Solid state form of pirtobrutinib

Abstract

The present disclosure encompasses a solid state form of Pirtobrutinib for use as BRK inhibitor. Formula (I)

Description

SOLID STATE FORM OF PIRTOBRUTINIBFIELD OF THE DISCLOSURE

[0001] The present disclosure encompasses a solid state form of Pirtobrutinib.BACKGROUND OF THE DISCLOSURE

[0002] Pirtobrutinib, 5-amino-3-[4-[[(5-fluoro-2-methoxybenzoyl)amino]methyl]phenyl]-l- [(25)-l,l,l-trifluoropropan-2-y1]pyrazole-4-carboxamide, has the following chemical structure:

[0003] Pirtobrutinib is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor. Pirtobrutinib is under clinical investigation for the treatment of various cancers, particularly B-cell malignancies, such as B-cell lymphomas and B-cell leukemias, for example relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, Richter’s transformation (Richter’s syndrome), and marginal zone lymphoma.

[0004] The compound is described in International Publication No. WO 2017 / 103611. Crystalline forms of Pirtobrutinib are described in International Publication Nos. WO 2020 / 028258 and WO 2022 / 240920. International Publication No. WO 2022 / 056100 describes a process for preparation of Pirtobrutinib.

[0005] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solidstate (13C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0006] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

[0007] Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical / physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Pirtobrutinib.SUMMARY OF THE DISCLOSURE

[0008] The present disclosure provides a crystalline polymorph of Pirtobrutinib. The crystalline form can be used to prepare other solid state forms and Pirtobrutinib salts and / or cocrystals.

[0009] The present disclosure also provides uses of said solid state form of Pirtobrutinib in the preparation of other solid state forms of Pirtobrutinib or salts and / or co-crystals thereof.

[0010] The present disclosure provides said crystalline form of Pirtobrutinib for use in medicine, particularly B-cell malignancies, such as B-cell lymphomas and B-cell leukemias, including for the treatment of: relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, Richter’s transformation (Richter’s syndrome), and marginal zone lymphoma; particularly chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, and marginal zone lymphoma, and more particularly relapsed or refractory mantle cell lymphoma (MCL).

[0011] The present disclosure also encompasses the use of said crystalline polymorph of Pirtobrutinib for the preparation of pharmaceutical compositions and / or formulations.

[0012] In another aspect, the present disclosure provides pharmaceutical compositions comprising said crystalline polymorph of Pirtobrutinib according to the present disclosure.

[0013] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining said crystalline polymorph of Pirtobrutinib with at least one pharmaceutically acceptable excipient.

[0014] The crystalline polymorph of Pirtobrutinib as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorph of Pirtobrutinib may be used as medicaments, particularly B-cell malignancies, such as B-cell lymphomas and B-cell leukemias, such as for the treatment of: relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, Richter’s transformation (Richter’s syndrome), and marginal zone lymphoma; particularly chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, and marginal zone lymphoma, and more particularly relapsed or refractory mantle cell lymphoma (MCL).

[0015] The present disclosure also provides methods for the treatment of patients with B- cell malignancies, such as B-cell lymphomas and B-cell leukemias, for example: relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, Richter’s transformation (Richter’s syndrome), and marginal zone lymphoma, particularly chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, and marginal zone lymphoma; and more particularly relapsed or refractory mantle cell lymphoma (MCL), by administering atherapeutically effective amount of said crystalline polymorph of Pirtobrutinib of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from relapsed or refractory mantle cell lymphoma (MCL) or otherwise in need of the treatment.

[0016] The present disclosure also provides uses of crystalline polymorph of Pirtobrutinib of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments, particularly B-cell malignancies, such as B-cell lymphomas and B- cell leukemias, for example for treating e.g., relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, Richter’s transformation (Richter’s syndrome), and marginal zone lymphoma; particularly chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, and marginal zone lymphoma; and more particularly relapsed or refractory mantle cell lymphoma (MCL).BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Pirtobrutinib Form 1.

[0018] Figure 2 shows a characteristic TGA thermogram of Pirtobrutinib Form 1.

