liquid chromatography kg kilogram kN Kilonewton 1 Liter My Microliter gm Micrometer μΜ Micromolar mg Milligram(s) mi Milliliter mm Millimeter nM Nanomolar NMT No more than PBPK Physiologically based pharmacokinetics PK Pharmacokinetics(es) PPI Proton pump inhibitor P-PSD Product particle size distribution XRPD X-ray powder diffraction h. r. Relative humidity rpm Revolutions per minute RRT Relative retention time TGA Thermogravimetric analysis USP United States Pharmacopeia w / w W / w II. Solid dosage forms The present disclosure relates, in part, to solid dosage forms comprising acalabrutinib maleate, in particular crystalline acalabrutinib maleate monohydrate. According to the Biopharmaceutical Classification System (BCS), acalabrutinib is a BCS Class II drug, meaning it has good permeability but low solubility in the gastrointestinal tract. See Pepin, X. J. H., et al., Bridging in vitro dissolution and in vivo exposure for acalabrutinib. Part II. A mechanistic PBPK model for IR formulation comparison, proton pump inhibitor drug interactions, and administration with acidic juices, European Journal of Pharmaceutics and Biopharmaceutics 142: 435-448 (2019). The bioavailability of BCS Class II drugs, including acalabrutinib, is often limited by their rate of dissolution and / or solvation. Furthermore, the free base of acalabrutinib exhibits a pH-dependent solubility, which decreases as the pH increases up to the maximum basic pKa, (i.e., approximately pH 6, where acalabrutinib is largely non-ionized). Increased stomach pH of a subject taking CALQUENCE® (for example, in a subject also taking a proton pump inhibitor or other gastric acidity-lowering agent) may reduce the solubility of acalabrutinib in the stomach and potentially give lead to lower bioavailability and / or greater intra- and intersubject variability in the pharmacokinetics of acalabrutinib. The present disclosure relates to the unexpected finding that solid dosage forms containing acalabrutinib maleate, as described below, have acceptable physical and pharmacological properties (e.g., dissolution, stability, manufacturability, pharmacokinetics, etc.) and, although are substantially bioequivalent to the currently marketed CALQUENCE® capsule dosage form under normal stomach acid conditions, they provide less variability in acalabrutinib pharmacokinetics over a broader range of stomach pH conditions. These solid dosage forms offer an additional therapeutic option for the treatment of B cell malignancies, such as chronic lymphocytic leukemia, small cell lymphocytic leukemia, and mantle cell lymphoma. In some embodiments, the disclosure relates, in part, to solid dosage forms comprising about 75 mg to about 125 mg (free base equivalent weight) of acalabrutinib maleate and at least one pharmaceutically acceptable excipient for oral administration to a being. human, where the pharmaceutical form satisfies the following conditions: At least about 75% of the acalabrutinib maleate dissolves in about 30 minutes, as determined in an in vitro dissolution test performed with a USB 2 dissolution apparatus (paddle apparatus), a solution volume of 900 ml, a 0.1 N hydrochloric acid dissolution medium and a paddle rotation of 50 rpm; and at least about 75% of the acalabrutinib maleate is dissolved in about 60 minutes, as determined in an in vitro dissolution test performed with a USP 2 dissolution apparatus (paddle apparatus), a solution volume of 900 ml, a 5 mM phosphate dissolution medium at pH 6.8 and a paddle rotation of 75 rpm. The 0.1 N hydrochloric acid dissolution medium is believed to be representative of the fasting stomach, while the 5 mM phosphate dissolution at pH 6.8 is believed to be representative of the worst-case scenario of a stomach treated with a gastric acid-reducing agent. In one aspect, the dosage form satisfies the following conditions: At least about 75% of the acalabrutinib maleate dissolves in about 20 minutes, as determined in an in vitro dissolution test performed with a USP 2 dissolution apparatus (paddle apparatus), a solution volume of 900 ml, a 0.1 N hydrochloric acid dissolution medium and a paddle rotation of 50 rpm; and at least about 75% of the acalabrutinib maleate is dissolved in about 45 minutes, as determined in an in vitro dissolution test performed with a USP 2 dissolution apparatus (paddle apparatus), a solution volume of 900 ml, a 5 mM phosphate dissolution medium at pH 6.8 and a paddle rotation of 75 rpm. In another aspect, the pharmaceutical form satisfies the following conditions: At least about 80% of the acalabrutinib maleate dissolves in about 20 minutes, as determined in an in vitro dissolution test performed with a USP 2 dissolution apparatus (paddle apparatus), a solution volume of 900 ml, a 0.1 N hydrochloric acid dissolution medium and a paddle rotation of 50 rpm; and at least about 80% of the acalabrutinib maleate is dissolved in about 30 minutes, as determined in an in vitro dissolution test performed with a USP 2 dissolution apparatus (paddle apparatus), a solution volume of 900 ml, a 5 mM phosphate dissolution medium at pH 6.8 and a paddle rotation of 75 rpm. In another aspect, the pharmaceutical form satisfies the following conditions: At least about 80% of the acalabrutinib maleate dissolves in about 15 minutes, as determined in an in vitro dissolution test performed with a USP 2 dissolution apparatus (paddle apparatus), a solution volume of 900 ml, a 0.1 N hydrochloric acid dissolution medium and a paddle rotation of 50 rpm; and at least about 80% of the acalabrutinib maleate is dissolved in about 20 minutes, as determined in an in vitro dissolution test performed with a USP 2 dissolution apparatus (paddle apparatus), a solution volume of 900 ml. , a 5 mM phosphate dissolution medium at pH 6.8 and a paddle rotation of 75 rpm. In some embodiments, the solid dosage forms of the present disclosure comprise from about 75 mg to about 125 mg of acalabrutinib maleate (free base equivalent weight). In one aspect, the dosage forms comprise about 75 mg to about 100 mg acalabrutinib maleate (free base equivalent weight), comprise about 75 mg acalabrutinib (free base equivalent weight), comprise about 80 mg acalabrutinib (free base equivalent weight). In another aspect, the dosage forms comprise approximately 80 mg of acalabrutinib maleate (equivalent weight of free base), comprising approximately 85 mg of acalabrutinib (equivalent weight of free base). approximately 90 mg to acalabrutinib (free base equivalent weight). about 90 mg of acalabrutinib maleate. In another aspect, the dosage forms comprise about 95 mg of acalabrutinib maleate (equivalent weight of free base). In another aspect, the dosage forms comprise approximately 75 mg of acalabrutinib maleate (free base equivalent weight). In another aspect, the dosage forms comprise approximately 80 mg of acalabrutinib maleate (free base equivalent weight). In another aspect, the dosage forms comprise approximately 85 mg of acalabrutinib maleate (free base equivalent weight). In another aspect, the dosage forms comprise approximately 90 mg of acalabrutinib maleate (free base equivalent weight). In another aspect, the dosage forms comprise approximately 95 mg of acalabrutinib maleate (free base equivalent weight). In another aspect, the dosage forms comprise approximately 100 mg of acalabrutinib maleate (free base equivalent weight). In some embodiments, the acalabrutinib maleate is acalabrutinib maleate monohydrate. In one aspect, acalabrutinib maleate monohydrate is crystalline acalabrutinib maleate monohydrate. In another aspect, crystalline acalabrutinib maleate is crystalline form A of acalabrutinib maleate monohydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of an of the dust with at least five peaks selected from the group consisting of 5.3, 9.8, 10.6, 11.6, 13.5, 13.8, 13.9, 14.3, 15.3, 15.6, 15.8, 15.9, 16.6, 17.4, 17.5, 18.7, 19.3, 19.6, 19.8, 20.0, 20.9, 21.3, 22.1,22.3, 22.7, 23.2, 23.4, 23.7, 23.9, 24.5, 24.8, 25.2, 25.6, 26.1,26.4, 26.7, 26.9, 27.1,27.6, 28.8, 29.5, 30.0, 30.3, 30.9, 31.5, 31.9, 32.5, 34.0 and 35.1, with peak positions measured at °20 ±0.2 °20. In another aspect, the maleal crystalline form A of acalabrutinib has an X-ray powder diffraction pattern comprising peaks at 5.3, 9.8, 10.6, 11.6 and 19.3°20 ±0.2°20. In another aspect, the powder X-ray diffraction pattern substantially matches the powder X-ray diffraction pattern of FIG. 1. In another aspect, the powder X-ray diffraction pattern of any of the above embodiments is measured in transmission mode. In another aspect, the powder X-ray diffraction pattern of any of the above embodiments is measured in reflection mode. In another aspect, the crystalline acalabrutinib maleate monohydrate of any of the above embodiments has a stoichiometry relative to acalabrutinib that is approximately equivalent to a monohydrate. The applicable X-ray powder diffraction measurement conditions are described in international publication n.sWO2017 / 002095. In some embodiments, the dosage form comprises acalabrutinib maleate, wherein the acalabrutinib maleate has a crystalline purity of at least about 80% by weight of the acalabrutinib present in the dosage form. In one aspect, the crystalline purity is at least crystalline is at least about 85% about 90% about 95% by weight. In another aspect, in weight. In another aspect, in weight. In another aspect, crystalline is at least about 98% by weight. In another aspect, the crystalline purity is at least about 99% by weight. In another aspect, acalabrutinib maleate is acalabrutinib maleate monohydrate. In another aspect, acalabrutinib maleate is form A of acalabrutinib maleate monohydrate. In some embodiments, the dosage form comprises acalabrutinib maleate, wherein the acalabrutinib maleate has a crystalline purity of at least about 95% by weight of the acalabrutinib present in the dosage form. In one aspect, the acalabrutinib maleate is acalabrutinib maleate monohydrate. In another aspect, acalabrutinib maleate is the crystalline form A of acalabrutinib maleate monohydrate. In another aspect, the crystalline purity is at least about 96% by weight. In another aspect, the crystalline purity is at least about 97% by weight. In another aspect, the crystalline purity is at least about 98% by weight. In another aspect, the crystalline purity is at least about 99% by weight. In other aspects, the acalabrutinib maleate has a crystalline purity of at least about 95% by weight of the acalabrutinib present in the dosage form and comprises less than about 2% by weight of the (2Z)-4-[ acid impurity. (2S)-2-{8-amino-1-[4-(2pyridinylcarbamoyl)phenyl]¡m¡dazo[1,5-a]pyrazin-3-yl}-1 -pyrrolidin¡l]-4- oxo-2-butene¡co which has the chemical structure shown below: In another aspect, the acalabrutinib maleate comprises less than about 1.5% by weight of the impurity. In another aspect, the acalabrutinib maleate comprises less than about 1% by weight of the impurity. In another aspect, the acalabrutinib maleate comprises less than about 0.5% by weight of the impurity. In another aspect, the acalabrutinib maleate is substantially free of the impurity. Selecting a salt of a compound instead of the free form thereof does not necessarily improve the solubility and absorption of the compound in the gastrointestinal tract to the desired extent. Furthermore, salts of a compound can differ significantly in physical and other properties that influence whether the salt is suitable for use in a dosage form. For example, the rapid conversion of a salt to a relatively insoluble free form in the acidic environment of the stomach, as well as in the pH 6 to pH 7.5 environment of the intestine, can cause precipitation of a portion of the free form. Such precipitation of the free form results in a lower amount of the administered dose available for uptake in the gastrointestinal tract, resulting in lower overall bioavailability of the compound. Surface properties (e.g. affecting wettability) and particle size (e.g. affecting dissolution rate) are also among the factors that can affect the performance of the salt selected for the dosage form. . For example, the citrate, fumarate, gentisate, napadisylate, nitrate, oxalate, phosphate, sulfate and L-tartrate salts of acalabrutinib were determined to be unsuitable for use in the solid dosage forms of the present disclosure. Citrate, fumarate, gentisate, and L-tartrate salts were eliminated from consideration because of their pKay / o values ​​because of evidence of complex solid-state behavior. For example, napadisylate salt had crystallinity problems. Nitrate salt could not be adequately manufactured at scale and is generally not favored for use in pharmaceuticals. Oxalate, phosphate, and sulfate salts showed complex hydrate behavior and were considered unsuitable for commercial manufacturing. In fact, the initial acalabrutinib maleate salt samples tested were considered unlikely to achieve the solubility and dissolution rate necessary to overcome the limitations of acalabrutinib free base in patients with elevated stomach pH. Furthermore, although crystalline form A of acalabrutinib maleate monohydrate is thermodynamically stable under ambient conditions, it also exhibits solid-state properties that were initially believed to present challenges in manufacturing commercial supplies of the drug. In some embodiments, the present disclosure relates to solid dosage forms wherein the dissolution rate of acalabrutinib maleate in the in vitro dissolution test performed with a USP 2 dissolution apparatus (paddle apparatus), a solution volume of 900 mi, a 5 mM phosphate dissolution medium at pH 6.8, and a paddle rotation of 75 rpm, does not decrease by more than 20% with respect to its initial dissolution rate after keeping the dosage form in a suitable container for six months at 40 °C and a relative humidity of 75%. In one aspect, the dissolution rate does not decrease by more than 10% with respect to its initial dissolution rate after preserving the dosage form in a suitable container for six months at 40 ° C and 75% relative humidity. In one aspect, the dissolution rate does not decrease by more than 15% with respect to its initial dissolution rate after preserving the dosage form in a suitable container for six months at 40 ° C and 75% relative humidity. In another aspect, the dissolution rate does not decrease by more than 5% with respect to its initial dissolution rate after preserving the pharmaceutical form in a suitable container for six months at 40 ° C and 75% relative humidity. In another aspect, the dissolution rate does not decrease by more than 3% with respect to its initial dissolution rate after preserving the pharmaceutical form in a suitable container for six months at 40 ° C and 75% relative humidity. In another aspect, the dissolution rate does not decrease by more than 2% with respect to its initial dissolution rate after preserving the pharmaceutical form in a suitable container for six months at 40 ° C and 75% relative humidity. In another aspect, the dissolution rate does not decrease by more than 1% with respect to its initial dissolution rate after preserving the pharmaceutical form in a suitable container for six months at 40 ° C and 75% relative humidity. In one aspect, the package is a blister package, such as an aluminum blister. In another aspect, the container is an HDPE bottle sealed with desiccant. In some embodiments, the present disclosure relates to solid dosage forms wherein no more than about 5% (w / w) of the acalabrutinib maleate present in the dosage form degrades upon storage of the dosage form in suitable packaging for six months. at 40 °C and 75% relative humidity. In one aspect, no more than about 3% (w / w) of the acalabrutinib maleate present in the dosage form degrades after storing the dosage form in a suitable container for six months at 40° C. and 75% relative humidity. In another aspect, no more than about 2% (w / w) of the acalabrutinib maleate present in the dosage form degrades after storing the dosage form in a suitable container for six months at 40°C and 75% relative humidity. In another aspect, no more than about 1% (w / w) of the acalabrutinib maleate present in the dosage form degrades after storing the dosage form in a blister package for six months at 40°C and 75% relative humidity. In another aspect, no more than about 0.5% (w / w) of the acalabrutinib maleate present in the dosage form degrades after storing the dosage form in a suitable container for six months at 40°C and 75% relative humidity. In one aspect, the package is a blister package, such as an aluminum blister. In another aspect, the container is an HDPE bottle sealed with desiccant. In another aspect, the degradation of acalabrutinib maleate is analyzed by high performance liquid chromatography. In some embodiments, the present disclosure relates to solid dosage forms wherein the dosage form is substantially bioequivalent to a 100 mg Calquence® capsule (the composition of which corresponds to the content of the reference capsule C4 of Table 6 of Example 4). when administered orally to a fasting human subject who has not been administered a gastric acidity reducing agent. In one aspect, the dosage form, when administered orally to a fasting human subject who has not been administered a gastric acidity reducing agent, has a confidence interval of the relative mean of the Cmax, the AUC (o-t>and the ABC™--) of the dosage form in relation to Calquence® 100 mg capsule for plasma acalabrutinib which are within 80% to 125%. In one aspect, the dosage form, when administered orally to a fasting human subject who has not been administered a gastric acidity reducing agent, has a confidence interval of the relative mean of the Cmax, the AUC (o-t)and the AUC(o-~) of the dosage form relative to Calquence® 100 mg capsule for plasma acalabrutinib and its active metabolite, ACP-5862 (i.e., 4-[8-amino-3 -[4-(but-218 inoylam¡no)butane¡l]im¡dazo[1,5-a]p¡reason-1-¡l]-N-p¡r¡din-2-¡lbenzam¡da) which They are within 80% to 125%. In some embodiments, the present disclosure relates to solid dosage forms wherein the dosage form, when administered twice daily to a population of fasting human subjects, satisfies one or more of the following pharmacokinetic conditions for acalabrutinib: the mean Cmax value in the human subject population is about 400 ng / ml to about 900 ng / ml; the mean value of AUC<o-24) in the human subject population is about 350 ng*h / ml to about 1900 ng*h / ml; and / or the mean AUC<o-» value) in the human subject population is approximately 350 ng«h / ml to approximately 1900 ng«h / ml. In one aspect, the dosage form is co-administered to the human subject population with a gastric acid reducing agent. In some embodiments, the present disclosure relates to solid dosage forms wherein the dosage form, when administered twice daily (BID) to a human subject, provides a mean steady-state Bruton's tyrosine kinase occupancy of at least approximately 90% in peripheral blood mononuclear cells. In one aspect, the dosage form, when administered twice daily to a human subject, provides a median steady-state Bruton's tyrosine kinase occupancy of at least 95% in peripheral blood mononuclear cells. In another aspect, the dosage form is co-administered to the human subject population with a gastric acid reducing agent. In some embodiments, the present disclosure relates to solid dosage forms wherein acalabrutinib maleate is present in an amount of about 15% to about 55% by weight (free base equivalent weight) of the dosage form. In one aspect, acalabrutinib maleate is present in an amount of about 25% to about 50% by weight of the dosage form. In another aspect, acalabrutinib maleate is present in an amount of about 25% to about 45% by weight of the dosage form. In another aspect, acalabrutinib maleate monohydrate is present in an amount of about 25% to about 40% by weight of the dosage form. In some embodiments, the present disclosure relates to solid dosage forms wherein the at least one pharmaceutically acceptable excipient is selected from at least one diluent, at least one disintegrant and at least one lubricant. In one aspect, the at least one pharmaceutically acceptable excipient comprises at least one diluent. In another aspect, the at least one pharmaceutically acceptable excipient comprises at least one disintegrant. In another aspect, the at least one pharmaceutically acceptable excipient comprises at least one diluent and at least one disintegrant. In another aspect, the at least one pharmaceutically acceptable excipient comprises at least one diluent, at least one disintegrant and at least one lubricant. Excipient interactions in the dosage form may affect the suitability of excipient combinations in the dosage forms of the present disclosure. Accordingly, the excipient combinations preferably selected do not materially affect the suitability of the dosage form for pharmaceutical use. In some embodiments, the present disclosure relates to solid dosage forms wherein the dosage comprises at least one diluent wherein the at least one diluent is present in an amount of about 10% to about 70% by weight of the dosage form. . In one aspect, the at least one diluent is present in an amount of about 20% to about 70% by weight of the dosage form. In another aspect, the at least one diluent is present in an amount of about 30% to about 70% by weight of the dosage form. In another aspect, the at least one diluent is present in an amount of about 40% to about 70% by weight of the dosage form. In another aspect, the maleal weight ratio of acalabrutinib to at least one diluent is about 1:3 to about 2:1. In another aspect, the weight ratio of acalabrutinib maleate monohydrate to at least one diluent is about 1:1 to about 1:2. When present, the one or more selected diluents do not affect the stability of the primary amine moiety of acalabrutinib. In one aspect, the diluent is not susceptible to reacting with the primary amine moiety in a Maillard reaction. For example, the extender is not a reducing sugar like lactose. Furthermore, the one or more diluents do not comprise a maleic acid sequestering agent, such as a metal salt. In one aspect, the one or more diluents do not comprise anhydrous dibasic calcium phosphate. Acceptable diluents include, for example, sugar alcohols (such as mannitol, sorbitol, maltitol and xylitol), hydrolyzed starches, partially pregelatinized starches and celluloses (such as microcrystalline cellulose and silicified microcrystalline cellulose), and combinations. thereof (such as a combination comprising mannitol and starch). In some embodiments, the at least one diluent comprises a plastic diluent and a brittle diluent. A plastic diluent, such as microcrystalline cellulose, is one that undergoes irreversible deformation after exceeding the elastic limit during compression, causing the particles to undergo viscous flow and remain deformed after the compression force is removed. A brittle diluent, such as mannitol, is one that undergoes fragmentation during compression, creating new surfaces for particle attachment. In one aspect, the dosage form comprises a plastic diluent and a brittle diluent in a total amount of about 10% to about 70% by weight of the dosage form; wherein the plastic diluent is present in an amount of from about 0% to about 70% by weight of the dosage form; and the brittle diluent is present in an amount of from about 0% to about 50% by weight of the dosage form. When the dosage form is a tablet, the ratio of plastic diluent to brittle diluent selected can influence the tensile strength of the tablet. Too much plastic diluent can weaken the tensile strength of the tablet. In one aspect, the w / w ratio of plastic diluent to brittle diluent in the dosage form is from about 0:100 to about 60:40. In another aspect, the w / w ratio of plastic diluent to brittle diluent in the dosage form is from about 0:100 to about 60:40, wherein the dosage form is a tablet having a tensile strength of at least 2.0. MPa. In some embodiments, the at least one diluent comprises mannitol. In one aspect, mannitol is present in an amount of about 10% to about 70% by weight of the dosage form. In some embodiments, the at least one diluent comprises microcrystalline cellulose. In one aspect, the microcrystalline cellulose is present in an amount of about 5% to about 50% by weight of the dosage form. In some embodiments, the at least one diluent comprises mannitol and microcrystalline cellulose. In one aspect, mannitol is present in an amount of from about 0% to about 70% by weight of the dosage form; wherein the microcrystalline cellulose is present in an amount of about 0% to about 50% by weight of the dosage form; and the total amount of mannitol and microcrystalline cellulose is about 10% to about 70% by weight of the dosage form. In another aspect, the w / w ratio of mannitol to microcrystalline cellulose is from about 0:100 to about 60:40. In another aspect, the w / w ratio of mannitol to microcrystalline cellulose in the dosage form is from about 0:100 to about 60:40, wherein the dosage form is a tablet having a tensile strength of at least 2.0 MPa. . In some embodiments, the present disclosure relates to solid dosage forms wherein the dosage comprises at least one disintegrant and the at least one disintegrant is present in an amount of about 0.5% to about 15% by weight of the tablet. In one aspect, the at least one disintegrant is present in an amount of about 1% to about 10% by weight of the tablet. In another aspect, the at least one disintegrant is present in an amount of about 2% to about 8% by weight of the tablet. In another aspect, the at least one disintegrant is present in an amount of about 3% to about 7% by weight of the tablet. In another aspect, the weight ratio of acalabrutinib maleate (free base equivalent weight) to at least one disintegrant is from about 2:1 to about 15:1. In another aspect, the weight ratio of acalabrutinib maleate to at least one disintegrant is from about 4:1 to about 10:1. When present, the one or more disintegrants selected preferably do not comprise an ionic disintegrant. In one aspect, the at least one disintegrant does not comprise sodium starch glycolate and / or croscarmellose sodium. In one aspect, the at least one disintegrant does not comprise sodium starch glycolate. In another aspect, the at least one disintegrant does not comprise croscarmellose sodium. Acceptable disintegrants include, for example, hydroxypropyl cellulose, corn starch, microcrystalline cellulose, crospovidone and combinations thereof. In one aspect, the at least one disintegrant comprises hydroxypropyl cellulose. In another aspect, the at least one disintegrant comprises low substituted hydroxypropylcellulose. In some embodiments, the present disclosure relates to solid dosage forms wherein the dosage comprises at least one lubricant and the at least one lubricant is present in an amount of from about 0.25% to about 4% by weight of the dosage form. In one aspect, the at least one lubricant is present in an amount of about 1% to about 4% by weight of the dosage form. In another aspect, the at least one lubricant is present in an amount of about 1.5% to about 3.5% by weight of the dosage form. In another aspect, the at least one lubricant is present in an amount of about 2% to about 3% by weight of the dosage form. In another aspect, the weight ratio of acalabrutinib maleate (free base equivalent weight) to at least one lubricant is from about 20:1 to about 12:1. In another aspect, the weight ratio of acalabrutinib maleate to at least one lubricant is from about 18:1 to about 14:1. Acceptable lubricants include, for example, sodium stearyl fumarate, stearic acid, myristic acid, palmitic acid, sugar esters (such as sorbitan monostearate and sucrose monopalmitate), and combinations thereof. In another aspect, the at least one lubricant comprises sodium stearyl fumarate. In general, the use of magnesium stearate as a selected lubricant should be avoided. In some embodiments, the present disclosure relates to solid dosage forms wherein the dosage form comprises: acalabrutinib maleate in an amount of about 15% to about 55% by weight (free base equivalent weight) of the dosage form; at least one diluent in an amount of about 10% to about 70% by weight of the dosage form; at least one disintegrant in an amount of about 0.5% to about 15% by weight of the dosage form; and at least one lubricant in an amount of about 0.25% to about 4% by weight of the dosage form; and where the sum of the individual quantities is equal to 100% of the total weight of the pharmaceutical form. In one aspect, the dosage form consists essentially of the components described above. In other aspects, acalabrutinib maleate is present as acalabrutinib maleate monohydrate. In some embodiments, the present disclosure relates to solid dosage forms wherein the dosage form comprises: acalabrutinib maleate monohydrate in an amount of about 20% to about 50% by weight (free base equivalent weight) of the dosage form; at least one diluent in an amount of about 20% to about 70% by weight of the dosage form; at least one disintegrant in an amount of about 1% to about 10% by weight of the dosage form; and at least one lubricant in an amount of about 1% to about 4% by weight of the dosage form; and where the sum of the individual quantities is equal to 100% of the total weight of the pharmaceutical form. In one aspect, the dosage form consists essentially of the components described above. In other aspects, acalabrutinib maleate is present as acalabrutinib maleate monohydrate. In some embodiments, the present disclosure relates to solid dosage forms wherein the dosage form comprises: acalabrutinib maleate in an amount of about 25% to about 50% by weight (free base equivalent weight) of the dosage form; at least one diluent in an amount of about 30% to about 70% by weight of the dosage form; at least one disintegrant in an amount of about 2% to about 8% by weight of the dosage form; and at least one lubricant in an amount of about 1.5% to about 3.5% by weight of the dosage form; and where the sum of the individual quantities is equal to 100% of the total weight of the pharmaceutical form. In one aspect, the dosage form consists essentially of the components described above. In other aspects, acalabrutinib maleate is present as acalabrutinib maleate monohydrate. In some embodiments, the present disclosure relates to solid dosage forms wherein the dosage form comprises: acalabrutinib maleate in an amount of about 25% to about 40% by weight (free base equivalent weight) of the dosage form; at least one diluent in an amount of about 40% to about 70% by weight of the dosage form; at least one disintegrant in an amount of about 3% to about 7% by weight of the dosage form; and at least one lubricant in an amount of about 2% to about 3% by weight of the dosage form; and where the sum of the individual quantities is equal to 100% of the total weight of the pharmaceutical form. In one aspect, the dosage form consists essentially of the components described above. In other aspects, acalabrutinib maleate is present as acalabrutinib maleate monohydrate. In some embodiments, the present disclosure relates to solid dosage forms wherein the dosage form comprises: acalabrutinib maleate in an amount of about 30% to about 35% by weight (free base equivalent weight) of the dosage form; and mannitol in an amount of about 30% to about 35% by weight of the dosage form; microcrystalline cellulose in an amount of about 25% to about 30% by weight of the dosage form; hydroxypropylcellulose in an amount of about 3% to about 7% by weight of the dosage form; and sodium stearyl fumarate in an amount of about 1% to about 4% by weight of the dosage form; and where the sum of the individual quantities is equal to 100% of the total weight of the pharmaceutical form. In one aspect, the dosage form consists essentially of the components described above. In other aspects, acalabrutinib maleate is present as acalabrutinib maleate monohydrate. In some embodiments, the present disclosure relates to solid dosage forms wherein acalabrutinib maleate has a D(V, 0.9) value of less than about 500 micrometers. In one aspect, acalabrutinib maleate has a D(V,o.9) value of less than about 450 micrometers. In another aspect, acalabrutinib maleate has a D(V, o.9) value of less than about 400 micrometers. In another aspect, acalabrutinib maleate has a D value <v, 0.9) of less than about 350 micrometers. In another aspect, acalabrutinib maleate has a D value <v, 0.9) of less than about 300 micrometers. In another aspect, acalabrutinib maleate has a D(V, 0.9) value of about 20 micrometers to about 500 micrometers. In another aspect, acalabrutinib maleate has a D value <v, 0.9) of about 50 micrometers to about 450 micrometers. In another aspect, acalabrutinib maleate has a D(V, c.9) value of about 75 micrometers to about 400 micrometers. In another aspect, acalabrutinib maleate has a D(V, 0.9) value of about 75 micrometers to about 350 micrometers. In another aspect, acalabrutinib maleate has a D(V, 0.9) value of about 100 micrometers to about 300 micrometers. In some embodiments, the present disclosure relates to solid dosage forms wherein the acalabrutinib maleate satisfies one or more of the following conditions: a value of D(V, 0.1) less than about 20 micrometers, a value of D(V, 0.1) 0.5) less than about 145 micrometers, and a value of D<v, 0.9) less than about 330 micrometers. In another aspect, acalabrutinib maleate has a D(V, 0.5) value of less than about 145 micrometers and a D(V, 0.9) value of less than about 330 micrometers. In another aspect, acalabrutinib maleate has a D(V, 0.1) value of less than about 20 micrometers, a D(V, 0.5) value of less than about 145 micrometers, and a D<v, 0.9) value of less than approximately 330 micrometers. In some embodiments, the present disclosure relates to solid dosage forms wherein the dosage form is a capsule. In one aspect, the capsule is prepared by a process comprising roller compaction. In some embodiments, the present disclosure relates to solid dosage forms wherein the dosage form is a tablet. In one aspect, the dosage form is a film-coated tablet. In another aspect, the film coating is a stabilizing film coating. In another aspect, the tablet is prepared by a process comprising direct compression. In another aspect, the tablet is prepared by a process comprising roller compaction. In another aspect, the tablet is prepared by a process comprising wet granulation. In another aspect, the tablet has a tensile strength of about 1.5 MPa to about 5.0 MPa. In another aspect, the tablet has a tensile strength of about 2.0 MPa to about 4.0 MPa. In another aspect, the tensile strength of the tablet does not decrease by more than 10% with respect to its initial tensile strength after storing the tablet in a suitable container for six months at 40 ° C and 75% relative humidity. In another aspect, the tensile strength of the tablet does not decrease by more than 8% with respect to its initial tensile strength after storing the tablet in a suitable container for six months at 40 ° C and 75% relative humidity. In another aspect, the tensile strength of the tablet does not decrease by more than 5% with respect to its initial tensile strength after storing the tablet in a suitable container for six months at 40 ° C and 75% relative humidity. In one aspect, the package is a blister package, such as an aluminum blister. In another aspect, the container is an HDPE bottle sealed with desiccant. In some embodiments, the tablet is a coated or uncoated tablet having a core weight of less than about 600 mg. In another aspect, the dosage form is a coated or uncoated tablet having a core weight of about 300 mg to about 500 mg. In another aspect, the dosage form is a coated or uncoated tablet having a core weight of about 350 mg to about 450 mg. In another aspect, the dosage form is a coated or uncoated tablet having a core weight of about 400 mg. III. Treatment methods The present disclosure also relates to methods of treating a BTK-mediated condition in a subject, in particular a human subject suffering from or susceptible to suffering from the condition, comprising administering to the subject, once or twice a day, a solid dosage form comprising acalabrutinib maleate as described in any of the embodiments of the disclosure. In one aspect, the solid dosage form comprising acalabrutinib maleate is administered once a day. In another aspect, the solid dosage form comprising acalabrutinib maleate is administered twice daily. In one embodiment, the present disclosure relates to methods of treating a B-cell hematological malignancy in a subject, in particular a human subject suffering from or susceptible to suffering from the disease, comprising administering to the subject, one or two times a day, of a solid dosage form comprising acalabrutinib maleate as described in any of the embodiments of the disclosure. In one aspect, the solid dosage form comprising acalabrutinib maleate is administered once a day. In another aspect, the solid dosage form comprising acalabrutinib maleate is administered twice daily. In some embodiments, the B cell hematological malignancy is selected from the group consisting of non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), lymphocytic cell leukemia. small B-cell lymphoma (ALL), diffuse large B-cell lymphoma (DLLB), follicular lymphoma (FL), B-cell acute lymphoblastic leukemia (B-ALL), Burkitt lymphoma, Waldenstrom macroglobulinemia (MW), multiple myeloma, myelodysplastic syndromes and myelofibrosis. In some embodiments, the B cell hematologic malignancy is non-Hodgkin lymphoma. In one aspect, non-Hodgkin lymphoma is an aggressive non-Hodgkin lymphoma. In another aspect, non-Hodgkin lymphoma is an indolent non-Hodgkin lymphoma. In some embodiments, the B cell hematologic malignancy is Hodgkin lymphoma. In some embodiments, the B cell hematologic malignancy is selected from the group consisting of mantle cell lymphoma, chronic lymphocytic leukemia, and small cell lymphocytic leukemia. In some embodiments, the B cell hematologic malignancy is a mantle cell lymphoma. In one aspect, mantle cell lymphoma is a lymphoma of the mantle area. In another aspect, mantle cell lymphoma is a nodular mantle cell lymphoma. In another aspect, mantle cell lymphoma is a diffuse mantle cell lymphoma. In another aspect, mantle cell lymphoma is a blastoid mantle cell lymphoma. In some embodiments, the B cell hematologic malignancy is chronic lymphocytic leukemia. In some embodiments, the B cell hematologic malignancy is small cell lymphocytic leukemia. In some embodiments, the B cell hematologic malignancy is a diffuse large B cell lymphoma. In one aspect, diffuse large B cell lymphoma is selected from the group consisting of de novo diffuse large B cell lymphoma, relapsed / refractory diffuse large B cell lymphoma, and transformed diffuse large B cell lymphoma. In another aspect, diffuse large B cell lymphoma is a de novo diffuse large B cell lymphoma. In another aspect, diffuse large B cell lymphoma is a relapsed / refractory diffuse large B cell lymphoma. In another aspect, diffuse large B lymphocyte lymphoma is a transformed diffuse large B lymphocyte lymphoma. In another aspect, transformed diffuse large B cell lymphoma is Richter syndrome. In some embodiments, diffuse large B cell lymphoma is selected from the group consisting of the subtypes of diffuse large B cell lymphoma of the germinal center and diffuse large B cell lymphoma activated. In one aspect, diffuse large B cell lymphoma is a relapsed / refractory diffuse germinal center B cell lymphoma. In another aspect, diffuse large B cell lymphoma is a relapsed / refractory activated diffuse large B cell lymphoma. In some embodiments, the B cell hematologic malignancy is a follicular lymphoma. In some embodiments, the B cell hematologic malignancy is Waldenstrom's macroglobulinemia. In some embodiments, the B cell hematologic malignancy is B cell acute lymphoblastic leukemia. In one aspect, the B cell acute lymphoblastic leukemia is an early B cell acute lymphoblastic leukemia. In another aspect, B cell acute lymphoblastic leukemia is an acute lymphoblastic leukemia of pre-B cells. In another aspect, B cell acute lymphoblastic leukemia is an acute lymphoblastic leukemia of mature B cells. In some embodiments, the B cell hematologic malignancy is Burkitt lymphoma. In one aspect, Burkitt lymphoma is a sporadic Burkitt lymphoma. In another aspect, Burkitt lymphoma is an endemic Burkitt lymphoma. In another aspect, Burkitt lymphoma is a human immunodeficiency virus-associated Burkitt lymphoma. The diagnosis of the specific B cell neoplasia suffered by a subject can be made in accordance with accepted clinical practice. See, for example, the 2016 staging guidelines established by the World Health Organization (WHO) for lymphoid neoplasms, or the National Comprehensive Cancer Network (NCCN) staging guidelines for non-Hodgkin lymphoma. In some embodiments, the human subject has previously received at least one chemoimmunotherapy for B cell neoplasia. In one aspect, the prior chemoimmunotherapy comprises treatment with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). In another aspect, prior chemoimmunotherapy comprises treatment with fludarabine, cyclophosphamide and rituximab (FCR). In another aspect, prior chemoimmunotherapy comprises treatment with rituximab and bendamustine (BR). In another aspect, prior chemoimmunotherapy comprises treatment with chlorambucil and obinutuzumab. In some embodiments, the human subject has previously received treatment with a BTK inhibitor other than acalabrutinib (such as ibrutinib or zanubrutinib). In another embodiment, the present disclosure relates to the use of solid dosage forms comprising acalabrutinib maleate as described in any of the embodiments of the disclosure for the treatment of B cell malignancies. In another embodiment, the present disclosure relates to the use of solid dosage forms comprising acalabrutinib maleate, as described in any of the embodiments of the disclosure, in the manufacture of medicaments for the treatment of B cell malignancies. In some embodiments, the solid dosage form comprising acalabrutinib maleate is co-administered to the subject along with a gastric acid-lowering agent, such as a proton pump inhibitor, an H2 receptor antagonist, or an antacid. In one aspect, the co-administration is simultaneous. In another aspect, coadministration is sequential. In some embodiments, the present disclosure relates to methods of improving the pharmacokinetics of orally administered acalabrutinib in a broader range of heartburn conditions in a subject suffering from or susceptible to a B-cell hematological malignancy, which It comprises administration to the subject once (QD) or twice (BID) per day of the solid dosage form containing acalabrutinib maleate as described in any of the embodiments of the disclosure. In one aspect, the method improves and / or decreases the intra-individual and / or inter-individual variability of the bioavailability of acalabrutinib. In another aspect, the method reduces the intra-individual and / or inter-individual variability of the pharmacokinetics of acalabrutinib. In another aspect, the method improves and / or decreases the intra-individual and / or inter-individual variability of the Cmax of acalabrutinib. In another aspect, the method improves and / or decreases the intra-individual and / or inter-individual variability of the Tmax of acalabrutinib. In another embodiment, it improves and / or decreases the intra-individual and / or inter-individual variability of the AUC(o-co) of acalabrutinib. In some embodiments, the present disclosure relates to methods of treating a human subject infected with SARS-CoV-2 and / or having coronavirus disease 2019 (COVID-19) comprising administering to the subject the dosage forms solids containing acalabrutinib maleate, as described in any of the embodiments of the disclosure. In another embodiment, the present disclosure relates to the use of solid dosage forms comprising acalabrutinib maleate, as described in any of the embodiments, in a human subject infected by SARS-CoV-2 and / or having the disease due to coronavirus disease 2019 (COVID-19). In another embodiment, the present disclosure relates to the use of solid dosage forms comprising acalabrutinib maleate, as described in any of the embodiments of the disclosure, in the manufacture of medicaments for the treatment of a human subject infected by SARS. -CoV-2 and / or have coronavirus disease 2019 (COVID-19). The methods of the present disclosure also contemplate treatments comprising co-administration of a solid dosage form comprising acalabrutinib maleate as described in any of the embodiments of the disclosure with one or more additional therapeutic agents. Accordingly, the dosage forms of the present disclosure may be administered alone or in combination with one or more additional therapeutic agents. When administered in combination with one or more additional therapeutic agents, the additional therapeutic agent may be administered simultaneously with the acalabrutinib maleate dosage form of the present disclosure or sequentially with the acalabrutinib maleate dosage form of the present disclosure. In one aspect, the therapeutic agent is an anti-CD20 antibody. In another aspect, the anti-CD20 antibody is selected from the group consisting of rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab tiuxetane, tositumomab and ublituximab. In another aspect, the anti-CD20 antibody is selected from the group consisting of rituximab, obinutuzumab and ofatumumab. In another aspect, the anti-CD20 antibody is rituximab. In another aspect, the anti-CD20 antibody is obinutuzumab. In another aspect, the anti-CD20 antibody is ofatumumab. IV. Kits The present disclosure further relates, in part, to kits comprising one or more solid dosage forms comprising acalabrutinib maleate as described in any of the embodiments of the disclosure. The kits may optionally include one or more additional therapeutic agents and / or instructions