[0019] Figure 3 shows a characteristic DSC thermogram of Pirtobrutinib Form 1.

[0020] Figure 4 shows X-ray powder diffraction pattern (XRPD) of amorphous Pirtobrutinib.

[0021] Figure 5 shows a characteristic X-ray powder diffraction pattern (XRPD) ofPirtobrutinib Form 2.

[0022] Figure 6 shows a characteristic TGA thermogram of Pirtobrutinib Form 2.

[0023] Figure 7 shows a DSC thermogram of Pirtobrutinib Form 2 obtained by example 3, procedure A.

[0024] Figure 8 shows the HPLC chromatogram of the starting material for example 1, Procedures A and B, Example 2 and Example 3, Procedures B, C and D.

[0025] Figure 9 shows the HPLC chromatogram of Example 3, Procedure D.

[0026] Figure 10 shows the HPLC chromatogram of Example 3, Procedure E.

[0027] Figure 11 shows the HPLC chromatogram of Example 3, Procedure F.

[0028] Figure 12 shows the HPLC chromatogram of Example 3, Procedure G.

[0029] Figure 13 shows the HPLC chromatogram of Example 3, Procedure H.

[0030] Figure 14 shows the HPLC chromatogram of Example 3, Procedure I.

[0031] Figure 15 shows the HPLC chromatogram of Example 3, Procedure J

[0032] Figure 16 shows the solid state13C-NMR of Pirtobrutinib form 2 (200-0 ppm).

[0033] Figure 17 shows the solid state13C-NMR of Pirtobrutinib form 2 (200-100 ppm).

[0034] Figure 18 shows the solid state13C-NMR of Pirtobrutinib form 2 (100-0 ppm).

[0035] Figure 19 shows an X-ray powder diffractogram of form A of Pirtobrutinib.DETAILED DESCRIPTION OF THE DISCLOSURE

[0036] The present disclosure encompasses a crystalline form of Pirtobrutinib, processes for preparation thereof, and pharmaceutical compositions thereof.

[0037] Solid state properties of Pirtobrutinib and crystalline polymorphs thereof can be influenced by controlling the conditions under which Pirtobrutinib and crystalline polymorphs thereof are obtained in solid form.

[0038] The solid state forms of Pirtobrutinib as described in any aspect or embodiment of the present disclosure may be polymorphically pure, or substantially free of any other solid state (or polymorphic) forms.

[0039] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" will be understood to mean that the solid state form contains about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. For example, polymorphically pure Pirtobrutinib Form 2 means that the solid state form is substantially free of other solid state forms of Pirtobrutinib. Thus, a crystalline polymorph of Pirtobrutinib described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the subject crystalline polymorph of Pirtobrutinib. In some embodiments of the disclosure, the described crystalline polymorph of Pirtobrutinib, salt or cocrystal may contain from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), or from about 5% to about 10% (w / w) of one or more other crystalline polymorph of the same Pirtobrutinib.

[0040] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of Pirtobrutinib of the present disclosure may have advantageousproperties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and / or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.

[0041] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Pirtobrutinib referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Pirtobrutinib characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0042] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline forms of Pirtobrutinib relates to a crystalline form of Pirtobrutinib which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would generally not contain more than 1% (w / w), of either water or organic solvents as measured for example by TGA.

[0043] The term "solvate," as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate isoften referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0044] As used herein, unless stated otherwise, unit cell data were obtained by solving the crystal structure, unit cell data is preferably measured at 298K.

[0045] As used herein, the term "isolated" in reference to crystalline polymorph of Pirtobrutinib of the present disclosure corresponds to a crystalline polymorph of Pirtobrutinib that is physically separated from the reaction mixture in which it is formed.

[0046] As used herein, unless stated otherwise, the XRPD measurements are taken using copper K a radiation wavelength 1.541874 A. XRPD peaks reported herein are optionally measured using CuK a radiation, X = 1.541874 A, typically at a temperature of 25 ± 3°C.