for use of the kit. Suitable containers and additional items for use are known in the art and may be included in the kit. The Kits may be provided, marketed and / or promoted to healthcare providers, including physicians, nurses, pharmacists, formulary officers and the like. In some embodiments, the kit comprises a semipermeable container containing one or more solid dosage forms comprising acalabrutinib maleate. In one aspect, the semipermeable container is a blister package. In some embodiments, the kit comprises a substantially impermeable container containing one or more solid dosage forms comprising acalabrutinib maleate. In one aspect, the impermeable container is an HDPE bottle with desiccant. In some embodiments, the kit comprises a plurality of separate containers, each of which contains a daily dose of the solid dosage forms comprising acalabrutinib maleate (for example, a container containing one or two of the solid dosage forms). The kits described above are preferably used in the treatment of the B lymphocyte neoplasms described herein. For example, in one aspect, the B cell neoplasm is non-Hodgkin lymphoma. In another aspect, B cell neoplasia is mantle cell lymphoma. In another aspect, B cell neoplasia is chronic lymphocytic leukemia. In another aspect, B cell neoplasia is small cell lymphocytic leukemia. In another aspect, B cell neoplasia is diffuse large B cell lymphoma. In another embodiment, the kits described above are for use in the treatment of a human subject infected with SARS-CoV-2 and / or having coronavirus disease 2019 (COVID-19). V. Preparation methods The present disclosure also relates to methods for preparing the solid dosage forms comprising acalabrutinib maleate described in the present disclosure, including those methods described in the examples presented below. In general, these dosage forms can be prepared by techniques such as direct mixing, dry granulation (roller compaction), wet granulation (high shear granulation), milling or sieving, drying (if wet granulation is used) , compression and, optionally, coating. SAW. Product by process The present disclosure also relates to solid dosage forms comprising acalabrutinib maleate prepared according to any of the methods described in the present disclosure, including methods described in the examples below. Vile. Examples Example 1: Evaluation of acalabrutinib salts 1. Dissolution study The phosphate, oxalate, and maleate salts of acalabrutinib were evaluated using a two-step in vitro dissolution method known as the pH shift method. The initial medium was deionized water or a simulated gastric juice containing hydrochloric acid and sodium chloride and whose pH was adjusted to 1.8. After the salts were in the initial medium for 30 min, the medium was changed to FaSSIF-V2 medium by adding a double-strength concentrate to give a final pH of 6.5. FaSSIF-V2 medium contained sodium phosphate buffer with sodium chloride, sodium taurocholate, and lecithin. The dissolution test was carried out using the USP 2 dissolution apparatus (paddles) operating at 50 rpm at 37 ± 0.5 °C in 250 ml of medium for the first 30 minutes and then in 500 ml of medium after the change. Samples of the dissolution medium were extracted from the aqueous phase at predetermined time points and analyzed by HPLC. The figs. 2 and 3 show the dissolution profiles of the three salts in the simulated media of gastric juice / FaSSIF-V2 and deionized water / FaSSIF-V2, respectively. Although all three salts showed very similar performance in the low pH simulated gastric juice medium, the maleate salt showed substantially reduced dissolution in the neutral water medium relative to the oxalate and phosphate salts. 2. Study of physical properties The physical properties of acalabrutinib phosphate, oxalate, and maleate salts were investigated, including physical stability, crystallinity, and particle habit. Solid state analysis of the phosphate salt showed a complex behavior of the hydrates around environmental conditions, where the solid changed between hydrated forms with the conversion from a crystalline form to a higher hydrate crystalline form at relative humidities ( h. r.) greater than 20% h. r., as evident in the dynamic vapor sorption (DVS) graph in fig. 4. Thermogravimetric analysis (TGA) indicated that the top hydrate was physically unstable, dehydrating rapidly in less than 10 minutes under open tray isothermal conditions at 40 °C, as demonstrated in fig. 5. The TGA standard further indicated that batches of phosphate salts were often not homogeneous in terms of water content and therefore in terms of physical form. X-ray powder diffraction (XRPD) showed that both crystalline forms could be identified as shown in fig. 6. The oxalate salt also showed complex hydrate behavior. The TGA indicated that the hydrate was very labile, as demonstrated in fig. 7. Under isothermal TGA conditions at 35 °C, water loss had a half-life of 4 minutes and an overall weight loss of 3.2% w / w. Water loss was uniform with approximately one mole of water per mole of oxalate salt. The DVS showed the conversion from a crystalline form to a crystalline form with a higher degree of hydration at ambient humidities, as demonstrated in fig. 8. When analyzed by optical microscopy, the oxalate salt showed a very fine needle habit. The maleate salt was isolated as monohydrate. Although isothermal TGA at 50 °C indicated that the monohydrate dehydrates as shown in Fig. 9A, the dehydration rate was slower than that of phosphate or oxalate salts at the lowest temperatures of 40 °C and 35 °C, respectively. The fig. 9B is a plot of TGA performed under an alternative set of conditions. The DVS plot of the maleate salt in fig. 10A indicated that the change in % w / w water over the humidity range was less than that observed with phosphate or oxalate salts. The fig. 10B is a DVS plot for a higher quality sample of the maleate salt. The crystalline habit of the maleate salt was large and block-shaped. Although the phosphate and oxalate salts showed substantially better dissolution in the neutral aqueous medium than the maleate salt, the physical properties of the phosphate and oxalate salts presented greater challenges in the development of a pharmaceutically acceptable formulation comprising an acalabrutinib salt. . 3. Dissolution of the micronized maleate salt In view of the formulation challenges associated with the physical properties of phosphate and oxalate salts, the maleate salt was retested in the pH shift dissolution method described above after undergoing particle size reduction. Typical mean values ​​of the particle size distribution D(V, 0.9) for the batches of micronized maleate salt and the batches of unground maleate salt tested were typically about 18pm and about 446pm, respectively. . Using the same method conditions as described above, a micronized sample of the maleate salt was tested and showed a dissolution profile that was significantly improved (and to a greater extent than one skilled in the art would have expected) relative to the unground sample of the maleate salt. The figs. 11 and 12 show the dissolution profiles of micronized and unground maleate salts in the simulated media of gastric juice / FaSSIF-V2 and deionized water / FaSSIF-V2, respectively. Example 2: Evaluation of the solubility of acalabrutinib maleate The solubility of acalabrutinib maleate was measured in unbuffered media and was found to be approximately 3 mg / ml at pH 4 with the pHmax calculated at 4.11. It was further determined that in unbuffered media with an initial pH greater than pH 4 and up to approximately pH 11, acalabrutinib maleate buffers its surface pH to a value ranging between 3.8 and 5 and that the solubility of acalabrutinib maleate in unbuffered media buffered from pH 4 to pH 11 remains around 3 mg / ml. In contrast, the solubility of acalabrutinib free base in unbuffered media decreases to less than approximately 0.1 mg / mL as the pH approaches pH 6. Additionally, the solubility of acalabrutinib maleate was measured in buffer solutions representative of the media used for dissolution of acalabrutinib maleate tablets. It was found that the final pH was also influenced by the presence of acalabrutinib maleate and, depending on the buffer used, acalabrutinib maleate was capable of becoming supersaturated compared to the free base at an equivalent final pH or presenting solubility values ​​close to those of the free base at an equivalent final pH. For example, acalabrutinib maleate in acetate buffer at pH 4.5 is supersaturated with a solubility significantly greater than that of the free base at pH 4.5. In phosphate buffer, phosphate concentration and eventual pH adjustment controlled the final pH and final solubility of acalabrutinib maleate, but the values ​​observed under all conditions were close to those of the acalabrutinib free base at an equivalent final pH. . The fig. 13 depicts solubility versus final pH values ​​for acalabrutinib maleate and acalabrutinib free base in a variety of buffered solutions. Example 3: Physicochemical properties of acalabrutinib maleate monohydrate Some physicochemical properties of acalabrutinib maleate monohydrate were determined, which are indicated in Table 2. TABLE 2 PROPERTY VALUE Structure Acalabrutinib maleate monohydrate Molecular weight (g / mol) 465.51 (free base), 599.61 (salt) Physical form Crystalline, salt-base ratio = 1.29 pKa (s) Maleic acid (1.83 (A), 6.07 (A) ) + Free base (3.54 (B), 5.77 (B) and 12.1 (A)) LogP / LogD (with pH) 2.0 Melting point Start at 150 °C (thermal degradation after loss of water) Intrinsic solubility 3 mg / ml (salt at pH 4) 48 ug / ml (free base at pH 8) Solubility at pH 4 (mg / ml) 3 Intrinsic permeability (cm / s) 5.4 10.4 Efflux potential Vmax in vitro =79.6 10-6 pg.s-1, Km = 5. 97 μΜ Unbound fraction (fu) 2.6 % Density (g / ml) (Mm / molar volume) 1.359 g / ml (salt) 1.36 g / ml (free base) Diffusivity in the water (x1 E-9 m2 / s) 0.646 (calculated for free base at 37 °C) Blood:plasma ratio 0.787 Example 4: Compressing acalabrutinib maleate Tablets comprising acalabrutinib maleate monohydrate and various excipients were prepared by direct compression or by roller compaction and are described below. The direct compression tablets were uncoated and the roller compacted tablets were film coated. All prepared tablets contained a unit dose of approximately 100 mg equivalent weight of acalabrutinib maleate monohydrate. A. Direct compression tablets The tablets with the compositions set forth in Tables 3 and 4 were prepared by direct compression. Before compression of the tablets, all components except the lubricant were mixed, sieved and mixed again. The sieved lubricant was added to the mixture, which was then lubricated by additional mixing. The tablets were compressed using a suitable tablet press and tooling suitable for the compression weight of the target tablet. In cases where tablets required additional lubrication (i.e., when the die was observed to puncture or stick), additional lubricant was applied externally to the tablet mold. TABLE 3 0441 COMPOSITION OF DIRECT COMPRESSION TABLETS Component T1 (g / lot) EB18254510 T2 (g / lot) EB18396006 T3 (g / lot) EB18396008 T4 (g / lot) EB18432106 T5 (g / lot) EB18431408 Acalabrutinib maleate 10a 14,835 b 14,835 b 16.125 b 16.125 b Lactose monohydrate 25.96 N / A N / A N / A N / A Microcrystalline cellulose N / A 23.4025 17.94 25.4375 19.5 Mannitol N / A 8.05 20.9875 8.75 22.8125 Anhydrous dibasic calcium phosphate N / A 7,475 N / A 8,125 N / A Sodium starch glycolate 1.92 N / A N / A N / A N / A Low substituted hydroxypropyl cellulose N / A 2.875 2.875 3.125 3.125 Magnesium stearate 0.57 0.8625 0.8625 N / A N / A Glyceryl dibehenate N / A N / A N / A 0.9375 0.93 75 aMicronized acalabrutinib maleatebAcalabrutinib maleate particle size, D(V,o.9) = 70 pm TABLE 4 COMPOSITION OF DIRECT COMPRESSION TABLETS Component T6 (g / lot) EB18432407 T7 (g / lot) EB19021246 T8 (g / lot) EB18431421 T9 (g / lot) EB19033106 T10 (g / lot) EB19033107 T11 (g / lot) EB19033101 T12 (g / lot) EB19033108 T13 (g / lot) EB19033109 T14 (g / lot) EB19033110 T15 (g / lot) EB19021245 Acalabrutinib maleate 16.125 a 12.9a 16.125a 21.5a 15.48b 7.74c 21. 5b 15.48d 21.5d 12.9 a Microcrystalline cellulose 24.5 19.6 18.563 11 17.82 8.91 11 17.82 11 14.9 Mannitol 8.75 7 22.8125 13.5 21.9 10.95 13.5 21.9 13.5 18.3 DPCA 8.125 6.5 N / A N / A N / A N / A N / A N / A N / A N / A Low substituted hydroxypropyl cellulose 3.125 2.5 3.125 2.5 3 1.5 2.5 3 2.5 2.5 Sodium stearyl fumarate 1.875 1.5 1.875 1.5 1.8 0.9 1.5 1.8 1.5 1.5 11Acalabrutinib maleate particle size, D(V,o.9) = 70 pmbAcalabrutinib maleate particle size, D(V, 0.9) = 150 pmcAcalabrutinib maleate particle size, D(V,o .9>=16 pmdAcalabrutinib maleate particle size, D(V,o.9) * 500 pm B. Roller Compaction Tablets Tablets with the compositions set forth in Table 5 were prepared by roller compaction. All components were mixed, except for the lubricant. The intragranular portion of lubricant was sieved and then added to the mixture, which was lubricated by further mixing. The lubricated mixture was compacted with rollers to form ribbons, which were subsequently ground to obtain granules. The extragranular portion of the lubricant was sieved and added to the granules, which were lubricated by further mixing. The tablet cores were compressed to a target weight and compression force of 400 mg and 14 kN using a 13 x 7.5 mm oval tablet jig. The resulting tablet cores were film coated with a 3% to 4% weight increase of the coating slurry. TABLE 5 COMPOSITION OF COMPACTION TABLETS WITH FILM-COATED ROLLERS Component T16 (kg / batch) TAAB T17 (kg / batch) TAAC T18 (kg / batch) TAAD T19 (kg / batch) EB19144101 T20 (g / batch) EB19079701 Acalabrutinib maleate 12.9a 12.9b 12.9C 1000d 241.9e Microcrystalline cellulose 10.9 10.9 10.9 845 202.5 Mannitol 13.2 13.2 13.2 1023.3 245.6 Low substituted hydroxypropylcellulose 2 2 2 155 37.5 Steari 1 fumarate sodium (intragranular) 0.2 0.2 0.2 15.5 3.8 Steari 1 sodium fumarate (extragranular) 0.8 0.8 0.8 58 18.8 Film coating (% weight gain) 3.4 3.7 3.7 4.0 N / A Acalabrutinib maleate particle size, D(V, 0.9) = 260 pm Acalabrutinib maleate particle size, D<v,o.9) = 198 pm Acalabrutinib maleate particle size, D(V,o.9> ® 270 pmdAcalabrutinib maleate particle size, 50:50 mixture of D<v, 0.9)» 70 pm and D(V, 0.9) ~ 150 pmcAcalabrutinib maleate particle size, D(V,o.9> ® 70 pm C. Roller compacted capsules In addition to the tablets described above, reference capsules comprising acalabrutinib free base and having the compositions set forth in Table 6 were prepared and used in several of the following examples. All components except the lubricant were mixed, sieved and mixed again. The sieved lubricant was added to the mixture, which was then lubricated by additional mixing. The lubricated mixture was fed into a roller compactor and the resulting ribbon was subsequently ground to produce granules suitable for encapsulation. The sieved extragranular lubricant was mixed with the acalabrutinib granules which, once lubricated, were filled with an encapsulator into size 1 hard gelatin capsules to a target fill weight of 240 mg (i.e., 100 mg free base). acalabrutinib). 004 1 TABLE 6 COMPOSITION OF CAPSULES COMPACTED WITH ROLLS Component C1 (kg / lot) W025985 C2 (kg / lot) W026394 C3 (kg / lot) WO27180 C4 (kg / lot) L0505009 Acalabrutinib 10,951 a 10,951 b 11,130c 11,765 d Microcrystalline cellulose silic ified 7,227 7,227 7.324 7.655 Partially pregelatinized starch 7.227 7.227 7.324 7.655 Sodium starch glycolate 0.657 0.657 0.666 0.696 Magnesium stearate (intragranular) 0.109 0.109 0.111 0.116 Magnesium stearate (extragranular) ) 0.109 0.109 0.111 0.114 Total capsule weight in blue / yellow gelatin capsules of size 1 240 mg 240 mg 240 mg 240 mg aAcalabrutinib free base particle size, D<v, o.9) « 365 pmbAcalabrutinib free base particle size, D<v, 0.9) ® 392 pmcAcalabrutinib free base particle size, D< v, 0.9) ~ 394 pmdAcalabrutinib free base particle size, D<v, 0.9)« 377 pm D. T21 film-coated tablet Another example of film-coated dosage form (T21) is described in Table 7. TABLE 7 ACALABRUTINIB MALEATE FILM-COATED TABLETS (T21) COMPONENTS % w / p QUANTITY (MG / TABLET) FUNCTION GRADE OF TABLET CORE ACALABRUTINIB MALEATE FILM-COATED TABLETS (T21) COMPONENTS % w / w QUANTITY (MG / TABLET) FUNCTION GRADE Crystalline form A of acalabrutinib maleate monohydrate 32.25 129.0* Active ingredient Mannitol 33.00 132.0 Filler Pearlitol 200SD Microcrystalline cellulose 27.25 10 9.0 Avicel PH102 Charge Low substituted hydroxypropyl cellulose 5.00 20.0 Disintegrant LH-31 Sodium stearyl fumarate 0.50 2.0 Intragranular lubricant PRUVSSF Sodium stearyl fumarate 2.00 8.0 Extragranular lubricant Tablet core weight 400.0 TABLET COATING Aquarius Preferred BPP313095 3.5 14.0 Coating with Ashland film Nominal weight of coated tablet 414.0 * 100 mg free base equivalent weight. Example 5: Evaluation of the in vitro dissolution profile Dissolution / n vitro studies were performed to evaluate the dissolution profiles of acalabrutinib maleate formulations under low and high pH conditions. The pH conditions were selected to simulate gastric pH conditions in which the tablet is administered alone (low pH conditions) or together with a proton pump inhibitor or an acid-reducing agent (high pH conditions). The dissolution studies are detailed below. 1. Dissolution test in 0.1 N HCl at low pH The fig. 14 shows the dissolution profiles obtained in a low pH test under immersion conditions for acalabrutinib maleate tablets T16, T17 and T18, and acalabrutinib free base capsule C1. The dissolution test was performed in 900 ml of dissolution medium containing 0.1 N hydrochloric acid and using the USP 2 dissolution apparatus (paddles) operating at 50 rpm at 37 ± 0.5 °C. Samples of the dissolution medium were extracted from the aqueous phase at predetermined time points and analyzed by HPLC or UV / visible spectroscopy. The results show that under low pH conditions, acalabrutinib maleate tablets and acalabrutinib free base capsule have similar dissolution profiles. 2. Dissolution test at neutral pH, low ionic strength, 5 mM phosphate at pH 6.8 The fig. 15 shows the dissolution profiles obtained in a neutral pH and low ionic strength test under immersion conditions for acalabrutinib maleate tablets T16, T17 and T18. The dissolution test was performed in 900 ml of dissolution medium containing 5 mM sodium phosphate adjusted to pH 6.8 and using the USP 2 dissolution apparatus (paddles) operating at 75 rpm at 37 ± 0.5 °C. Samples of the dissolution medium were extracted from the aqueous phase at predetermined time points and analyzed by UV / visible spectroscopy. The results show that these acalabrutinib maleate tablets substantially retained the dissolution profile shown at the low pH conditions when tested at the high pH conditions. 3. Dissolution test at neutral pH, high ionic strength, 50 mM phosphate at pH 6.8 The fig. 16 shows dissolution profiles obtained from a neutral pH and high ionic strength test for acalabrutinib T13 maleate tablet and acalabrutinib C2 free base capsule. The dissolution test was performed in 900 ml of dissolution medium containing 50 mM sodium phosphate adjusted to pH 6.8 and using the USP 2 dissolution apparatus (paddles) operating at 75 rpm at 37 ± 0.5 °C. Samples of the dissolution medium were extracted from the aqueous phase at predetermined time points and analyzed by HPLC. The results show a better dissolution profile under high pH conditions for acalabrutinib maleate tablet relative to acalabrutinib freebase capsule. 4. Water dissolution test The fig. 17 shows the dissolution profiles obtained in a neutral medium without buffering capacity (i.e., conditions similar to those of a stomach treated with a proton pump inhibitor) for the acalabrutinib T1 maleate tablet and the acalabrutinib T1 freebase capsule. acalabrutinib C1. The dissolution test was performed in 300 ml of dissolution medium containing deionized water and using the USP 2 dissolution apparatus (paddles) operating at 50 rpm and 37 ± 0.5 °C. Samples of the dissolution medium were extracted from the aqueous phase at predetermined time points and analyzed by HPLC. The fig. 18 shows the dissolution profiles obtained in a neutral medium without buffer capacity for the acalabrutinib maleate tablet T13 and the acalabrutinib C1 free base capsule. The dissolution test of T13 tablet was carried out in 900 ml volume of dissolution medium containing deionized water and using the USP 2 dissolution apparatus (paddles) operating at 75 rpm and 37 ± 0.5 °C and was compared with the reference tablet C1 for which the test was carried out at 300 ml and 50 rpm. Samples of the dissolution medium were extracted from the aqueous phase at predetermined time points and analyzed by HPLC. The results presented in figs. 17 and 18 show a better dissolution profile under high pH conditions for acalabrutinib maleate tablets relative to acalabrutinib freebase capsule. 5. Test in biorelevant medium The dissolution of acalabrutinib maleate T19 tablet was evaluated under gastric conditions associated with an acidic gastric compartment and also under gastric conditions associated with dosing in combination with a proton pump inhibitor or an acid-reducing agent. The initial medium used was a simulated gastric juice containing hydrochloric acid and sodium chloride and a pH adjusted to 1.8 or a low-buffering capacity medium designed to replicate a stomach treated with proton pump inhibitors (see Segregur D., et al. al., Impact of Acid-Reducing Agents on Gastrointestinal Physiology and Design of Biorelevant Dissolution Tests to Reflect These Changes, J. Pharm. Sci., 108(11): 2461-3477 (2019)). The PPI buffer was maleate-based and contained sodium chloride adjusted to pH 6. After the T19 tablet was present in the starting medium for 30 minutes, the medium was converted to FaSSIF-V2 medium by the addition of a concentrate of double concentration to give a final pH of 6.5. FaSSIF-V2 medium contained sodium phosphate buffer with sodium chloride, sodium taurocholate, and lecithin. The dissolution test was carried out using the USP 2 dissolution apparatus (paddles) operating at 75 rpm at 37 ± 0.5 °C at 250 ml for the first 30 minutes and then 500 ml after the changeover. Samples of the dissolution medium were extracted from the aqueous phase at predetermined time points and analyzed by HPLC. Upon pH change to FaSSIF-V2 for both starting media, acalabrutinib (at a free base equivalent dose of 100 mg) did not precipitate and was supersaturated for at least another 90 minutes, as evident in Fig. 19. In a separate dissolution test, acalabrutinib T19 maleate tablet and acalabrutinib C3 freebase capsule were evaluated under the same pH change conditions described above, using simulated gastric juice at pH 1.8 as initial medium. The fig. 20 presents results indicating that the maleate tablet has an in vitro dissolution performance under biorelevant conditions corresponding to a fasted stomach that is comparable to the free base capsule. Overall, the results of in vitro dissolution tests indicate that the dissolution profiles of acalabrutinib maleate tablets tested under low pH and high pH conditions are substantially comparable, further suggesting that such tablets when administered alone or when coadministered with a proton pump inhibitor or acid-reducing agent are bioequivalent. Example 6: Evaluation in the TIM-1 model A study was performed using the TNO TIM-1 (TIM-1) system, an important tool in the testing cascade to understand the mechanical behavior of the product in vitro and demonstrate the clinical relevance of the selected in vitro method. The TIM-1 system has been previously described in detail in the literature. See, for example, Barker, R., et al., Application and validation otan advancedgastrointestinal in vitro model for the evaluation of drug product performance in pharmaceutical development, J. Pharm. Sci., Volume 103, Issue 11, 15, Pages 3704-3712 (September 2014). The TIM-1 system is a multicompartmental, dynamic system that uses relevant in vivo media, volumes, pH values, and hydrodynamics to mimic conditions found in the upper gastrointestinal tract of an adult human. The system also imitates the absorption sump through hollow fiber ultrafiltration. Volumes, media composition, emptying rates, temperature and pH are controlled dynamically by computer, allowing various physiologies of the subject to be defined, such as fasting, feeding or other more complex pathologies. More specifically, the present study was carried out on the TIM-1 system to evaluate the relative performance of acalabrutinib T19 maleate tablet and acalabrutinib C2 freebase capsule, evaluated in gastric conditions associated with an acidic gastric compartment and also in gastric conditions associated with dosing in combination with a proton pump inhibitor or an acid-reducing agent. The selected conditions represented a human with a gastric pH of 2 and 6. The gastric emptying rate was set to rapid mode, to represent the most challenging scenario for the formulations from a pH change perspective. This means that the ti / 2 of the stomach compartment was 15 minutes, which is typical of the in vivo setting for a fasted adult. The TIM-1 system was dosed with the test article and the selected protocol was run for 300 minutes. The system then operated automatically and samples were collected from the absorption compartments and analyzed every 60 minutes by HPLC. The fig. 21 demonstrates that the performance of acalabrutinib maleate tablet was equivalent to that of acalabrutinib free base capsule under the low pH condition (pH 2). It also demonstrates that the performance of acalabrutinib maleate tablet was not affected by the high pH condition (pH 6) and did not precipitate upon the pH change that occurred with gastric emptying into the duodenum. Example 7: Impact of particle size and drug loading on dissolution rate A study was carried out to evaluate the impact of drug particle size and drug loading on the in vitro dissolution of acalabrutinib maleate tablets. The tablets tested contained acalabrutinib maleate (100 mg free base equivalent) with a particle size D(V,0.9) (measured by laser diffraction) ranging from 16 micrometers to 500 micrometers and a drug loading of 26 wt % or 43% by weight. The dissolution test was carried out in 900 ml of 5 mM sodium phosphate buffer medium using the USP2 dissolution apparatus (paddles) at 75 rpm and 37 ± 0.5 °C. Acalabrutinib maleate tablets T9, T10, T11, T12, T13, T14 and T15 were evaluated in the study. The particle size of the active ingredient and the drug loading for each tablet are summarized in Table 8. TABLE 8 Tablet T9 EB19033106 T10 EB19033107 T11 EB19033101 T12 EB19033108 T13 EB19033109 T14 EB19033110 T15 EB19021245 Particle size D(V, 0.9) (pm) 70 150 16 150 5 00 500 70 Drug loading (wt%) 43 26 26 43 26 43 26 The fig. 22 further shows the particle size distributions of acalabrutinib maleate tablets T10, T11, T13 and T15. The tablets in which the impact of drug loading was evaluated were acalabrutinib maleate tablets T10, T11, T13 and T15 (drug loading 26% by weight) and acalabrutinib maleate tablets T9, T2 and T14 (drug loading of drug of 43% by weight), respectively. The figs. 23 and 24 show the results of dissolution tests of acalabrutinib maleate tablets T10, T11,T13 and T15 (drug loading 26% by weight) and acalabrutinib maleate tablets T9, T12 and T14 (drug loading 43% by weight), respectively. The dissolution rate of the tablet generally decreased as the acalabrutinib maleate particle size increased, although this observation was not true for the tablet with the finer acalabrutinib particle size (T11). A possible explanation for the difference in the result for the T11 tablet is that the dissolution rate, which was rapid at the initial time points, was reduced due to the lack of wettability of the drug. The in vitro dissolution rates of acalabrutinib maleate tablets with particle size distributions in the range of D<v,o.9) from 70 μm to 500 μm under the conditions tested were relatively uniform when the drug loading increased. from 26% by weight to 43% by weight. Example 8: Modeling and simulation of acalabrutinib exposure with GastroPlus A software modeling and simulation study was performed to predict acalabrutinib exposure in a human subject following administration of the acalabrutinib maleate tablets of Example 7 (i.e., T10, T11, T13, and T15). The tablet dissolution rate data obtained in Example 7 were used to derive a batch-specific drug particle size distribution (P-PSD) for each tablet according to the methodology described by Pepin, et al. (Pepin, :421-434 (2019)) and a measured solubility of 2,144 mg / ml. The derived P-PSD was then used as input to a PBPK model described by Pepin et al. (Pepin, Biopharm., 142: 435-448 (2019)) to predict human exposure to acalabrutinib for each of the tablets. The simulation predicted that tablets T10, T11, T13 and T15, under acidic stomach conditions, with 100 mg free base equivalent, had mean AUC and Cmax values ​​comparable to the mean AUC and Cmax values ​​of the reference capsule. Acalabrutinib free base C4. Table 9 summarizes the calculated mean exposure values ​​for acalabrutinib maleate tablets and the ratios of those calculated values ​​to the corresponding values ​​for the acalabrutinib freebase reference capsule. The exposure rate of the T11 tablet was close to the lower limit of bioequivalence, possibly due to a slower dissolution rate related to wettability issues. TABLE 9 Condition Batch Parameter Mean DE Relationship with Rei Acid L0505009 ABC(O-t) pred. (ngh / ml) 700 215 1 Free base Acid EB19- 021245 ABC(O-t) pred. (ngh / ml) 679 201 0.97 D90 = 70 um Acid EB19- 033101 ABC(O-t) pred. (ngh / ml) 630 171 0.9 D90 = 16 um Acid EB19- 033107 ABC(O-t) pred. (ngh / ml) 675 198 0.96 D90 = 150 um Acid EB19- 033109 ABC(O-t) pred. (ngh / ml) 662 189 0.95 D90 = 500 um Acid L0505009 Cmax pred. (ng / ml) 649 299 1 Free base Acid EB19- 021245 Cmax pred. (ng / ml) 614 276 0.95 D90 = 70 um Acid EB19- 033101 Cmax pred. (ng / ml) 534 229 0.82 D90 = 16 um Acid EB19- 033107 Cmax pred. (ng / ml) 607 270 0.93 D90 = 150 um Acid EB19- 033109 Cmax pred. (ng / ml) 586 256 0.9 D90 = 500 um A similar simulation predicted that tablets T10, T11, T13 and T15, under neutral to acidic stomach conditions, with 100 mg free base equivalent, had mean AUC and Cmax values ​​that remained substantially in the pH range relative to with the mean AUC and Cmax values ​​of the acalabrutinib C4 reference capsule in the same pH range. The simulation supported the conclusion that the effect of acid-reducing agents on acalabrutinib exposure can be substantially reduced relative to the acalabrutinib freebase C4 reference capsule, with acalabrutinib maleate tablets maintaining bioequivalence in the range of acidic to neutral pH. Table 10 summarizes the calculated mean exposure values ​​for acalabrutinib maleate tablets and the ratios of those calculated values ​​to the corresponding values ​​for the acalabrutinib freebase reference capsule. TABLE 10 D90 (um) Condition Parameter Mean SD Relationship with acidity 70 EB19-021245 Acid ABC(O-t) pred. (ngh / ml) 679 20 1 70 EB19-021245 - Neutral ABC(O-t) pred. (ngh / ml) 655 18 4 0.96 16 EB19-033101 - Acid ABC(O-t) pred. (ngh / ml) 630 17 1 16 EB19-033101 - Neutral ABC(O-t) pred. (ngh / ml) 594 15 1 0.94 150 EB19-033107 Acid ABC(O-t) pred. (ngh / ml) 675 19 8 150 EB19-033107 - Neutral ABC(O-t) pred. (ngh / ml) 637 17 2 0.94 500 EB19-033109 - Acid ABC(O-t) pred. (ngh / ml) 662 18 9 500 EB19-033109 - Neutral ABC(O-t) pred. (ngh / ml) 611 15 6 0.92 Free base L0505009 - Acid ABC(O-t) pred. (ngh / ml) 700 21 5 Free base L0505009 - Neutral ABC(O-t) pred. (ngh / ml) 259 58 0.37 70 EB19-021245 - Acid Cmax pred. (ng / ml) 614 27 6 70 EB19-021245 - Neutral Cmax pred. (ng / ml) 571 24 4 0.93 16 EB19-033101 - Acid Cmax pred. (ng / ml) 534 22 9 16 EB19-033101 - Neutral Cmax pred. (ng / ml) 473 194 0.89 150 EB19-033107-Acid Cmax pred. (ng / ml) 607 270 150 EB19-033107- Neutral Cmax pred. (ng / ml) 539 220 0.89 500 EB19-033109 - Acid Cmax pred. (ng / ml) 586 256 500 EB19-033109- Neutral Cmax pred. (ng / ml) 495 193 0.85 Free base L0505009 - Acid Cmax pred. (ng / ml) 649 299 Free base L0505009 - Neutral Cmax pred. (ng / ml) 138 38 0.21 Example 9: In vivo study in dogs An in vivo study was conducted to evaluate coadministration of acalabrutinib maleate and omeprazole relative to coadministration of acalabrutinib and omeprazole free base in a canine model. In the study, previously treated beagle dogs were administered capsules containing 100 mg of acalabrutinib free base, with and without 10 mg of pretreatment omeprazole, and AUC(o-24) values ​​of acalabrutinib were measured. In addition, the same dogs were administered, after an appropriate drug rest period, size 13 capsules containing a binary mixture of acalabrutinib maleate (100 mg equivalent weight) and 200 mg of microcrystalline cellulose, with and without pretreatment of omeprazole, and the AUC(o-24> values ​​of acalabrutinib were measured. The results of the study are depicted in Fig. 25. Acalabrutinib maleate capsules (100 mg free base equivalent weight) when administered with the omeprazole pretreatment, maintained exposure comparable to that of acalabrutinib freebase capsules when administered without omeprazole pretreatment. Example 10: Evaluation of excipients and combinations of excipients A study was conducted to evaluate the suitability of certain excipients and combinations of excipients in the formulation of a dosage form of acalabrutinib maleate. A. Disintegrants Binary mixtures of disintegrants and acalabrutinib maleate (1:5 ratio) were prepared and evaluated in in vitro dissolution tests. The binary mixtures and an acalabrutinib maleate control were dissolved in 250 ml of deionized water using the USP2 dissolution apparatus (paddles) at 37 ± 0.5 °C and 75 rpm. After the 120 minute time point, the paddle speed was increased to 250 rpm and after 135 minutes the pH was adjusted to pH 1.8-2 to increase solubility to determine if any undissolved material remained. The binary mixtures tested were sodium starch glycolate / acalabrutinib maleate (1:5 ratio), croscarmellose sodium / acalabrutinib maleate (1:5 ratio), and low-substituted hydroxypropylcellulose / acalabrutinib maleate (1:5 ratio). The results are shown in fig. 26. Only the acalabrutinib maleate control and the low-substituted hydroxypropylcellulose / acalabrutinib maleate mixture (1:5 ratio) did not show a significant increase in dissolution upon increasing paddle speed or adding acid, suggesting that a complete dissolution had been achieved. In the case of croscarmellose sodium / acalabrutinib maleate mixture (1:5 ratio) and croscarmellose sodium / acalabrutinib maleate mixture (1:5 ratio), a significant increase in dissolution was observed after acid adjustment , which demonstrated that complete release could be a problem at higher pH levels and suggested that an excipient / active ingredient interaction was occurring, possibly caused by the conversion of acalabrutinib maleate to a less soluble form, such as base free. B. Lubricants Binary mixtures of lubricants and acalabrutinib maleate (1:15) were prepared and evaluated in in vitro dissolution tests under the same conditions described above for the disintegrant mixtures. The binary mixtures tested were glyceryl dibehenate / acalabrutinib maleate (1:15), magnesium stearate / acalabrutinib maleate (1:15), and sodium stearyl fumarate / acalabrutinib maleate (1:15). The results are shown in fig. 27. The acalabrutinib maleate control, glyceryl dibehenate / acalabrutinib maleate mixture (1:15) and sodium stearyl fumarate / acalabrutinib maleate mixture (1:15) did not show a significant increase in dissolution after increasing paddle speed or adding acid, suggesting that complete dissolution has been achieved. In the case of the mixture of magnesium stearate and acalabrutinib maleate (1:15), a significant increase in dissolution was observed with increasing paddle speed and acid adjustment showed that complete release could be a problem at higher pH levels and suggested that an excipient / active ingredient interaction was occurring, possibly caused by the conversion of acalabrutinib maleate to a less soluble form, such as the free base. Furthermore, when binary compacts of magnesium stearate and acalabrutinib maleate were evaluated, these binary compacts showed an increase in the degree of degradation of acalabrutinib compared to acalabrutinib maleate alone. C. Diluent Direct compression tablet cores containing dilume, disintegrant, lubricant and acalabrutinib maleate were prepared and evaluated in in vitro dissolution tests under the same conditions described above for the disintegrant mixtures. Each tablet core contained microcrystalline cellulose / mannitol or microcrystalline cellulose / anhydrous calcium phosphate / mannitol as diluent. The specific core of the tested tablet contained (1) microcrystalline cellulose, anhydrous dibasic calcium phosphate, mannitol, low-substituted hydroxypropylcellulose, magnesium stearate and acalabrutinib maleate (T2), (2) microcrystalline cellulose, mannitol, low-substituted hydroxypropylcellulose, 004 1 magnesium stearate and acalabrutinib maleate (T3), (3) microcrystalline cellulose, calcium phosphate dibasic anhydrous, mannitol, low-substituted hydroxypropyl cellulose, sodium stearyl fumarate and acalabrutinib maleate (T6), (4) microcrystalline cellulose, mannitol, low-substituted hydroxypropylcellulose, sodium stearyl fumarate and acalabrutinib maleate (T8), (5) microcrystalline cellulose, anhydrous dibasic calcium phosphate, mannitol, low-substituted hydroxypropylcellulose, glyceryl dibehenate and acalabrutinib maleate (T4), or (6) microcrystalline cellulose, mannitol, low-substituted hydroxypropyl cellulose, glyceryl dibehenate and acalabrutinib maleate (T5). The results are shown in fig. 28 (tablet cores T2 and T3), fig. 29 (tablet cores T6 and T8) and fig. 30 (T4 and T5 tablet cores). For all mixtures tested, the presence of anhydrous dibasic calcium phosphate resulted in a greater increase in dissolution in the acid setting, suggesting an interaction of anhydrous dibasic calcium phosphate with acalabrutinib maleate. In contrast, no significant increase was observed in mixtures that did not contain anhydrous dibasic calcium phosphate. Furthermore, when binary compacts of anhydrous dibasic calcium phosphate and acalabrutinib maleate were evaluated, these binary compacts showed an increase in the degree of degradation of acalabrutinib compared to acalabrutinib maleate alone. Example 11: Evaluation of the stability of acalabrutinib maleate tablets A. Stability of the T19 tablet A stability study was conducted to evaluate acalabrutinib maleate (T19) tablets under open storage conditions and when presented in the following three containers: • Bulk packaging: laminated aluminum foil pouch, 4 ply, pre-cut -185 χ 280 mm (60 tablets per pouch) • 110 ml HPDE bottle induction sealed with a 1 g silica gel desiccant cartridge ( 60 tablets per bottle) • 110 ml HPDE bottle induction sealed with a 2 g silica gel desiccant cartridge (60 tablets per bottle) The conservation conditions investigated in the stability study are detailed in table 11. TABLE 11 FINAL SAMPLING CONDITION 25 °C / 60 % h. r. 156 weeks 30°C / 75% h. r. 156 weeks Light exposure 10 days FINAL SAMPLING CONDITION 40 °C / 75 % h. r. 26 weeks 30°C / 75% h. r. (open) 4 weeks 40°C / 75% h. r. (open) 4 weeks 50 °C 13 weeks At 26 weeks, the following data were available: • Description: There are no changes in the physical appearance of any of the samples. • Content determination: No trends were observed in the content determination data in any of the samples analyzed. • Organic impurities: or for samples that were stored in appropriate packaging (HDPE bottle with desiccant or bulk aluminum bag), the impurity level met the specification limit of NMT 0.7% for qualified impurities and NMT 0.2%. for unqualified impurities. o Conservation for four weeks exposed to 40 °C / 75% h. r. resulted in a concentration of 4-{2-[(2S)-1-(2-butynoyl)-2-pyrrolidin¡l]5-carbam¡m¡m¡l-1H-¡m¡dazol -4-¡l}-N-(2-p¡r¡d¡n¡l)benzamide which was above the specification limit of NMT 0.2%. All other impurities met the specification limits of NMT 0.7% for qualified impurities and NMT 0.2% for non-qualified impurities. • Enantiomeric purity: all samples met the criteria (>99.6%) of the method at initial sampling and at 26 weeks. • Dissolution (HCl 0.1 N): no trends were observed in any sample. All samples met specification (Q = 80% at 20 minutes). • Dissolution (pH 6.8): no trends were observed in any sample. All samples met Q = 80% at 20 minutes. • Water content: No trends were observed in any of the samples stored with desiccant or in the bulk container. All open-storage samples showed an increase in water content at 4 weeks, with the largest increase in the 40°C / 75% h sample. r. • Water activity: no trends were observed in the results. • Microbiological quality: all results met the specification (Ph. Eur / USP). Based on the data generated, it was considered that a bulk aluminum bag was suitable to ensure an adequate shelf life of the bulk and that an HDPE bottle with desiccant was suitable to ensure an adequate shelf life for the film-coated tablets. acalabrutinib analyzed. B. Additional stability assessments A stability study was performed to evaluate the chemical stability of acalabrutinib maleate T2 and T3 tablets and the following general observations were made: • The presence of anhydrous dibasic calcium phosphate contributed to the formation of 4-{8amino-3-[(2S)-2-pyrrolid¡n¡l]-imidazo[1,5-a]-pyrazin- 1 -yl}-N-(2-pyridin¡l)-benzamide and RRT 0.05. • The presence of magnesium stearate contributed to the formation of 4-{2-[(2S)-1 -(2butynoyl)-2-pyrrolidin¡l]-5-carbamim¡doyl-1 H-ímidazole -4-¡l}-N-(2-pyridinyl)-benzamide and RRT 0.82. • The presence of microcrystalline cellulose contributed to the formation of 4-{3-[(2S)-1acetoacetyl-2-pyrrolidin¡l]-8-amino¡midazo[1,5-a] pyrazin-1 -yl}-N-(2-pyridinyl)benzamide, RRT 0.82, and RRT 0.05. A limited stability study with limited data evaluation was performed on acalabrutinib maleate tablets T7 and T15 and the following observations were made: • The main degradation products were 4-{3-[(2S)-1 -acetoacetyl-2-pyrrolidinyl]8-aminoimidazo[1.5-a]pyrazin-1-yl}-N-(2-pyrrolidinyl )-benzamide, RRT 0.82, and 4-{2-[(2S)-1(2-butynoyl)-2-pyrrolidinyl]-5-carbamimidoyl-1 H-imídazol-4-íl}-N -(2-p¡r¡d¡n¡l)-benzamide. • Increased levels of 4-{3-[(2S)-1 -acetoacetyl-2-pyrrol¡din¡l]-8-amino¡midazo[1.5a]pyrazin-1 -yl}-N-(2-pyridinyl)benzamide and RRT 0.82 was higher than that observed for acalabrutinib maleate tablets T2 and T3. • Moisture appears to contribute significantly to the formation of RRT 0.82, but could probably be controlled by proper packaging. Example 12: Preparation of acalabrutinib maleate A. Conversion of acalabrutinib free base to acalabrutinib maleate IVIA / a / ZUZZ / U I 004 I ACALABRUTINIB MALEATE Acalabrutinib (18 kg, 1.0 molar equivalents) in tetrahydrofuran (162 1, 9.0 relative volumes) and water (9 I, 0.5 relative volumes) was heated to 50 °C and filtered. Tetrahydrofuran (9 I, 0.5 relative volumes) was used as a circuit wash. Maleic acid (5kg, 1.1 molar equivalents) in tetrahydrofuran (68 I, 3.75 relative volumes) was added at 50 °C, followed by a wash of the circuit with tetrahydrofuran (5 I, 0.25 relative volumes). The mixture was seeded with acalabrutinib maleate (18 mg, 0.001 relative weight), held for 1 hour at 50 °C and then cooled to 20 °C for 1 hour and held for 1 hour, before being circulated at through a wet mill to achieve the desired particle size distribution. The product was then filtered and washed with tetrahydrofuran (36 ñ, 2.0 relative volumes), and then dried by nitrogen flow (at >20% relative humidity) at 40 °C to obtain acalabrutinib maleate (20.4 kg, 88%) in the form of the monohydrate. B. Conversion of 4-(8-am¡no-3-[(2s)-2-pyrrol¡din¡ll¡m¡dazo[1 ,5-alpyrazin-1 -yl)-n-(2pyridiniD- benzamide to acalabrutinib maleate ACALABRUTINIB MALEATE In an alternative method to prepare acalabrutinib maleate, the maleate salt was prepared without intermediate isolation of the acalabrutinib free base. To a mixture of 4-{8amino-3-[(2S)-2-pyrrolidin¡l]im¡dazo[1,5-a]pyraz¡ n-1 -yl}-N-(2- prídíníl)-benzamide (15.0 g, 1.0 molar equivalents) and triethylamine (13.2 ml, 2.6 molar equivalents) in tetrahydrofuran (80 ml, 5.3 relative volumes) 2-butynoic acid (3.3 g) was added , 1.1 molar equivalents) in tetrahydrofuran (15 ml, 1.0 relative volumes) (for 1 hour), and after 8 minutes, propylphosphonic anhydride (53% w / w in ethyl acetate) (23.7 g, 1.1 equivalents) was added simultaneously molars) in tetrahydrofuran (15 ml, 1.0 relative volumes) (for 1 hour). The mixture was stirred until the reaction was complete. The mixture was quenched with water (30 ml, 2.0 relative volumes) and the aqueous phase was separated and discarded. The remaining organic phase was sieved through a filter with a circuit wash with tetrahydrofuran (7 ml, 0.5 relative volumes). The mixture was then heated to 50 °C and treated with maleic acid (8 g, 1.9 molar equivalents) in tetrahydrofuran (59 ml, 3.9 relative volumes). The mixture was seeded with acalabrutinib maleate (15 mg, 0.001 relative weight), and then cooled to 20 °C for 5 hours, filtered and washed three times with ethanol (30 ml, 2.0 relative volumes), then with ether tere-butyl methyl (58 ml, 3.9 relative volumes), and then dry aspirated onto the filter for 30 minutes to produce acalabrutinib maleate (16 g, 74%) as the monohydrate. Analysis of the product from method B above indicated the presence of an impurity, (2Z)-4-[(2S)-2-{8-amino-1 -[4-(2-pyridi nilcarbamol) acid. phen¡l]im idazo[1.5-a]pyrazin-3-¡l}-1 pyrrolidin¡l]-4-oxo-2-buteno¡co, which was not observed in the product of method A. This impurity was present in an amount that would potentially require toxicity rating of 044 1 impurities for regulatory registration of an acalabrutinib maleate