[0047] As used herein, unless stated otherwise,13C NMR reported herein are measured at 16.4 T at a magic angle spinning frequency ®r / 27t = 20 kHz, preferably at a temperature of 298 K ± 3°K.

[0048] As used herein crystalline form A of Pirtobrutinib refers to a crystalline form as described in WO 2020 / 028258, which may be characterized by X-ray powder diffraction pattern as depicted in Figure 19.

[0049] As used herein, and unless stated otherwise, the term Pirtobrutinib Premix refers to a solid dispersion of Pirtobrutinib with a pharmaceutically acceptable carrier, and optionally other pharmaceutically acceptable excipients. Such a solid dispersion can be a co-precipitate of Pirtobrutinib with a pharmaceutically acceptable carrier, and optionally other pharmaceutically acceptable excipients. Such a co-precipitate may be prepared by mixing crystalline form 2 of Pirtobrutinib and a pharmaceutically acceptable carrier and optionally other pharmaceutically acceptable excipients in a suitable solvent(s) to form a mixture, and removing the solvent(s) from the mixture. The mixture may be a solution (e.g. wherein the components are dissolved), or a suspension or dispersion (e.g. wherein none of the components are dissolved but form a suspension or dispersion, or wherein some but not all of the components are dissolved). The solvent may be removed from the mixture by techniques such as spray drying, lyophilization or evaporation. Suitable pharmaceutically acceptable carriers for preparing the solid dispersion include pharmaceutically acceptable polymeric carriers, including polyvinylpyrrolidone (PVP), copovidone (copolymer of 1 -vinyl-2-pyrrolidone and vinyl acetate), polyethylene glycol, hydroxypropylmethyl cellulose (hypromellose, HPMC), and hydroxylpropylmethyl celluloseacetate succinate, HPMCAS). Preferably the pharmaceutically acceptable carrier is a hydroxypropylmethyl cellulose acetate succinate (HPMCAS). Thus, in a preferred embodiment according to any aspect of the present disclosure, the term Pirtobrutinib Premix refers to a coprecipitate of Pirtobrutinib with hypromellose acetate succinate (HPMCAS) polymers such as HPMCAS-HG, HPMCAS-MG, HPMCAS-LF, HPMCAS-LG, HPMCAS-MF and HMPCAS-HF (where H, M and L relate to different grades of HPMCAS based on the molecular ratio of acetate to succinate substituents on the polymer; wherein L typically has a ratio of <1, M has a ratio of approximately 1, and H has a ratio of >1; and F refers to fine particle size and G relates to granular particle sizes.

[0050] In any aspect or embodiment of the disclosure, the solvent for preparing the Pirtobrutinib premix can be any suitable solvent or a mixture of solvents, for example, the solvent or mixture of solvents can be an organic or aqueous solvent that is preferably capable of dissolving the Pirtobrutinib and the pharmaceutically acceptable carrier as described herein. For example, aliphatic alcohols (such as methanol, ethanol and isopropanol), ethers (such as diethyl ether and tetrahydrofuran), ketones (such as acetone) and esters (such as ethylacetate), and water, or mixtures thereof, may be used.

[0051] As used herein the term "spray-drying" refers to the method of producing a dry powder from a solution or slurry. The solution or slurry is for example atomized or rapidly dried with a hot gas, e.g., air or nitrogen, that causes the solvent to evaporate quickly and uniformly.

[0052] Preferably, according to any aspect or embodiment, the Pirtobrutinib premix is a spray-dried dispersion of Pirtobrutinib.

[0053] As used herein the term "spray-dried dispersion of Pirtobrutinib" refers to the powder obtained from the spray-drying of crystalline form 2 of Pirtobrutinib with a pharmaceutically acceptable carrier, (particularly a pharmaceutically acceptable carrier polymeric carrier as described above), and one or more solvents.