tablet formulated with the active ingredient prepared by method B. Example 13: Preparation of Acalabrutinib Maleate Tablets The fig. 31 provides a schematic overview of a process for preparing the acalabrutinib maleate T21 tablet of Example 4. Specifically, the acalabrutinib maleate, mannitol, microcrystalline cellulose and low-substituted hydroxypropylcellulose are added to a suitable diffusion mixer and they mix. The intragranular portion of sodium stearyl fumarate is added to the powders and mixed before roller compaction. The tapes are produced by compacting the lubricated mixture with rollers. The ribbons are then ground into granules by passing the ribbons through a suitable mill. The granules are mixed with the extragranular portion of sodium stearyl fumarate using a suitable diffusion mixer. The lubricated granules are compressed into tablet cores using a suitable tablet press. The orange coating suspension is prepared and applied to the tablet cores by a conventional coating process. Example 14: Relative bioavailability study A phase I, open-label, single-dose, sequential, randomized study is conducted with acalabrutinib maleate tablets in healthy human subjects to evaluate the relative bioavailability, the effect of the proton pump inhibitor (rabeprazole), the effect of feeding and the effect of particle size. The study is divided into two parts. Part 1 of the study aims to evaluate the relative bioavailability of acalabrutinib maleate tablets compared to acalabrutinib freebase capsules as a pilot study to inform the design of part 2 of the study. Part 1 of the study also aims to test the impact of a proton pump inhibitor (PPI) and the effect of food on exposure to acalabrutinib maleate tablets. After reviewing the safety and pharmacokinetic data from part 1, the study will continue with part 2. Part 2 of the study plans to analyze the effect of active substance size variants on exposure to acalabrutinib maleate tablets and the relative bioavailability of acalabrutinib maleate tablets versus solution. The results of the study will provide information on the pharmacokinetic and pharmacodynamic profiles of the acalabrutinib maleate tablets to be evaluated. TO . Study design Part 1 - Objectives of the study Primary objective: • To evaluate the relative bioavailability of acalabrutinib maleate tablet compared to acalabrutinib freebase capsule under fasted conditions. Secondary objectives: • To evaluate the pharmacokinetic profile of ACP-5862 acalabrutinib maleate tablet compared to acalabrutinib freebase capsule under fasted conditions. • To evaluate the effects of the proton pump inhibitor rabeprazole on the pharmacokinetic profiles of acalabrutinib and its metabolite (ACP-5862) obtained after administration of acalabrutinib maleate tablet. • To evaluate the effect of food on the pharmacokinetics of acalabrutinib and its metabolite (ACP-5862) obtained after administration of acalabrutinib maleate tablet. • To evaluate the safety and tolerability of single doses of acalabrutinib maleate tablet in healthy subjects. • Measure the pharmacodynamic parameter of BTK receptor occupancy for acalabrutinib maleate tablet and acalabrutinib free base capsule in isolated PBMCs. Exploratory objectives: • Assess differences in exposure by H. pylori breath test status (present or absent). • Collect pH information from SmartPill and use this information as input to the PBPK model to calculate individual dissolution in vivo. Part 2 - Objectives of the study Primary objective: • To evaluate the impact of drug particle size on the bioavailability of acalabrutinib maleate tablets. Secondary objectives: • To evaluate the impact of drug particle size on the pharmacokinetic profile of ACP-5862 in acalabrutinib maleate tablets. • Compare the pharmacokinetics of acalabrutinib maleate tablets versus acalabrutinib oral solution in healthy subjects. • To evaluate the safety and tolerability of single doses of acalabrutinib maleate tablets with different drug particle size distributions in healthy subjects. • To evaluate the safety, tolerability, taste and odor of single doses of acalabrutinib oral solution in healthy subjects. Part 1 - Study Design: Part 1 of the study is a randomized, open-label, single-center, crossover study with three treatment periods and four treatments to evaluate the relative bioavailability, PPI effect, and feeding effect of a novel acalabrutinib maleate tablet. in healthy subjects (men or women of non-fertile age). Part 1 of the study includes: • A selection period of maximum 28 days; • Three treatment periods during which subjects will be admitted from before dinner the night before administration (day -1) until at least 48 hours after administration and discharged on day 3; and • A follow-up visit 7 to 10 days later. Between each administration of acalabrutinib there will be a drug rest period of at least 7 days. Each subject will receive three of the four treatments below in three treatment periods under fasted or fed conditions: Subjects will be randomized to receive treatment A or B in treatment periods 1 and 2, followed by treatment C or D in period 3 of treatment. The 100 mg acalabrutinib maleate tablet (variant 1) has the composition of the T21 tablet (see example 4, table 7), where the active ingredient has a particle size D(V,o.9) not exceeding 218 pm. • Treatment A: 100 mg acalabrutinib free base capsule, fasted (>10 h)*. • Treatment B: 100 mg acalabrutinib maleate tablet (variant 1), on an empty stomach (>10 h)*. • Treatment C: 100 mg acalabrutinib maleate tablet (variant 1), with food*,**. • Treatment D: rabeprazole 20 mg χ 1 (fasting) 2 hours before administration of acalabrutinib maleate 100 mg tablets (variant 1)* and after previous administration of rabeprazole 20 mg BID (with food) on days -3, -2 and -1. * Each subject will be administered a SmartPill with 120 ml of still water, immediately followed by a single oral dose of acalabrutinib maleate tablet (treatment B, C or D) or acalabrutinib freebase capsule ( treatment A) administered with 120 ml of still water, followed by FC sampling for 24 hours. **Subjects will begin consuming a high-fat meal (per FDA) 30 minutes prior to administration of SmartPill / acalabrutinib maleate 100 mg tablet. Subjects must eat the food within 25 minutes; however, the SmartPill / IMP should be administered 30 minutes after the start of the meal. Part 2 - Study Design: Part 2 of this study will be a single-center, randomized, open-label, crossover study with 4 treatment periods and 4 treatments to determine the effect of particle size on the PK of a single dose of acalabrutinib maleate tablets in healthy subjects (men or women of non-fertile age). Part 2 of the study includes: • A selection period of maximum 28 days; • Four treatment periods during which subjects will be admitted from before dinner the night before administration (day -1) until at least 48 hours after administration and discharged on day 3; and • A follow-up visit 7 to 10 days later. Between each administration of acalabrutinib there will be a drug rest period of at least 3 days. Each subject will receive the following treatments: • Treatment A: acalabrutinib maleate 100 mg tablet (variant 1), fasting • Treatment B: acalabrutinib maleate 100 mg tablet (variant 2), fasting • Treatment C: acalabrutinib maleate 100 mg tablet (variant 3), fasting • Treatment D: 100 mg acalabrutinib solution, fasting The acalabrutinib maleate 100 mg tablet (variant 1) comprises active ingredient with an intermediate particle size, while the acalabrutinib maleate 100 mg tablet (variant 2) comprises active ingredient with a smaller particle size and the tablet of acalabrutinib maleate 100 mg (variant 3) comprises active ingredient with a larger particle size. Specifically, the 100 mg acalabrutinib maleate tablets have the composition of the T21 tablet (see example 4, table 7), where variant 1 comprises the active ingredient with a particle size D(V,o.9) not greater than 218 pm, variant 2 comprises the active ingredient with a particle size D(V, 0.9) not exceeding 160 pm and variant 3 comprises the active ingredient with a particle size D(V, 0.9) no greater than 319 pm. Expected duration of the study In part 1, each subject will participate in the study for approximately 7 to 8 weeks. In part 2, each subject will participate in the study for approximately 6 to 7 weeks. Population object of the study In part 1 of the study, a total of 28 healthy subjects, men and women, aged between 18 and 55 years (inclusive), will be included to ensure at least 24 subjects will be evaluated. In part 2 of the study, a total of 24 healthy subjects, men and women, aged between 18 and 55 years (inclusive), will be included to guarantee 20 subjects evaluated at the end of the last treatment period. Results assessment criteria Pharmacokinetic endpoints: Serial venous blood samples will be obtained for the determination of plasma concentrations of acaladrutinid and the methadolite (ACP-5862). Wherever possible, pharmacokinetic parameters will be evaluated for acaladrutiid and the metadolite ACP5862 at plasma concentrations. Parts 1 and 2: • Primary PK parameters: Cmax, AUCúit, AUC¡nf of acaladrutinid • Secondary PK parameters: Cmax, AUCúit, AUC¡nf of ACP-5862; Acaladrutinid and ACP-5862: AUC0-12, AUCúit, AUCmf, %AUCextrap, Cmax, t< / 2, tmax, Kel, Fry, CL / F (precursor only), Vz / F (precursor only), ACP ratio -5862 (metadolith) to acaladrutinid (precursor) (M / P) for Cmax, ABCúit, ABC¡nf. • Where appropriate, additional PK parameters may be determined. Safety and tolerability assessment criteria: Safety and tolerability variables will include: • Adverse events / serious adverse events. • Analytical evaluations (hematology, biochemistry, coagulation and urinalysis). • Physical exploration. • Electrocardiogram (12-lead ECG). • Vital signs (systolic and diastolic BP, pulse, respiratory rate, body temperature). • Evaluation of taste and smell (part 2 only). Exploratory endpoints (part 1): • Acalabrutinib and ACP-5862: A repeated measures analysis of covariance (ANCOVA) will be used to analyze the PK parameters (ABCúit, AUC¡nf and Cmax) and to evaluate differences in exposure according to gastric pH and gastric emptying rate , the appropriate statistical procedure will be used. • Temperature, pH and pressure profiles throughout the Gl tract; Stomach pH immediately (first midpoint) after administration of acalabrutinib products (part 1 only). • H. pylorien breath test result. Part 1 - Statistical methods To evaluate the relative bioavailability of acalabrutinib maleate tablet compared to acalabrutinib freebase capsule under fasted conditions, the primary PK parameters of acalabrutinib and its metabolite, ACP-5862, will be compared, comparing treatment B (acalabrutinib) to treatment A. (acalabrutinib free base capsule). The analyzes will be carried out using a linear mixed effects analysis of variance model using the natural logarithm of Cmax, AUC¡nf and AUCúit as response variables, the sequence, period and treatment as a fixed effect and the voluntary effect. nested within the sequence as a random effect. By transforming from the logarithmic scale, the geometric means will be estimated and presented along with the CIs (95%, bilateral) for the AUC¡nf, the AUCúit and the Cmax. In addition, the geometric mean relationships will be estimated and presented, along with CIs (90%, bilateral). To evaluate the effects of the proton pump inhibitor rabeprazole on the PK profiles of acalabrutinib and its metabolite (ACP-5862) obtained after administration of acalabrutinib maleate tablet, the primary PK parameters of acalabrutinib and its metabolite, ACP, will be compared. -5862, comparing treatment D (rabeprazole) with treatment B (acalabrutinib), using the same analysis of variance (ANOVA) model. To evaluate the effect of feeding on the PK of acalabrutinib and its metabolite (ACP5862) obtained after administration of acalabrutinib maleate tablet, the primary parameters of the PK of acalabrutinib and its metabolite, ACP-5862, will be compared, comparing the treatment C (fed) with B (fasted), using the same ANOVA model. Part 2 - Statistical methods To evaluate the impact of drug particle size on the bioavailability of acalabrutinib maleate tablets, the primary PK parameters of acalabrutinib and its metabolite, ACP-5862, will be compared between treatment B (smaller than target) vs. to A (target), C (greater than the target) versus A (target) and C (greater than the target) versus B (smaller than the target) and the analyzes will be performed using a linear analysis of variance model of mixed effects using the natural logarithm of Cmax, AUC¡nf and AUCúit as response variables, the sequence, the period, the treatment as a fixed effect and the volunteer nested within the sequence as a random effect. By transforming from the logarithmic scale, the geometric means will be estimated and presented along with the CI (95%, bilateral) for AUC¡nf, AUCúit and Cmax. Additionally, geometric mean ratios will be estimated and presented, along with CIs (90%, two-sided). To compare the PK of acalabrutinib maleate tablet versus acalabrutinib oral solution, the primary PK parameters of acalabrutinib and its metabolite, ACP-5862, will be compared, comparing treatment D (solution) with treatment A (target), using the same ANOVA model. Part 1 and Part 2 Statistical Methods Additionally, the 90% CI for the difference in median tmax will be calculated and presented, using the same comparisons from the ANOVAs. Median differences and 90% confidence intervals will be tabulated for each comparison and analyte. The results are expected to demonstrate that coadministration of PPIs or other acid-reducing agents together with acalabrutinib maleate tablets does not affect the exposure to acalabrutinib and ACP-5862. B. Study results Pharmacokinetic parameters Results from part 1 of the study demonstrated that acalabrutinib maleate tablet (variant 1) and acalabrutinib capsule had similar bioavailability. • The mean pharmacokinetic exposures (Cmax and AUC) of acalabrutinib and the metabolite ACP-5862 were similar following oral administration of acalabrutinib maleate tablet (variant 1) versus acalabrutinib capsule under fasted conditions. The relative bioavailability was approximately 91% and 98% for the Cmax and AUC of acalabrutinib, respectively, and was approximately 100% and 103% to 104% for the Cmax and AUC of ACP-5862, respectively. . • Coadministration of PPI (rabeprazole) with acalabrutinib maleate tablet (variant 1) had no apparent effect on the pharmacokinetic exposures of acalabrutinib and the ACP-5862 metabolite. Cmax was slightly lower (~24% difference in geometric means) and AUCs were slightly higher (~14 to 17% difference in geometric means) for acalabrutinib. The Cmax of ACP-5862 was approximately 30% lower, with comparable AUCs in the presence versus absence of PPI. • For acalabrutinib maleate tablet (variant 1), food reduced the Cmax of acalabrutinib and ACP-5862 by approximately 54% and 36%, respectively, and had no effect on overall AUCs. • Since there were no differences in BTK occupancy between treatments, and intersubject variability (% geometric CV) in Cmax of acalabrutinib and ACP-5862 was up to approximately 81%, it is unlikely that differences observed in Cmax have a clinically significant impact. Summaries of plasma pharmacokinetic parameters from part 1 of the study are presented in Tables 12-16 below. TABLE 12 Part 1: Summary of plasma pharmacokinetic parameters of acalabrutinib Parameter (unit) Statistics A (N = 30) B (N = 29) C (N = 14) D (N = 14) Cmax (ng / ml) Geometric mean % of geometric CV 541.6 41.06 504.9 49.88 255.6 46.52 371.9 81.44 ABCinf (h-ng / ml) Geometric mean % of geometric CV 569.9 25.55 559.5 34.63 528.7 18.20 694.1 39.74 AUCult (h-ng / ml) Geometric mean % of geometric CV 565.7 25.41 556.2 34.73 525.7 18.34 669.7 40.5 4 tmax (h) Median Min, Max 0.75 0.48, 2.02 0.73 0.25, 1.53 2.00 0.25, 4.00 1.01 0.23, 3.00 t1 / 2Az(h) Mean SD 1.954 2.031 1.515 0.6280 1.347 0.3991 2.863 2 .313 CL / F (l / h) Mean SD 180.9 46.45 188.7 64.41 192.0 34.22 154.4 61.75 Vz / F (I) Mean SD 469.3 332.5 386.8 135.9 373.9 134.8 583.6 456.9 A: 100 mg capsule of acalabrutini or, on an empty stomach B: acalabrutinib maleate 100 mg tablet (variant 1), on an empty stomach C: acalabrutinib maleate 100 mg tablet (variant 1), with food D: 20 mg rabeprazole QD (fasting) 2 hours before administration of acalabrutinib maleate 100 mg tablets (variant 1) and after prior administration of 20 mg rabeprazole BID (with food) on days -3 , -2 and -1. BID = twice a day; CV = coefficient of variation; Max = maximum; Min = minimum; N = number of subjects in the FC analysis set; QD = once a day; SD = standard deviation. TABLE 13 Part 1: Summary of plasma pharmacokinetic parameters of the metabolite ACPIVIA / a / ZUZZ / U I OΟ4Ί 5862 Parameter (unit) Statistics A (N = 30) B (N = 29) C (N = 14) D (N = 14) Cmax (ng / ml) Geometric mean % of geometric CV 533.7 37.21 538.5 42.19 358.4 33.19 365.3 56.45 ABCinf (h-ng / ml) Geometric mean % of geometric CV 1625 24.14 1672 24.84 1644 17.13 1783 28.71 AUCult (h-ng / ml) Geometric mean % of geometric CV 1534 24.58 1575 25.87 1532 17.36 1656 29.58 tmax (h) Mean na Min, Max 1.00 0.73, 3.00 0.80 0.50, 2.98 2.98 0.98, 4.02 1.75 0.52, 6.00 t1 / 2Az(h) Mean SD 7.824 1.558 8.152 1.287 7.945 1.439 7.848 1.5 79 M:P[ABC] Geometric mean % of geometric CV 2.756 21.06 2.890 25.32 3.007 17.89 2.484 22.32 M:P [Cmax] Geometric mean % of geometric CV 0.9526 27.67 1.031 32.12 1.356 30.17 0.9496 37.94 A: 100 mg capsule of acalabrutini or, on an empty stomach B: acalabrutinib maleate 100 mg tablet (variant 1), on an empty stomach C: acalabrutinib maleate 100 mg tablet (variant 1), with food D: 20 mg rabeprazole QD (fasting) 2 hours before administration of acalabrutinib maleate 100 mg tablets (variant 1) and after prior administration of 20 mg rabeprazole BID (with food) on days -3 , -2 and -1. BID = twice a day; CV = coefficient of variation; Max = maximum; Min = minimum; 5 N = number of subjects in the FC analysis set; QD = once a day; SD = standard deviation. TABLE 14 Part 1: Statistical comparisons of pharmacokinetic parameters to evaluate 0041 relative bioavailability 10 Pairwise comparison (B / A) 15 Analyte Parameter (unit) Treatment N n Geometric LSM 95% CI Reaction (%) 90% CI % CV Inter- % CV Intra 20 Acalabr utinib Cmax (ng / ml) A B 30 29 29 556.2 503.3 (471.7, 655.7) (426.9, 593.5) 90. 50 (79.4 2, 103.1 33.5 29.8 25 AUCinf (h-ng / ml) A B 30 29 29 571.4 559 .4 (510.1, 640.3) (499.2, 626.8) 97. 90 (91.6 2, 104.6 26.6 14.9 30 AUCult (h-ng / ml) A B 30 29 29 567.2 556.1 (506.1, 635.6) (496.2, 623.2) 98. 05 ( 91.7 7, 104.8 26.6 14.9 35 ACP- 5862 Cmax (ng / ml) A 30 537.4 (463.4, 623.2) B 29 29 536.5 (462.6, 622.2) 99. 84 (91.9 4, 108.4 ) 35.5 18.6 AUCinf (h-ng / ml) A B 30 29 29 1615 1673 (1472, 1773) (1525, 1837) 103 .6 (1 00. 1, 107.3) 23.5 7.8 ABCLT (H-ING / ML) A B 30 29 1525 1576 (1385, 1679) (1431, 1735) 103 .3 (99.8 6, 106.9) 24.4 7.6 A: 100 mg d e acalabrutini or , fasting IVIA / a / ZUZZ / U I OΟ4Ί B: acalabrutinib maleate 100 mg tablet (variant 1), on an empty stomach. For statistical analysis, only subjects with valid FC parameters in both treatments are included. Result based on a linear mixed-effects ANOVA of the log-transformed FC parameter with sequence, period, and treatment as a fixed effect, and subject nested within sequence as a random effect. The geometric mean ratio and corresponding 90% CI are retransformed and presented as percentages. The geometric LSM and the corresponding 95% CI are also re-transformed. ANOVA = analysis of variance; CI = confidence interval; LSM = least squares mean; N = number of subjects in the FC analysis set; n = number of subjects included in the statistical comparison analysis; PK = pharmacokinetics. TABLE 15 Part 1: Statistical comparisons of pharmacokinetic parameters for the evaluation of the effect of PPIs Analyte Parameter (unit) Treatment N n Geometric LSM 95% CI Pairwise comparison (D / B) Ratio (%) 90% CI Acala- brutinib Cmax (ng / ml) B D 29 14 14 486.9 371.9 (338.2, 700.9) (258.3, 535.5) 76.39 (54.88, 106.3) AUCinf (h-ng / ml) B D 29 14 14 591.1 694.1 (466.9, 748.4) (548.2, 878.7) 117.4 (105.4, 130.8) AUCult (h-ng / ml) ) B D 29 14 14 587.8 669.7 (462.6, 746.9) (527.0, 850.9) 113.9 (101.4, 128.0) ACP- 5862 Cmax (ng / ml) B D 29 14 14 523.6 365.3 (390.7, 701.9) (2 72.5, 489.6) 69.76 (51.31, 94.86) ABCINF (H-ING / ML) B D 29 14 1470 1783 (1491, 2101) (1502, 2117) 100.7 (93.26, 108.8) ABCLT (H-ING / ML) B D 29 14 14 166 1656 (1397, 1985 ) (1389, 1973) 99.40 (90.81, 108.8) B: acalabrutinib maleate 100 mg tablet (variant 1), on an empty stomach D: 20 mg rabeprazole QD (fasting) 2 hours before administration of acalabrutinib maleate 100 mg tablets (day 1) and after prior administration of 20 mg rabeprazole BID (with food) on days -3 , -2 and -1. For statistical analysis, only subjects with valid FC parameters in both treatments were included. Result based on a linear mixed-effects ANOVA of the log-transformed FC parameter with sequence and treatment as a fixed effect, and subject nested within sequence as a random effect. The geometric mean ratio and corresponding 90% CI are retransformed and presented as percentages. The geometric LSM and the corresponding 95% CI are also re-transformed. ANOVA = analysis of variance; BID = twice a day; CI = confidence interval; LSM = least squares mean; N = number of subjects in the FC analysis set; n = number of subjects included in the statistical comparison analysis; PK = pharmacokinetics; QD = once a day. TABLE 16 Part 1: Statistical comparisons of pharmacokinetic parameters to evaluate the effect of food Analyte Parameter (unit) Treatment N n Geometric LSM 95% CI Pairwise Comparison (C / B) Ratio (%) 90% CI Acalabrutinib Cmax (ng / ml) B C 29 14 14 555.4 255.6 (446.2, 691.4) (205.3 , 318.1) 46.01 (35.92, 58.95) AUCinf (h-ng / ml) B C 29 14 14 541.2 528.7 (483.0, 606.5) (471.9, 592.5) 97.69 (87.19, 109.5) AUCult (h-ng / ml) B C 2 9 14 14 538.2 525.7 (480.0, 603.4) (468.9, 589.4) 97.69 (87.18, 109.5) ACP- 5862 Cmax (ng / ml) B C 29 14 14 560.6 358.4 (469.4, 669.5) (300.1,4 28.1) 63.94 (54.15, 75.49) AUCinf (h-ng / ml) B C 29 14 14 1617 1644 (1470, 1778) (1495, 1809) 101.7 (96.90, 106.7) AUCult (h-ng / ml) B C 29 14 14 1531 1532 (1387, 1691) ( 1388, 1692) 100.1 (95.47, 104.9) B: acalabrutinib maleate 100 mg tablet (variant 1), on an empty stomach C: acalabrutinib maleate 100 mg tablet (variant 1), with food. For statistical analysis, only subjects with valid FC parameters in both treatments were included. Result based on a linear mixed-effects ANOVA of the log-transformed FC parameter with sequence and treatment as a fixed effect, and subject nested within sequence as a random effect. The geometric mean ratio and corresponding 90% CI are retransformed and presented as percentages. The geometric LSM and the corresponding 95% CI are also re-transformed. ANOVA = analysis of variance; CI = confidence interval; LSM = least squares mean; N = number of subjects in the FC analysis set; n = number of subjects included in the statistical comparison analysis; PK = pharmacokinetics. The results of the part 2 study showed that acalabrutinib maleate particle size had no significant effect on the pharmacokinetics of acalabrutinib and ACP-5862 over the particle size range tested. Upon administration, variants 1, 2, and 3 resulted in comparable pharmacokinetic exposures. • The mean pharmacokinetic exposures (Cmax and AUC) of acalabrutinib and the metabolite ACP-5862 were similar after oral administration of an acalabrutinib maleate tablet with different particle sizes (variants 1,2 and 3). The 90% CIs for the geometric mean ratios were close to or within the range of 80% to 125%. • Acalabrutinib solution had a higher Cmax and comparable AUC versus acalabrutinib maleate tablet (variant 1). The relative bioavailability was approximately 122% and 102% for the Cmax and AUC of acalabrutinib, respectively, and was approximately 124% and 106% to 107% for the Cmax and AUC of ACP-5862. , respectively. Summaries of plasma pharmacokinetic parameters from part 2 of the study are presented in Tables 17-21. TABLE 17 Part 2: Summary of plasma pharmacokinetic parameters of acalabrutinib Parameter (unit) Statistics A (N = 24) B (N = 24) C (N = 24)a D (N = 24) Cmax (ng / ml) Geometric mean % of geometric CV 596.5 44.29 543.3 56.12 602.2 60.51 727.2 44.90 AUCinf (h-ng / ml) Geometric mean % of geometric CV 667.2 32.91 616.1 33.01 632.7 30.00 677.0 36.84 Parameter (unit) Statistics A (N = 24) B (N = 24) C (N = 24)a D (N = 24) AUCult (h-ng / ml) Geometric mean % of geometric CV 662.9 33.27 612.8 33.21 628.7 30.14 673.5 36.99 tmax (h) Median Min, Max 0.50 0.25, 1.50 0.75 0.25, 3.00 0.50 0.25, 2.00 0.50 0.25, 1.00 t1 / 2Áz(h) Mean SD 1.768 0.7369 1.364 0.4 352 1.794 0.7305 1.685 0.7755 CL / F (l / h) Mean DE 157.4 49.95 170.4 54.44 164.1 42.61 156.9 57.76 Vz / F (I) Mean DE 400.8 245.8 334.8 193.1 414.6 191.8 378.8 222.5 Data from 23 subjects are included in the summary; In one subject, concentrations could not be assessed, so PK parameters could not be calculated. A: acalabrutinib maleate 100 mg tablet (variant 1), on an empty stomach B: 100 mg acalabrutinib maleate tablet (variant 2), on an empty stomach C: acalabrutinib maleate 100 mg tablet (variant 3), on an empty stomach D: 100 mg acalabrutinib solution, on an empty stomach. CV = coefficient of variation; Max = maximum; Min = minimum; N = number of subjects in the pharmacokinetic analysis set; PK = pharmacokinetics; SD = standard deviation. TABLE 18 Part 2: Summary of plasma pharmacokinetic parameters of the ACP5862 metabolite Parameter (unit) Statistics A (N = 24) B (N = 24) C (N = 24)a D (N = 24) Cmax (ng / ml) Geometric mean % of geometric CV 536.5 39.38 532.8 33.25 594.5 33.65 662.6 26.54 AUCinf (h-ng / ml) Geometric mean % of geometric CV 1746 24.46 1775 24.80 1792 25.78 1845 26.79 0041 Parameter (unit) Statistics A (N = 24) B (N = 24) C (N = 24)a D (N = 24) AUCult (h-ng / ml) Geometric mean % of geometric CV 1653 24.97 1674 25.69 1702 26.03 1762 27.08 tmax (h) Median Min, Max 0.77 0.48, 2.02 0.88 0.50, 3.00 0.75 0.48, 3.50 0.74 0.48, 1.52 t1 / 2Áz (h) Mean SD 7.668 1.035 7.856 1.755 7,406 1,005 7,130 1,145 M:P [ABC] Geometric mean Geometric CV % 2.529 25.04 2.785 24.62 2.738 25.00 2.635 23.30 M:P [Cmax] Geometric Mean Geometric CV % 0.8695 29.87 0.9480 39.18 0.9544 36.26 0.8809 25.13 8Data from 23 subjects are included in the summary; In one subject, concentrations could not be assessed, so PK parameters could not be calculated. A: acalabrutinib maleate 100 mg tablet (variant 1), on an empty stomach B: 100 mg acalabrutinib maleate tablet (variant 2), on an empty stomach C: acalabrutinib maleate 100 mg tablet (variant 3), on an empty stomach; D: 100 mg acalabrutinib solution, on an empty stomach. CV = coefficient of variation; Max = maximum; Min = minimum; N = number of subjects in the pharmacokinetic analysis set; PK = pharmacokinetics; SD = standard deviation. TABLE 19 Part 2: Statistical comparisons of acalabrutinib pharmacokinetic parameters to evaluate the effect of particle size Parameter (unit) Treatment N n Geometric LSM 95% CI Pairwise Comparisons Pair Ratio (%) 90% CI Cmax (ng / ml) A 24 596.5 (489.9, 726.4) B 24 24 543.3 (446.2, 661.6) B / A 91.08 (79.35, 104.5) 5 A C 24 24 23 599.0 600.1 (484.5, 740.5) (485.5, 741.9) C / A 100.2 (82.95, 121. 0) 10 B C 24 24 23 536.7 599.7 (425.8, 676.4) (475.9, 755.9) C / B 111.8 (90.67, 137.7) AUCinf (h-ng / ml) A B 24 24 24 667.2 616.1 (583.4, 763.0) (538.7, 704.6) B / A 92 .35 (85.64 , 99.58) 15 A C 24 24 23 674.5 631.9 (590.3, 770.8) (553.0, 722.1) C / A 93.68 (85.37, 102.8) 20 B C 24 24 23 622.1 630.7 (545.6, 709. 2) (553.2, 719.0) C / B 101.4 (94.20, 109.1) 25 ABCult (h-ng / ml) A B 24 24 24 662.9 612.8 (579.0, 758.9) (535.3, 701.7) B / A 92.46 (85.72, 99.72) 30 A C 24 24 23 670.1 62 7.9 (585.8, 766.6 ) (548.9, 718.3) C / A 93.71 (85.35, 102.9) B C 24 24 23 618.8 626.7 (542.3, 706.0) (549.3, 715.0) C / B 101.3 (94.08, 109.1) A: acaabrutinib maleate 100 mg tablet (variant 1), on an empty stomach B: 100 mg acalabrutinib maleate tablet (variant 2), on an empty stomach C: 100 mg acalabrutinib maleate tablet (variant 3), on an empty stomach. In one subject in treatment C, full concentrations could not be quantified, so PK parameters could not be calculated. Result based on a linear mixed-effects ANOVA of log-transformed FC parameter 5 with sequence, period, and treatment as a fixed effect, and subject nested within sequence as a random effect. The geometric mean ratio and corresponding 90% CI are retransformed and presented as percentages. The geometric LSM and the corresponding 95% CI are also re-transformed. ANOVA = analysis of variance; CI = confidence interval; LSM = least squares mean; N = number of subjects in the FC analysis set; n = number of subjects included in the statistical comparison analysis; PK = pharmacokinetics. TABLE 20 Part 2: Statistical Comparisons of ACP-5862 Pharmacokinetic Parameters 0041 to evaluate the effect of particle size 15 Pairwise Comparisons Parameter (unit) Treatment N n Geometric LSM 95% CI Pair Ratio (%) 90% CI 20 Cmax (ng / ml) A B 24 24 24 536.5 532.8 (463.1, 621.6) (459.9, 617.2) B / A 99.30 (88.73, 111.1) 25 A C 24 24 23 537.7 593.0 (461.5, 626.5) (509.0, 691.0) C / A 110.3 (97.02, 125.4) 30 B C 24 24 23 528.5 594.2 (457.9, 609.8) (514.9, 685.7) C / B 112.4 (103.1, 122.7) 35 ABCINF (H-ING / ML) A B 24 24 24 1746 1775 (1574, 1936) (1600, 1968) B / A 101.7 (98.39 105.0) to 24 1746 (1566, 1946) C 24 23 1788 (1604, 1993) C / A 102.4 (98.78, 106.2) B C 24 24 23 1774 1789 (1589, 1980) (1603, 1997) C / B 100.9 (97.11, 104.8) ABCLT (H-ING / ML ) A B 24 24 24 1653 1674 (1486, 1839) (1505, 1862) B / A 101.3 (97.60, 105.1) A C 24 24 23 1653 1699 (1481, 1845) (1522, 1896) C / A 102.8 (98.74, 107.0 ) B C 24 24 23 1673 1700 (1495, 1872) (1519, 1902) C / B 101.6 (97.52, 105.9) A: acaabrutinib maleate 100 mg tablet (variant 1), on an empty stomach B: acalabrutinib maleate 100 mg tablet (variant 2), on an empty stomach C: acalabrutinib maleate 100 mg tablet (variant 3), on an empty stomach fasting 044 1 In one subject in treatment C, full concentrations could not be quantified, so PK parameters could not be calculated. Result based on a linear mixed-effects ANOVA of the log-transformed FC parameter with sequence, period, and treatment as a fixed effect, and subject nested within sequence as a random effect. The geometric mean ratio and corresponding 90% CI are retransformed and presented as percentages. The geometric LSM and the corresponding 95% CI are also re-transformed. ANOVA = analysis of variance; CI = confidence interval; LSM = least squares mean; N = number of subjects in the FC analysis set; n = number of subjects included in the statistical comparison analysis; PK = pharmacokinetics. TABLE 21 Part 2: Statistical comparisons of pharmacokinetic parameters for the evaluation of relative bioavailability Analyte Parameter (unit) Treatment N n Geometric LSM 95% CI Pairwise comparison (D / A) Ratio (%) 90% CI Acala- brutinib Cmax (ng / ml) A D 24 24 24 596.5 727.2 (501.3, 710.0) ( 611.1, 865.5) 121.9 (106.7, 139.3) AUC inf (h-ng / ml) A D 24 24 24 667.2 677.0 (577.2, 771.2) (585.7, 782.6) 101.5 (95.30, 108.1) AUC ) A D 24 24 24 662.9 673.5 (572.9, 766.9) (582.1, 779.2) 101.6 (95.32, 108.3) ACP- 5862 Cmax (ng / ml) A D 24 24 24 536.5 662.6 (469.3, 613.4) (579. 6, 757.6) 123.5 (109.9, 138.8) ) AUCinf (h-ng / ml) A D 24 24 24 1746 1845 (1567, 1944) (1657, 2055) 105.7 (102.7, 108.8) AUCult (h-ng / ml) A D 24 24 24 1653 1762 (1482, 1844) (1580, 1966) 106.6 (103.2, 110.2) A: acalabrutinib maleate 100 mg tablet (variant 1), on an empty stomach D: 100 mg acalabrutinib solution, on an empty stomach. Result based on a linear mixed-effects ANOVA of the log-transformed FC parameter with sequence and treatment as a fixed effect, and subject nested within sequence as a random effect. The geometric mean ratio and corresponding 90% CI are retransformed and presented as percentages. The geometric LSM and the corresponding 95% CI are also re-transformed. ANOVA = analysis of variance; CI = confidence interval; LSM = least squares mean; N = number of subjects in the FC analysis set; n = number of subjects included in the statistical comparison analysis; PK = pharmacokinetics. Pharmacodynamics Part 1 of the study investigated BTK receptor occupancy by acalabrutinib when administered in capsule or tablet form. The results showed that there was similar BTK occupancy in all post-dose sampling (4, 12 and 24 hours) after administration of tablets and capsules. Furthermore, BTK occupancy by the tablet formulation was not affected by food or PPI administration. Exploratory It was found that the stomach pH did not influence the acalabrutinib maleate exposure of the acalabrutinib maleate 100 mg film-coated tablets and, therefore, the in vivo dissolution of the tablets was not sensitive to the stomach pH. Security Overall, no new safety concerns were found with acalabrutinib 100 mg film-coated tablets and the new formulation was well tolerated. Example 15: Bioequivalence evaluation An open-label, randomized, two-way crossover bioequivalence study is conducted in healthy subjects to evaluate the bioequivalence of acalabrutinib maleate tablet (test formulation) and acalabrutinib freebase capsule (reference formulation). The study aims to demonstrate, in accordance with regulatory requirements, that acalabrutinib maleate tablet and acalabrutinib freebase capsule are bioequivalent. Study title: Phase I open-label, randomized study with crossover groups of 2 treatments and 2 periods in healthy subjects to evaluate the bioequivalence of acalabrutinib in tablets and acalabrutinib in capsules. 004 1 Rationale of the study: Acalabrutinib is a Biopharmaceutical Classification System (BCS) class II drug (high permeability, low solubility), which has two basic dissociation constants in the physiological pH range. The solubility of acalabrutinib decreases with increasing pH. At a pH less than 4, the drug is highly soluble. However, in patients taking acid-reducing agents (i.e., with a pH greater than 4), the solubility of the drug in the stomach / intestine is insufficient to ensure complete solubilization and absorption. Previous observations from a phase I study (ACE-HV-112 study) showed that when acalabrutinib was administered in 100 mg capsules following dosing of 40 mg of omeprazole (a proton pump inhibitor) once daily ( QD), there is a 43% reduction in AUC and a 72% reduction in Cmax compared to administration of the drug under normal acidic pH conditions. At a dose of 100 mg free residue equivalent, acalabrutinib maleate (AMT) tablet shows pH-independent release in vitro, unlike acalabrutinib capsule (i.e. Calquence). The results of the relative bioavailability study (see Example 14) have shown that the systemic exposures of acalabrutinib and its active metabolite, ACP-5862 after administration of AMT are similar in the presence or absence of PPI, and comparable to those observed with the acalabrutinib 100 mg capsule. This bioequivalence study aims to confirm that AMT 100 mg eliminates the impact of PPI on the pharmacokinetics (PK) of acalabrutinib in humans. Planned number of subjects Approximately 64 subjects will be randomized (approximately 32 per treatment sequence) to ensure at least 52 evaluable subjects (26 per sequence) at the end of treatment period 2. Study objectives Primary objective: To demonstrate the bioequivalence of AMT and acalabrutinib capsule, administered under fasting conditions. Secondary objectives: • Compare the pharmacokinetic profile of ACP-5862, the active metabolite of acalabrutinib, following administration of AMT and acalabrutinib capsule. • Compare the safety and tolerability of single doses of AMT and acalabrutinib capsule. Exploratory objective: • Measure the pharmacodynamics (PD) of acalabrutinib. Study design This study will be a multicenter, phase I, open-label, randomized, 2-sequence, 2-treatment, 2-period, crossover study to evaluate bioequivalence with single doses of acalabrutinib administered orally in healthy subjects at approximately three centers. study in the United States. The study is designed to demonstrate the bioequivalence of AMT (treatment A) compared to marketed acalabrutinib capsule (treatment B) under fasted conditions. The study will include: • Visit 1: a screening period of up to 28 days before the first dose. • Visit 2: two treatment periods: o Subjects will be entered into the study site on day -2 of treatment period 1 to confirm fitness prior to the first dose. Eligibility criteria will be reconfirmed on day -1 of each treatment period. o On day 1 of treatment periods 1 and 2, subjects will be administered the randomly assigned treatment (A or B), followed by a drug rest period of at least five days between treatment periods 1 and 2 . o Subjects will be discharged from the study site on the morning of day 3 of treatment period 2 after scheduled study assessments have been completed. • Visit 3: a follow-up visit / early termination visit 7 to 10 days after the last PEI administration. In the follow-up visit / early termination visit, the facility visit or part of it may be replaced by a telemedicine visit, if necessary (when a telemedicine visit is performed, laboratory tests will not be performed, ECGs and tympanic temperature measurement). The term telemedicine visit refers to virtual or video visits. During a civil crisis, natural disaster, or public health crisis, such as the COVID-19 pandemic, in-person visits may be substituted with a telemedicine visit if local / regional guidelines allow. A telemedicine contact will allow documentation and collection of data related to adverse events (AEs) and concomitant medications, in accordance with study requirements. Subjects will be randomized to receive treatment sequence 1 (AB) or treatment sequence 2 (BA). The AMT has the composition of the T21 tablet (see example 4, table 7), where the active ingredient has a particle size D<v, o.9> not exceeding 218 pm. • Treatment A: AMT, 100 mg, on an empty stomach. • Treatment B: acalabrutinib capsule, 100 mg, on an empty stomach. Subjects will receive single fixed doses of acalabrutinib on two occasions, under fasted conditions. Expected duration of the study Each subject will participate in the study for approximately six weeks. Population object of the study Healthy adult men and women aged between 18 and 55 years (inclusive), with a BMI between 18.5 and 30 kg / m2 inclusive, non-smokers; women must be non-fertile. Test and reference formulations Test Formulation Reference Formulation Formulation: Acalabrutinib Maleate Tablet (T21 Tablet) Acalabrutinib Capsule (Commercial) Pharmaceutical Dose / Concentration: 100 mg 100 mg Dose: 100mg (100 mg free base equivalent) 100 mg Route of Administration: Oral Oral Dosing regimen: Single dose Single dose Results assessment criteria Safety and tolerability assessment criteria: • Adverse events. • Analytical evaluations (hematology, coagulation, biochemistry and urinalysis). • Physical exploration. • Electrocardiogram (ECG). • Vital signs (systolic blood pressure [BP], diastolic BP, pulse, respiratory rate, tympanic temperature). Pharmacokinetic endpoints: Primary FC parameters: • Acalabrutinib - AUC¡nf, AUCúit, Cmax Secondary FC parameters: • Acalabrutinib – tmax, ti / 2Áz, MRT, λζ, CL / F, Vz / F • ACP-5862 — ABCinf, AUCúit, Cmax, tmax, ti / 2 λζ, MRT, λζ, M:P[AUC], M :P[Cmax] Statistical methods All statistical analyzes and the preparation of tables, figures and lists will be carried out with SAS® version 9.4 or a more recent version. Analysis data sets: The safety analysis set will include all subjects who received at least one dose in treatment period 1 and for whom post-dose safety data are available. The PK analysis set will consist of all subjects in the safety analysis set who have at least a measurable post-dose concentration of acalabrutinib, without significant protocol deviations or adverse events considered to affect the data analysis. of FC. The random set will consist of all subjects randomized in the study. Presentation and analysis of safety and tolerability data: All safety data (scheduled and unscheduled) will be presented in the data listings. Continuous variables will be summarized using descriptive statistics (number of subjects [n], mean, standard deviation [SD], minimum, median, maximum) by treatment. Categorical variables will be summarized in frequency tables (frequency and proportion) by treatment. The analysis of security variables will be based on the security analysis set. Adverse events will be summarized by system organ class (SOC) and preferred term using the current version of the Medical Dictionary for Regulatory Activities (MedDRA) vocabulary. Tables and lists of data will be presented for vital signs, analytical tests and ECGs. Any new or worsening clinically relevant abnormal physical examination findings compared to the initial evaluation will be reported as an adverse event. Analytical data will be reported in the units provided by the clinical laboratory and in units of the International System. Presentation of pharmacokinetic data: Lists of blood sample collection times for FC will be provided, as well as deviations arising from sampling time. For each analyte, plasma concentrations and PK parameters will be summarized by treatment. Diagnostic PK parameters will be summarized and listed. Tabulations will be based on the FC analysis set. Data from subjects excluded from the PK analysis group will be included in the data lists, but not in the descriptive statistics or inferential statistics. For each analyte, individual plasma concentration versus real time will be plotted on linear and semi-logarithmic scales with all treatments overlaid on the same graph and on separate graphs for each subject. The combined individual plasma concentration versus actual times will be plotted on linear and semi-logarithmic scales with separate graphs for each treatment and analyte. The geometric mean plasma concentration versus nominal sampling time will be plotted on a linear scale (7+ geometric SD) and on a logarithmic scale (no geometric SD plotted), with all treatments superimposed on the same figure and on separate figures for each analyte. All graphs will be based on the PK analysis set, with the exception of individual graphs per subject which will be based on the safety analysis set. Statistical analysis of pharmacokinetic data: Bioequivalence between Treatment A: AMT (test) versus Treatment B: Acalabrutinib Capsule (Reference) will be evaluated based on the PK analysis set. Analyzes will be performed using a linear mixed effects analysis of variance model using the natural logarithm of Cmax, AUCúh and AUC¡nf of acalabrutinib as response variables, with sequence, period and treatment as fixed effects and the subject nested within the sequence as a random effect. By transforming from the logarithmic scale, the geometric means will be estimated and presented along with the confidence intervals (CI) (95%, two-sided) for Cmax, AUCúit and AUC¡nf. Additionally, geometric mean ratios will be estimated and presented, along with CIs (90%, two-sided). In addition, the % inter and intra CV will be estimated for the Cmax, AUC¡nf and AUCúh of acalabrutinib and ACP5862, respectively. Bioequivalence criteria: If the 90% CI for the transformed geometric mean of the log ratio of Cmax and AUCúit or AUC¡nf between the test and the reference is completely contained within 80.00% and 125.00%, it will be concluded that both treatments are bioequivalent. Statistical analysis to establish bioequivalence will be performed by combining PK data from all study centers. Presentation and analysis of pharmacodynamic data: The results of the PD screening endpoint (BTK receptor occupancy) will be listed and summarized as appropriate, based on the set of pharmacokinetic analyses. Determination of sample size: Based on a bioequivalence range of 80.00% to 125.00% for Cmax and AUC¡nf of acalabrutinib, an intra-subject CV of 29.8% for Cmax and 15.1% for AUC¡nf (study ACE-HV-115 ) and an average test / reference ratio of 0.95, 52 evaluated subjects are needed to achieve a power of 90%. Altogether, a total of 64 subjects will provide at least 95% power to determine bioequivalence with respect to each of Cmax and AUC¡nf, respectively. VIII. Achievements Embodiment 1: A solid dosage form comprising about 75 mg to about 125 mg (free base equivalent weight) of acalabrutinib maleate and at least one pharmaceutically acceptable excipient for oral administration to a human, wherein the dosage form satisfies the following conditions: (i) at least approximately 75% of the acalabrutinib maleate dissolves in approximately 30 minutes, as determined in an in vitro dissolution test performed with a USP Dissolution Apparatus 2 (paddle apparatus), 900 ml of solution volume, 0.1 N hydrochloric acid dissolution medium and a blade rotation of 50 rpm; and (i) at least about 75% of the acalabrutinib maleate dissolves in about 60 minutes, as determined in an in vitro dissolution test performed with a USP Dissolution Apparatus 2 (paddle apparatus), a volume of 900 ml solution, a 5 mM phosphate dissolution medium at pH 6.8 and a blade rotation of 75 rpm. Embodiment 2: The dosage form of Embodiment 1, wherein the dosage form satisfies the following conditions: (i) at least about 75% of the acalabrutinib maleate dissolves in about 20 minutes, as determined in an in-dissolution test. vitro performed with a USP 2 dissolution apparatus (paddle apparatus), 900 ml of solution volume, 0.1 N hydrochloric acid dissolution medium and a paddle rotation of 50 rpm; and (i) at least about 75% of the acalabrutinib maleate dissolves in about 45 minutes, as determined in an in vitro dissolution test performed with a USP Dissolution Apparatus 2 (paddle apparatus), a volume of 900 ml solution, a 5 mM phosphate dissolution medium at pH 6.8 and a blade rotation of 75 rpm. Embodiment 3: The dosage form of Embodiment 1, wherein the dosage form satisfies the following