[0054] The Pirtobrutinib pre-mix can be a co-precipitate of Pirtobrutinib with a pharmaceutically acceptable carrier, and optionally other pharmaceutically acceptable excipients. Preferably the pharmaceutically acceptable carrier is a pharmaceutically acceptable polymeric carrier as described above, and more particularly, a hypromellose acetate succinate (HPMCAS) polymers such as HPMCAS-MG, HPMCAS-LF, HPMCAS-LG, HPMCAS-MF, HMPCAS-HF, and HPMCAS-HG. The Pirtobrutinib premix can be prepared by removal of thesolvent from a mixture comprising Pirtobrutinib, a pharmaceutically acceptable polymeric carrier (as described above), and optionally one or more other pharmaceutically acceptable excipients, for example by evaporation under reduced pressure such as a rotary evaporator, or freeze drying, or, preferably by spray-drying (i.e. to form a spray-dried dispersion).

[0055] In any aspect or embodiment, the Pirtobrutinib premix comprises Pirtobrutinib and a carrier, preferably wherein the carrier is a pharmaceutically acceptable polymeric carrier, particularly polyvinylpyrrolidone (PVP), copovidone (copolymer of 1 -vinyl-2-pyrrolidone and vinyl acetate), polyethylene glycol, hydroxypropylmethyl cellulose (hypromellose, HPMC), and hydroxylpropylmethyl cellulose acetate succinate, HPMCAS). More particularly, the pharmaceutically acceptable carrier is a hydroxypropylmethyl cellulose acetate succinate (HPMCAS), preferably wherein the carrier is hypromellose acetate succinate (HPMCAS) polymers such as HPMCAS-MG, HPMCAS-LF, HPMCAS-LG, HPMCAS-MF, HMPCAS-HF, and HPMCAS-HG. Preferably the pre-mix contains a weight ratio of carrier: Pirtobrutinib which is about 4:1 to about l:4.In embodiments pre-mix contains a weight ratio of carrier: Pirtobrutinib which is about 3 : 1, about 7:3, about 13 :7, about 3 :2, about l l :9, about l: 1, about 9: 11, about 2:3, about 7: 13, about 3 :7, about 1 :3, or about 1 :4. In embodiments the weight ratio of carrier: Pirtobrutinib in the premix is 1 :1.

[0056] The Pirtobrutinib premix may be preferably an amorphous premix.

[0057] In some embodiments the present disclosure relates to processes for preparation of a premix of Pirtobrutinib, preferably an amorphous premix, comprising combining crystalline form 2 of Pirtobrutinib, with a pharmaceutically acceptable carrier, preferably hypromellose acetate succinate (HPMCAS) polymers such as HPMCAS-MG, HPMCAS-LF, HPMCAS-LG, HPMCAS-MF, HMPCAS-HF, and HPMCAS-HG, and optionally other pharmaceutically acceptable excipients, with a solvent to provide a mixture. Preferably, in the mixture, both crystalline form 2 of Pirtobrutinib and the carrier are dissolved. The solvent is then removed from the second mixture by techniques such as spray drying, lyophilization or evaporation. The resulting mixture may be in the form of a powder, which may be subjected to drying steps and / or to particle size reduction steps (e.g., by milling). Preferably the pre-mix contains a weight ratio of carrier: Pirtobrutinib as described in any aspect or embodiment herein, which is about 4: 1 to about 1:4 or about 3: 1 to about 1:3, about 2:1 to about 1:2, about 1.5: 1 to about 1:1.5, about 1.2: 1 to about 1: 1.2, or about 1:1. According to any embodiment, the pre-mix contains a weight ratioof carrier: Pirtobrutinib which is about 3: 1, about 7:3, about 13:7, about 3:2, about 11 :9, about 1: 1 , about 9:11, about 2:3, about 7: 13, about 3 : 7, about 1 : 3 , or about 1 : 4. In embodiments the weight ratio of carrier: Pirtobrutinib in the premix is 1 :1.