conditions: (i) at least about 80% of the acalabrutinib maleate dissolves in about 20 minutes, as determined in an in-dissolution test. vitro performed with a USP 2 dissolution apparatus (paddle apparatus), 900 ml of solution volume, 0.1 N hydrochloric acid dissolution medium and a paddle rotation of 50 rpm; and (i) at least about 80% of the acalabrutinib maleate dissolves in about 30 minutes, as determined in an in vitro dissolution test performed with a USP Dissolution Apparatus 2 (paddle apparatus), a volume of 900 ml solution, a 5 mM phosphate dissolution medium at pH 6.8 and a blade rotation of 75 rpm. Embodiment 4: The dosage form of Embodiment 1, wherein the dosage form satisfies the following conditions: (i) at least about 80% of the acalabrutinib maleate dissolves in about 15 minutes, as determined in an in-dissolution test. vitro performed with a USP 2 dissolution apparatus (paddle apparatus), 900 ml of solution volume, 0.1 N hydrochloric acid dissolution medium and a paddle rotation of 50 rpm; and (i) at least about 80% of the acalabrutinib maleate dissolves in about 20 minutes, as determined in an in vitro dissolution test performed with a USP Dissolution Apparatus 2 (paddle apparatus), a volume of 900 ml solution, a 5 mM phosphate dissolution medium at pH 6.8 and a blade rotation of 75 rpm. Embodiment 5: The dosage form of any of embodiments 1 to 4, wherein the acalabrutinib maleate is acalabrutinib maleate monohydrate. Embodiment 6: The pharmaceutical form of embodiment 5, wherein acalabrutinib maleate monohydrate is crystalline form A. Embodiment 7: The dosage form of any of embodiments 1 to 6, wherein the at least one pharmaceutically acceptable excipient is selected from at least one diluent, at least one disintegrant and at least one lubricant. Embodiment 8: The pharmaceutical form of any of embodiments 1 to 7, wherein the dissolution rate of acalabrutinib maleate in the 5 mM phosphate dissolution medium at pH 6.8 does not decrease by more than 20% with respect to its rate of initial dissolution after preserving the pharmaceutical form in a suitable container for six months at 40 °C and 75% relative humidity. Embodiment 9: The pharmaceutical form of any of embodiments 1 to 7, wherein the dissolution rate of acalabrutinib maleate in the 5 mM phosphate dissolution medium at pH 6.8 does not decrease by more than 10% with respect to its rate of initial dissolution after preserving the pharmaceutical form in a suitable container for six months at 40 °C and 75% relative humidity. Embodiment 10: The dosage form of any of embodiments 1 to 7, wherein the dissolution rate of acalabrutinib maleate in the 5 mM phosphate dissolution medium at pH 6.8 does not decrease by more than 5% with respect to its rate of initial dissolution after preserving the pharmaceutical form in a suitable container for six months at 40 °C and 75% relative humidity. Embodiment 11: The pharmaceutical form of any of embodiments 1 to 7, wherein the dissolution rate of acalabrutinib maleate in the 5 mM phosphate dissolution medium at pH 6.8 does not decrease by more than 2% with respect to its rate of initial dissolution after preserving the pharmaceutical form in a suitable container for six months at 40 °C and 75% relative humidity. Embodiment 12: The dosage form of any of embodiments 1 to 11, wherein no more than about 5% (w / w) of the acalabrutinib maleate present in the dosage form degrades upon storage of the dosage form in a suitable container for six months at 40 °C and 75% relative humidity. Embodiment 13: The dosage form of any of embodiments 1 to 11, wherein no more than about 2% (w / w) of the acalabrutinib maleate present in the dosage form degrades upon storage of the dosage form in a suitable container for six months at 40 °C and 75% relative humidity. Embodiment 14: The dosage form of any of embodiments 1 to 11, wherein no more than about 1% (w / w) of the acalabrutinib maleate present in the dosage form degrades upon storage of the dosage form in a suitable container for six months at 40 °C and 75% relative humidity. Embodiment 15: The dosage form of any of embodiments 1 to 11, wherein no more than about 0.5% (w / w) of the acalabrutinib maleate present in the dosage form degrades upon storage of the dosage form in a suitable container for six months at 40 °C and 75% relative humidity. Embodiment 16: The dosage form of any of embodiments 1 to 15, wherein the dosage form is bioequivalent to a 100 mg Calquence® capsule when administered orally to a fasted human subject who has not been administered a gastric acidity reducing agent, wherein the pharmaceutical form is bioequivalent when the confidence interval of the relative mean of the Cmax, the AUC(O-t) and the AUC(0-°°) of the pharmaceutical form with respect to the Calquence® 100 mg capsule is between 80% and 125%. Embodiment 17: The dosage form of any of embodiments 1 to 15, wherein the dosage form, when administered twice daily to a population of fasting human subjects, satisfies one or more of the following pharmacokinetic conditions for acalabrutinib: (i) the mean Cmax value in the human subject population is about 400 ng / ml to about 900 ng / ml; (i) the mean value of AUC(0-24) in the human subject population is about 350 ng*h / ml to about 1900 ng*h / ml; and / or (i¡) the mean AUC(0-°°) value in the human subject population is approximately 350 ng*h / ml to approximately 1900 ng«h / ml. IVIA / a / ZUZZ / U I OΟ4Ί Embodiment 18: The dosage form of embodiment 17, wherein the dosage form is co-administered to the human subject population with a gastric acid reducing agent. Embodiment 19: The dosage form of any of embodiments 1 to 18, wherein the dosage form, when administered twice daily to a human subject, provides a median steady-state Bruton's tyrosine kinase occupancy of at least approximately 90% in peripheral blood mononuclear cells. Embodiment 20: The dosage form of any of embodiments 1 to 18, wherein the dosage form, when administered twice daily to a human subject, provides a median steady-state Bruton's tyrosine kinase occupancy of at least approximately 95% in peripheral blood mononuclear cells. Embodiment 21: The dosage form of embodiment 19 or 20, wherein the dosage form is co-administered to the human subject population with a gastric acid reducing agent. Embodiment 22: The dosage form of any of presentations 1 to 21, wherein acalabrutinib maleate is present in an amount of about 15% to about 55% by weight (free base equivalent weight) of the dosage form. Embodiment 23: The dosage form of any of presentations 1 to 21, wherein acalabrutinib maleate is present in an amount of about 20% to about 50% by weight (free base equivalent weight) of the dosage form. Embodiment 24: The dosage form of any of presentations 1 to 21, wherein acalabrutinib maleate is present in an amount of about 25% to about 50% by weight (free base equivalent weight) of the dosage form. Embodiment 25: The dosage form of any of presentations 1 to 21, wherein acalabrutinib maleate is present in an amount of about 25% to about 40% by weight (free base equivalent weight) of the dosage form. Embodiment 26: The dosage form of any of embodiments 1 to 25, wherein the at least one pharmaceutically acceptable excipient comprises at least one diluent. Embodiment 27: The dosage form of embodiment 26, wherein the at least one diluent is present in an amount of about 10% to about 70% by weight of the dosage form. Embodiment 28: The dosage form of embodiment 26, wherein the at least one diluent is present in an amount of about 20% to about 70% by weight of the dosage form. Embodiment 29: The dosage form of embodiment 26, wherein the at least one diluent is present in an amount of about 30% to about 70% by weight of the dosage form. Embodiment 30: The dosage form of embodiment 26, wherein the at least one diluent is present in an amount of about 40% to about 70% by weight of the dosage form. Embodiment 31: The dosage form of any of embodiments 26 to 30, wherein the at least one diluent does not affect the stability of the primary amine moiety of acalabrutinib. Embodiment 32: The dosage form of any of embodiments 26 to 30, wherein the at least one diluent does not comprise lactose. Embodiment 33: The pharmaceutical form of any of embodiments 26 to 32, wherein the at least one diluent does not comprise a maleic acid sequestering agent. Embodiment 34: The dosage form of any of embodiments 26 to 33, wherein the at least one diluent does not comprise anhydrous dibasic calcium phosphate. Embodiment 35: The dosage form of any of embodiments 26 to 34, wherein the at least one diluent comprises a plastic diluent and a brittle diluent. Embodiment 36: The dosage form of embodiment 35, wherein the w / w ratio of plastic diluent to brittle diluent is from about 0:100 to about 60:40. Embodiment 37: The dosage form of embodiment 35 or 36, wherein: (i) the at least one diluent comprises a plastic diluent and a brittle diluent in a total amount of about 10% to about 70% by weight of the pharmaceutical form; (i) the plastic diluent is present in an amount of from about 0% to about 70% by weight of the dosage form; and (iii) the brittle diluent is present in an amount of from about 0% to about 50% by weight of the dosage form. Embodiment 38: The dosage form of any of embodiments 26 to 34, wherein the at least one diluent comprises mannitol. Embodiment 39: The pharmaceutical form of any of embodiments 26 to 34, wherein the at least one diluent comprises microcrystalline cellulose. Embodiment 40: The dosage form of any of embodiments 26 to 34, wherein the at least one diluent comprises mannitol and microcrystalline cellulose. Embodiment 41: The dosage form of embodiment 40, wherein the w / w ratio of mannitol to microcrystalline cellulose is from about 0:100 to about 60:40. Embodiment 42: The dosage form of embodiment 38, wherein mannitol is present in an amount of about 10% to about 70% by weight of the dosage form. Embodiment 43: The dosage form of embodiment 39, wherein the microcrystalline cellulose is present in an amount of about 5% to about 50% by weight of the dosage form. Embodiment 44: The dosage form of embodiment 40, wherein: (i) mannitol is present in an amount of about 0% to about 70% by weight of the dosage form; (i) the microcrystalline cellulose is present in an amount of about 0% to about 50% by weight of the dosage form; and (iii) the total amount of mannitol and microcrystalline cellulose is about 10% to about 70% by weight of the dosage form. Embodiment 45: The dosage form of any of embodiments 26 to 44, wherein the weight ratio of acalabrutinib maleate (free base equivalent weight) to at least one diluent is about 1:3 to about 2:1. Embodiment 46: The dosage form of any of embodiments 26 to 44, wherein the weight ratio of acalabrutinib maleate (free base equivalent weight) to at least one diluent is about 1:1 to about 1:2. Embodiment 47: The dosage form of any of embodiments 1 to 46, wherein the at least one pharmaceutically acceptable excipient comprises at least one disintegrant. Embodiment 48: The dosage form of embodiment 47, wherein the at least one disintegrant is present in an amount of about 0.5% to about 15% by weight of the tablet. Embodiment 49: The dosage form of embodiment 47, wherein the at least one disintegrant is present in an amount of about 1% to about 10% by weight of the tablet. Embodiment 50: The dosage form of embodiment 47, wherein the at least one disintegrant is present in an amount of about 2% to about 8% by weight of the tablet. Embodiment 51: The dosage form of embodiment 47, wherein the at least one disintegrant is present in an amount of about 3% to about 7% by weight of the tablet. Embodiment 52: The dosage form of any of embodiments 47 to 51, wherein the at least one disintegrant does not comprise an ionic disintegrant. 044 1 Embodiment 53: The pharmaceutical form of any of embodiments 47 to 51, wherein the at least one disintegrant does not comprise sodium starch glycolate. Embodiment 54: The pharmaceutical form of any of embodiments 47 to 53, wherein the at least one disintegrant does not comprise croscarmellose sodium. Embodiment 56: The dosage form of any of embodiments 47 to 54, wherein the at least one disintegrant comprises a nonionic disintegrant. Embodiment 57: The pharmaceutical form of any of embodiments 47 to 56, wherein the at least one disintegrant comprises hydroxypropylcellulose. Embodiment 58: The pharmaceutical form of any of embodiments 47 to 56, wherein the at least one disintegrant comprises low substituted hydroxypropylcellulose. Embodiment 59: The dosage form of any of embodiments 47 to 59, wherein the weight ratio of acalabrutinib maleate (free base equivalent weight) to at least one disintegrant is from about 2:1 to about 15:1. Embodiment 60: The dosage form of any of embodiments 47 to 59, wherein the weight ratio of acalabrutinib maleate (free base equivalent weight) to at least one disintegrant is from about 4:1 to about 10:1. Embodiment 61: The dosage form of any of embodiments 1 to 60, wherein the at least one pharmaceutically acceptable excipient comprises at least one lubricant. Embodiment 62: The dosage form of embodiment 61, wherein the at least one lubricant is present in an amount of about 0.25% to about 4% by weight of the dosage form. Embodiment 63: The dosage form of embodiment 61, wherein the at least one lubricant is present in an amount of about 1% to about 4% by weight of the dosage form. Embodiment 64: The dosage form of any of embodiment 61, wherein the at least one lubricant is present in an amount of about 1.5% to about 3.5% by weight of the dosage form. Embodiment 65: The dosage form of any of embodiment 61, wherein the at least one lubricant is present in an amount of about 2% to about 3% by weight of the dosage form. Embodiment 66: The dosage form of any of embodiments 61 to 65, wherein the at least one lubricant does not comprise magnesium stearate. Embodiment 67: The dosage form of any of embodiments 51 to 66, wherein the at least one lubricant does not comprise glyceryl dibehenate. Embodiment 68: The dosage form of any of embodiments 61 to 67, wherein the at least one lubricant comprises sodium stearyl fumarate. Embodiment 69: The dosage form of any of embodiments 61 to 68, wherein the weight ratio of acalabrutinib maleate (equivalent weight of free base) to at least one lubricant is from about 20:1 to about 12:1. Embodiment 70: The dosage form of any of embodiments 61 to 68, wherein the weight ratio of acalabrutinib maleate (equivalent weight of free base) to at least one lubricant is from about 18:1 to about 14:1. Embodiment 71: The dosage form of any of embodiments 1 to 70, wherein the at least one pharmaceutically acceptable excipient comprises at least one diluent, at least one disintegrant and at least one lubricant. Embodiment 72: The dosage form of embodiment 7, wherein the dosage form comprises: (i) acalabrutinib maleate in an amount of about 15% to about 55% by weight (free base equivalent weight) of the dosage form ; (i) at least one diluent in an amount of about 10% to about 70% by weight of the dosage form; (i¡) at least one disintegrant in an amount of about 0.5% to about 15% by weight of the pharmaceutical form; and (iv) at least one lubricant in an amount of about 0.25% to about 4% by weight of the dosage form; and where the sum of the individual quantities is equal to 100% of the total weight of the pharmaceutical form. Embodiment 73: The dosage form of embodiment 7, wherein the dosage form comprises: (i) acalabrutinib maleate in an amount of about 20% to about 50% by weight (free base equivalent weight) of the dosage form ; (i) at least one diluent in an amount of about 20% to about 70% by weight of the dosage form; (i¡) at least one disintegrant in an amount of about 1% to about 10% by weight of the pharmaceutical form; and (iv) at least one lubricant in an amount of about 1% to about 4% by weight of the dosage form; and where the sum of the individual quantities is equal to 100% of the total weight of the pharmaceutical form. Embodiment 74: The dosage form of embodiment 7, wherein the dosage form comprises: (i) acalabrutinib maleate in an amount of about 25% to about 50% by weight (free base equivalent weight) of the dosage form ; (i) at least one diluent in an amount of about 30% to about 70% by weight of the dosage form; (i¡) at least one disintegrant in an amount of about 2% to about 8% by weight of the pharmaceutical form; and (iv) at least one lubricant in an amount of about 1.5% to about 3.5% by weight of the dosage form; and where the sum of the individual quantities is equal to 100% of the total weight of the pharmaceutical form. Embodiment 75: The dosage form of embodiment 7, wherein the dosage form comprises: (i) acalabrutinib maleate in an amount of about 25% to about 40% by weight (free base equivalent weight) of the dosage form ; (i) at least one diluent in an amount of about 40% to about 70% by weight of the dosage form; (iii) at least one disintegrant in an amount of about 3% to about 7% by weight of the dosage form; and (iv) at least one lubricant in an amount of about 2% to about 3% by weight of the dosage form; and where the sum of the individual quantities is equal to 100% of the total weight of the pharmaceutical form. Embodiment 76: The dosage form of embodiment 7, wherein the dosage form comprises: (i) acalabrutinib maleate in an amount of about 30% to about 35% by weight (free base equivalent weight) of the dosage form ; (i) mannitol in an amount of about 30% to about 35% by weight of the dosage form; (iii) microcrystalline cellulose in an amount of about 25% to about 30% by weight of the dosage form; (iv) hydroxypropylcellulose in an amount of about 3% to about 7% by weight of the dosage form; and (v) sodium stearyl fumarate in an amount of about 1% to about 4% by weight of the dosage form; and where the sum of the individual quantities is equal to 100% of the total weight of the pharmaceutical form. Embodiment 77: The dosage form of any of embodiments 1 to 76, wherein acalabrutinib maleate has a D(v, 0.9) value of less than about 500 micrometers. Embodiment 78: The dosage form of any of embodiments 1 to 76, wherein acalabrutinib maleate has a D(v, 0.9) value of less than about 450 micrometers. Embodiment 79: The dosage form of any of embodiments 1 to 76, wherein acalabrutinib maleate has a D(v, 0.9) value of less than about 400 micrometers. Embodiment 80: The dosage form of any of embodiments 1 to 76, wherein acalabrutinib maleate has a D(v, 0.9) value of less than about 350 micrometers. Embodiment 81: The dosage form of any of embodiments 1 to 76, wherein acalabrutinib maleate has a D(v, 0.9) value of less than about 300 micrometers. Embodiment 82: The dosage form of any of embodiments 1 to 76, wherein acalabrutinib maleate has a D(v, 0.9) value of about 20 micrometers to about 500 micrometers. Embodiment 83: The dosage form of any of embodiments 1 to 76, wherein acalabrutinib maleate has a D(v, 0.9) value of about 50 micrometers to about 450 micrometers. Embodiment 84: The dosage form of any of embodiments 1 to 76, wherein acalabrutinib maleate has a D(v, 0.9) value of about 75 micrometers to about 400 micrometers. Embodiment 85: The dosage form of any of embodiments 1 to 76, wherein acalabrutinib maleate has a D(v, 0.9) value of about 75 micrometers to about 350 micrometers. Embodiment 86: The dosage form of any of embodiments 1 to 76, wherein acalabrutinib maleate has a D(v, 0.9) value of about 100 micrometers to about 300 micrometers. Embodiment 87: The dosage form of any of embodiments 1 to 86, wherein the dosage form is a capsule. Embodiment 88: The capsule of embodiment 87, wherein the capsule is prepared by a process comprising roller compaction. Embodiment 89: The dosage form of any of embodiments 1 to 86, wherein the dosage form is a tablet. Embodiment 90: The dosage form of any of embodiments 1 to 86, wherein the dosage form is a film-coated tablet. Embodiment 91: The tablet of embodiment 89 or 90, wherein the tablet is prepared by a process comprising direct compression. Embodiment 92: The tablet of embodiment 89 or 90, wherein the tablet is prepared by a process comprising roller compaction. Embodiment 93: The tablet of any of embodiments 89 to 92, wherein the tablet has a tensile strength of about 1.5 MPa to about 5.0 MPa. Embodiment 94: The tablet of any of embodiments 89 to 92, wherein the tablet has a tensile strength of about 2.0 MPa to about 4.0 MPa. Embodiment 95: The tablet of any of embodiments 89 to 94, wherein the tensile strength of the tablet does not decrease by more than 10% with respect to its initial tensile strength after storing the tablet in a blister package for six months at 40 °C and 75% relative humidity. Embodiment 96: The tablet of any of embodiments 89 to 94, wherein the tensile strength of the tablet does not decrease by more than 8% with respect to its initial tensile strength after storing the tablet in a blister package for six months at 40 °C and 75% relative humidity. Embodiment 97: The tablet of any of embodiments 89 to 94, wherein the tensile strength of the tablet does not decrease by more than 5% with respect to its initial tensile strength after storing the tablet in a blister package for six months at 40 °C and 75% relative humidity. Embodiment 98: A method of treating a BTK-mediated condition in a subject suffering from or susceptible to suffering from the condition, comprising administering to the subject, once or twice a day, the solid dosage form of any of the embodiments 1 at 97. *********** The present written description uses examples to disclose the invention and to enable anyone skilled in the art to practice the invention, including the manufacture and use of any of the disclosed salts, substances or compositions, and the performance of any of the methods or disclosed processes. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. These other examples are intended to be within the scope of the claims if they have elements that do not differ from the literal language of the claims, or if they include equivalent elements with insubstantial differences from the literal language of the claims. Although preferred embodiments of the invention are shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the described embodiments of the invention may be employed in the practice thereof. The section titles, as used in this section and throughout the disclosure, are not intended to be limiting. All references (patent and non-patent) cited above are incorporated by reference into this patent application. The discussion of these references is intended simply to summarize the statements made by their authors. No reference (or part of any reference) is admitted to represent the relevant prior art (or the prior art at all). Applicants reserve the right to challenge the accuracy and relevance of references cited. It is stated that in relation to this date, the best method known to the applicant to put the aforementioned invention into practice is the one that is clear from the present description of the invention.