[0058] In some embodiments the present disclosure relates to processes for preparation of a spray-dried dispersion, comprising combining crystalline form 2 of Pirtobrutinib, as described in any aspect or embodiment herein, with a pharmaceutically acceptable carrier, preferably a pharmaceutically acceptable polymeric carrier, particularly polyvinylpyrrolidone (PVP), copovidone (copolymer of 1 -vinyl-2-pyrrolidone and vinyl acetate), polyethylene glycol, hydroxypropylmethyl cellulose (hypromellose, HPMC), and hydroxylpropylmethyl cellulose acetate succinate, HPMCAS); and more particularly hypromellose acetate succinate (HPMCAS) polymers especially such as HPMCAS-MG, HPMCAS-LF, HPMCAS-LG, HPMCAS-MF, HMPCAS-HF, and HPMCAS-HG, and optionally other pharmaceutically acceptable excipients, and a solvent, to yield a mixture. Preferably, both the crystalline form 2 of Pirtobrutinib and the carrier are dissolved. The solvent is then removed from the mixture by spray drying. The resulting mixture may be in the form of a powder, which may be subjected to drying steps and / or to particle size reduction steps (e.g., by milling). Preferably the pre-mix contains a weight ratio of carrier: Pirtobrutinib which is about 4: 1 to about 1 :4 or about 3 : 1 to about 1:3, about 2: 1 to about 1:2, about 1.5: 1 to about 1 :1.5, about 1.2: 1 to about 1 :1.2, or about 1: 1. In any embodiment, the pre-mix can contains a weight ratio of carrier: Pirtobrutinib which is about 3: 1, about 7:3, about 13:7, about 3:2, about 11 :9, about 1: 1, about 9: 11, about 2:3, about 7:13, about 3:7, about 1 :3, or about 1 :4. In any embodiment the weight ratio of carrier: Pirtobrutinib in the premix is 1: 1.

[0059] The present disclosure provides Pirtobrutinib amorphous premix (or solid dispersion) or spray-dried dispersion of Pirtobrutinib which is obtainable by a process according to any aspect or embodiment disclosed herein. The Pirtobrutinib solid dispersion and the spray-dried dispersion may be used for the preparation of pharmaceutical compositions. For example, the Pirtobrutinib premix may be combined with one or more pharmaceutically acceptable excipients for form a pharmaceutical composition.

[0060] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” or “ambient temperature,” often abbreviated as “RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., theroom or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0061] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term "v / v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v / v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added.

[0062] A process or step may be referred to herein as being carried out "overnight." This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.

[0063] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.

[0064] The solid state form of Pirtobrutinib as described in any aspect or embodiment of the present disclosure may be chemically pure, or substantially free of any other compounds.

[0065] A compound may be referred to herein as chemically pure or purified compound or as substantially free of any other compounds. As used herein, the terms "chemically pure" or "purified" or "substantially free of any other compounds" refer to a compound that is substantially free of any impurities including enantiomers of the subject compound, or other isomers. A chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% (w / w) or less, about 5% (w / w) or less, about 4% (w / w) or less, about 3% (w / w) or less, about 2% (w / w) or less, about 1.5% (w / w) or less, about 1% (w / w) or less, about 0.8% (w / w) or less, about 0.6% (w / w) or less, about 0.4% (w / w) or less, about 0.2% (w / w) or less, about 0.1% (w / w) or less, or about 0% of any other compound as measured, for example, by HPLC. Alternatively, A chemically pure or purified compound or a compound that is substantially free of any other compound will beunderstood to mean that it contains about 10% area percent or less, about 5% area percent or less, about 4% area percent or less, about 3% area percent or less, about 2% area percent or less, about 1.5% area percent or less, about 1% area percent or less, about 0.8% area percent or less, about 0.6% area percent or less, about 0.4% area percent or less, about 0.2% area percent or less, about 0.1% area percent or less, or about 0% of any other compound as measured by HPLC.

[0066] Thus, pure or purified Pirtobrutinib described herein as substantially free of any compounds would be understood to contain greater than about 90% (w / w), greater than about 95% (w / w), greater than about 96% (w / w), greater than about 97% (w / w), greater than about 98% (w / w), greater than about 98.5% (w / w), greater than about 99% (w / w), greater than about 99.2% (w / w), greater than about 99.4% (w / w), greater than about 99.6% (w / w), greater than about 99.8% (w / w), greater than about 99.9% (w / w), or about 100% of the subject Pirtobrutinib. Alternatively, pure or purified Pirtobrutinib, described herein as substantially free of any compounds would be understood to contain greater than about 90% area percent, greater than about 95% area percent, greater than about 96% area percent, greater than about 97% area percent, greater than about 98% area percent, greater than about 98.5% area percent, greater than about 99% area percent, greater than about 99.2% area percent, greater than about 99.4% area percent, greater than about 99.6% area percent, greater than about 99.8% area percent, greater than about 99.9% area percent, or about 100% of the subject Pirtobrutinib.

[0067] The present disclosure includes a crystalline polymorph Pirtobrutinib designated Form 2. The crystalline Form 2 of Pirtobrutinib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 5; an X-ray powder diffraction pattern having peaks at 11.4, 16.7 and 25.1 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0068] Crystalline Form 2 of Pirtobrutinib may be further characterized by an X-ray powder diffraction pattern having peaks at 11.4, 16.7 and 25.1 degrees 2-theta ± 0.2 degrees 2-theta, and also having one or two peaks selected from 10.2 and 21.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0069] Crystalline Form 2 of Pirtobrutinib may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 10.2, 11.4, 16.7, 21.1 and 25.1 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0070] Crystalline Form 2 of Pirtobrutinib may be further characterized by an X-ray powder diffraction pattern having peaks at 10.2, 11.4, 16.7, 21.1 and 25.1 degrees 2-theta ± 0.2 degrees2-theta, and also having one, two, three, four or five additional peaks selected from 14.4, 15.3, 18.4, 22.0 and 24.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0071] Crystalline Form 2 of Pirtobrutinib may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 11.4, 16.7 and 25.1 degrees 2-theta ± 0.2 degrees 2- theta, and also having one, two, three, four or five additional peaks selected from 14.4, 15.3, 18.4, 22.0 and 24.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0072] Crystalline Form 2 of Pirtobrutinib may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 10.2, 11.4, 14.4, 15.3, 16.7, 18.4, 21.1, 22.0, 24.5 and 25.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0073] According to any aspect or embodiment of the present disclosure, crystalline Form 2 of Pirtobrutinib may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments described herein, and wherein the X-ray powder diffraction pattern also has an absence of peaks at 3.0 to 4.5 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to any aspect or embodiment of the present disclosure, crystalline Form 2 of Pirtobrutinib may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments described herein, and wherein the X-ray powder diffraction pattern also has absence of peaks at 5.5 to 6.0 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to any aspect or embodiment of the present disclosure, crystalline Form 2 of Pirtobrutinib may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments described herein, and wherein the X-ray powder diffraction pattern also has an absence of peaks at 7.7 to 8.7 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to any aspect or embodiment of the present disclosure, crystalline Form 2 of Pirtobrutinib may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments described herein, and wherein the X-ray powder diffraction pattern also has an absence of peaks at 11.9 to 12.2 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to any aspect or embodiment of the present disclosure, crystalline Form 2 of Pirtobrutinib may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments described herein, and wherein the X-ray powder diffraction pattern also has an absence of peaks at 18.9 to 19.1 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to any aspect or embodiment of the present disclosure, crystalline Form 2 of Pirtobrutinib may be characterized by an X-ray powder diffraction pattern as described in anyof the embodiments described herein, and wherein the X-ray powder diffraction pattern also has an absence of peaks at 22.7 to 23.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0074] Alternatively or in addition to any of the above characterizing data, crystalline Form 2 of Pirtobrutinib may be characterized by: a solid state13C NMR spectrum having characteristic peaks at 55.82, 110.13, 120.20 and 162.82 ppm ± 0.2 ppm; or a solid state13C NMR spectrum having the following chemical shift absolute differences from reference peak at94.91 ppm ± 0.2 ppm: 39.09, 15.22, 25.29 and 67.91sppm ± 0.1 ppm; or a solid state13C NMR spectrum substantially as depicted in any of Figures 16, 17 or 18.

[0075] In any aspect or embodiment of the present disclosure, crystalline Form 2 of Pirtobrutinib may be isolated. Particularly, crystalline Form 2 of Pirtobrutinib according to any aspect or embodiment of the disclosure may be isolated.