Claims

1. A solid dosage form comprising approximately 75 mg to approximately 125 mg (freebase equivalent weight) of acalabrutinib maleate and at least one pharmaceutically acceptable excipient for oral administration to a human, wherein the dosage form meets the following conditions: at least approximately 75% of the acalabrutinib maleate dissolves in approximately 30 minutes, as determined in an in vitro dissolution test performed using a USP 2 dissolution apparatus (paddle apparatus), a dissolution volume of 900 ml, a dissolution medium of 0.1 N hydrochloric acid, and a paddle rotation of 50 rpm; and at least approximately 75% of the acalabrutinib maleate dissolves in approximately 60 minutes, as determined in an in vitro dissolution test performed using a USP 2 dissolution apparatus (paddle apparatus), a dissolution volume of 900 ml, a 5 mM phosphate dissolution medium at pH 6.8 and a paddle rotation of 75 rpm.

2. The pharmaceutical form of claim 1, wherein the pharmaceutical form satisfies the following conditions: at least approximately 80% of the acalabrutinib maleate dissolves in approximately 15 minutes, as determined in an in vitro dissolution test performed using a USP 2 dissolving apparatus (paddle apparatus), a dissolving volume of 900 ml, a 0.1 N hydrochloric acid dissolving medium, and a paddle rotation of 50 rpm; and at least approximately 80% of the acalabrutinib maleate dissolves in approximately 20 minutes, as determined in an in vitro dissolution test performed using a USP 2 dissolving apparatus (paddle apparatus), a dissolving volume of 900 ml, a 5 mM phosphate dissolving medium at pH 6.8, and a paddle rotation of 75 rpm.

3. The pharmaceutical form of claim 1 or 2, wherein the acalabrutinib maleate is the crystalline A form of acalabrutinib maleate monohydrate.

4. The pharmaceutical form of any of claims 1 to 3, wherein the at least one pharmaceutically acceptable excipient is selected from at least one diluent, at least one disintegrant, and at least one lubricant.

5. The pharmaceutical form of any of claims 1 to 4, wherein the dissolution rate of acalabrutinib maleate in 5 mM phosphate dissolution medium at pH 6.8 does not decrease by more than 20% with respect to its initial dissolution rate after storing the pharmaceutical form in a suitable container for six months at 40 °C and 75% relative humidity.

6. The pharmaceutical form of any of claims 1 to 5, wherein no more than approximately 5% (w / w) of the acalabrutinib maleate present in the pharmaceutical form degrades after storing the pharmaceutical form in a suitable container for six months at 40°C and 75% relative humidity.

7. The pharmaceutical form of any of claims 1 to 6, wherein the pharmaceutical form is bioequivalent to a 100 mg Calquence® capsule when administered orally to a fasting human subject who has not been administered a gastric acid-reducing agent, wherein the pharmaceutical form is bioequivalent when the confidence interval of the relative mean of the Cmax, the AUC<o-t) y la ABC(o-~> The difference between the pharmaceutical form and the 100 mg Calquence® capsule is between 80% and 125%.

8. The pharmaceutical form of any of claims 1 to 7, wherein acalabrutinib maleate is present in an amount of approximately 100 mg (freebase equivalent weight).

9. The pharmaceutical form of any of claims 1 to 8, wherein the at least one pharmaceutically acceptable excipient comprises at least one diluent.

10. The pharmaceutical form of claim 9, wherein the at least one diluent does not affect the stability of the primary amine residue of acalabrutinib.

11. The pharmaceutical form of claim 9 or 10, wherein the at least one diluent comprises a plastic diluent and a brittle diluent.

12. The pharmaceutical form of any of claims 9 to 11, wherein the weight ratio of acalabrutinib maleate (weight equivalent of free base) to at least one diluent is from approximately 1:3 to approximately 2:

1.

13. The pharmaceutical form of any of claims 1 to 12, wherein the at least one pharmaceutically acceptable excipient comprises at least one disintegrant.

14. The pharmaceutical form of claim 13, wherein the at least one disintegrant does not comprise an ionic disintegrant.

15. The pharmaceutical form of claim 13 or 14, wherein the weight ratio of acalabrutinib maleate (free base equivalent weight) to at least one disintegrant is from approximately 2:1 to approximately 15:

1.

16. The pharmaceutical form of claim 4, wherein the pharmaceutical form comprises: acalabrutinib maleate in an amount of approximately 15% to approximately 55% by weight (weight equivalent of freebase) of the pharmaceutical form; at least one diluent in an amount of approximately 10% to approximately 70% by weight of the pharmaceutical form; at least one disintegrant in an amount of approximately 0.5% to approximately 15% by weight of the pharmaceutical form; and at least one lubricant in an amount of approximately 0.25% to approximately 4% by weight of the pharmaceutical form; and wherein the sum of the individual amounts is equal to 100% of the total weight of the pharmaceutical form.

17. The pharmaceutical form of claim 4, wherein the pharmaceutical form comprises: acalabrutinib maleate in an amount of approximately 30% to approximately 35% by weight (weight equivalent of free base) of the pharmaceutical form; and mannitol in an amount of approximately 30% to approximately 35% by weight of the pharmaceutical form; microcrystalline cellulose in an amount of approximately 25% to approximately 30% by weight of the pharmaceutical form; hydroxypropylcellulose in an amount of approximately 3% to approximately 7% by weight of the pharmaceutical form; and sodium stearyl fumarate in an amount of approximately 1% to approximately 4% by weight of the pharmaceutical form; and wherein the sum of the individual amounts is equal to 100% of the total weight of the pharmaceutical form.

18. The pharmaceutical form of any of claims 1 to 17, wherein the acalabrutinib maleate has a D(V, o.9) value of approximately 20 micrometers to approximately 500 micrometers.

19. The pharmaceutical form of any of claims 1 to 18, wherein the pharmaceutical form is a tablet.

20. The tablet of claim 19, wherein the tablet has a tensile strength of approximately 1.5 MPa to approximately 5.0 MPa.

21. The tablet of claim 20, wherein the tensile strength of the tablet does not decrease by more than 10% from its initial tensile strength after storing the tablet in a blister pack for six months at 40°C and 75% relative humidity.

22. A method for treating a BTK-mediated condition in a subject suffering from or susceptible to suffering from the condition, comprising administering to the subject, once or twice daily, the solid pharmaceutical form of any of claims 1 to 21.