[0076] In any aspect or embodiment crystalline Form 2 of Pirtobrutinib may be polymorphically pure.

[0077] In any aspect or embodiment of the present disclosure, crystalline Form 2 of Pirtobrutinib may be anhydrous.

[0078] Alternatively form 2 of Pirtobrutinib can be characterized by the following unit cell data: cell length a 7.25 A cell length b 17.28 A cell length c 34.66 A cell angle alpha 90 ° cell angle beta 90 ° cell angle gamma 90 ° cell volume 4342.2 A3symmetry cell setting orthorhombic symmetry space group name_ 7’2 / 2 / 2 / Cell data is measured at 298K.

[0079] Alternatively, form 2 of Pirtobrutinib as defined in any aspect or embodiment herein may be additionally characterized by the above unit cell data.

[0080] Crystalline Form 2 of Pirtobrutinib may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at10.2, 11.4, 16.7, 21.1 and 25.1 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD patern as depicted in Figure 5, and combinations thereof.

[0081] The present disclosure provides the above described crystalline polymorph of Pirtobrutinib for use in the preparation of pharmaceutical compositions comprising Pirtobrutinib and / or solid state forms thereof.

[0082] The present disclosure also encompasses the use of crystalline polymorph of Pirtobrutinib of the present disclosure for the preparation of pharmaceutical compositions of crystalline polymorph Pirtobrutinib and / or solid state forms thereof.

[0083] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorph of Pirtobrutinib of the present disclosure with at least one pharmaceutically acceptable excipient.

[0084] Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the solid state form of Pirtobrutinib of the present disclosure. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

[0085] Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0086] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®),liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0087] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac- Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[0088] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0089] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[0090] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0091] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and / or facilitate patient identification of the product and unit dosage level.

[0092] In liquid pharmaceutical compositions of the present invention, Pirtobrutinib and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0093] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0094] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and / or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.

[0095] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[0096] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

[0097] According to the present disclosure, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[0098] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

[0099] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0100] The dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the disclosure, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and / or sorbitol, an opacifying agent and / or colorant.

[0101] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0102] A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water that causes the powders to clump into granules. The granulate is screened and / or milled, dried, and then screened and / or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and / or a lubricant.

[0103] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.

[0104] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

[0105] A capsule filling of the present disclosure can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.

[0106] A pharmaceutical formulation of Pirtobrutinib can be administered. Pirtobrutinib may be formulated for administration to a mammal, in embodiments to a human, by injection. Pirtobrutinib can be formulated, for example, as a viscous liquid solution or suspension, such asa clear solution, for injection. The formulation can contain one or more solvents. A suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

[0107] The present disclosure further provides the use of the crystalline polymorph of Pirtobrutinib as described in any aspect or embodiment, for the preparation of a Pirtobrutinib premix. The premix can be a solid dispersion, for example a spray dried dispersion as described above. The spray dried dispersion can be prepared by a process comprising spray drying a mixture of Pirtobrutinib according any aspect or embodiment of the disclosure, , a pharmaceutically acceptable carrier (particularly a pharmaceutically acceptable polymeric carrier as described above), and one or more solvents (particularly a solvent suitable for spray drying as described above), Preferably, the spray dried dispersion can be prepared by a process comprising mixing Pirtobrutinib as described in any aspect or embodiment, a pharmaceutically acceptable carrier, preferably a pharmaceutically acceptable polymeric carrier material (preferably as described above), and one or more solvents (preferably as described above) to form a mixture, and spray drying the mixture. The process may further comprise blending the spray dried dispersion with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation. The present disclosure further includes a product (i.e. a premix, preferably a solid dispersion, more preferably a spray dried dispersion or a pharmaceutical composition or pharmaceutical formulation obtainable by these processes.

[0108] The crystalline polymorph of Pirtobrutinib, the Pirtobrutinib premix, preferably a solid dispersion, and more preferably a spray-dried dispersion thereof and the pharmaceutical compositions and / or formulations of Pirtobrutinib of the present disclosure can be used as medicaments, particularly for treating B-cell malignancies, such as B-cell lymphomas and B-cell leukemias, in embodiments for the treatment of patients with relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, Richter’s transformation (Richter’s syndrome), and marginal zone lymphoma; and particularly chronic lymphocytic leukemia, small lymphocytic lymphoma,Waldenstrom's macroglobulinemia, and marginal zone lymphoma; and more particularly relapsed or refractory mantle cell lymphoma (MCL).

[0109] The present disclosure also provides methods of treating of patients with B-cell malignancies, such as B-cell lymphomas and B-cell leukemias, particularly relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, Richter’s transformation (Richter’s syndrome), and marginal zone lymphoma; and particularly chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, and marginal zone lymphoma; and more particularly relapsed or refractory mantle cell lymphoma (MCL) by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Pirtobrutinib, Pirtobrutinib premix, Pirtobrutinib solid dispersion or spray-dried dispersion thereof of the present disclosure, or at least one of the above pharmaceutical compositions and / or formulations, to a subject in need of the treatment.

[0110] Having thus described the disclosure with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure as disclosed in the specification. The Examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way.Powder X-ray Diffraction ("XRPD") method

[0111] Powder X-ray Diffraction was performed on an X-Ray powder diffractometer PanAlytical EMPYREAN; CuKa radiation (A. = 1.54187 A); pixCel detector with active length 2.140 degrees 2-theta; laboratory temperature 25 ± 3 °C; zero background sample holders. Prior to analysis, the samples were gently ground using a mortar and pestle to obtain a fine powder.The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed using a cover glass.Measurement parameters:Scan range: 3 - 40 degrees 2-thetaScan mode: continuousStep size: 0.0131 degreesStep size: 42 sSample spin: 60 rpmSample holder: zero background silicon plate

[0112] The described peak positions were determined using silicon powder as an internal standard in an admixture with the sample measured.SS-NMR Method

[0113] The13C CP / MAS spectra were recorded at 16.4 T using a Bruker Avance NEO 700 SB NMR spectrometer (Karlsruhe, Germany, 2021) with 3.2 mm probe head. In this case, the MAS frequency is set to 20 kHz for measurements.

[0114] The NMR spectrometer is always completely calibrated and all experimental parameters are carefully optimized prior the recording of the spectra. Magic angle is set using KBr during the standard optimization procedure and homogeneity of magnetic field is optimized using adamantane sample (resulting line-width at half-height Dnl / 2 was less than 3.5 Hz at 250 ms of acquisition time). Frictional heating of the spinning samples is compensated by active cooling, and the temperature calibration is performed with Pb(NCh)2.Single crystal X-ray crystal structure determination for form 1

[0115] Data were collected on a Bruker D8 VENTURE system equipped with a multilayer monochromator and a Mo Ka Incoatec microfocus sealed tube (A. = 0.71073 A) using combined (p and co scans at 180 K. Data collection: APEX3 v2015 (Bruker AXS); unit cell refinement: APEX3 v2015 (Bruker AXS); data reduction: SAINT (Bruker AXS Inc., 2013); program used to solve structure: SIR92 (Altomare et al., 1994); program used to refine structure: CRYSTALS (Betteridge et al., 2003); Data export and void calculation was done by Platon (Spek, 2003).Single crystal electron diffraction (ED) crystal structure determination for form 2

[0116] 3D ED / microED experiments were performed on a XtaLAB Synergy-ED electron diffractometer consisting of a 200 kV emitter (corresponding to a wavelength of 0.0251 A), lens system, HyPix-ED detector and controlled by CrysAlisPro for ED (Rigaku, VI.171.43.70a, 2023). The sample was spread on a TEM grid and then measured at room temperature and vacuum conditions. The selected data set was collected in continuous rotation at a virtual detector distance of 648 mm in a tilt range of -75° to +75°, a step size of 0.5° and a scan speed of l° / s at spot size 3 (of 5) with 10 pm CL and 100 pm SA apertures. Data reduction, scaling and absorption corrections were performed using CrysAlisPro (Rigaku, VI.171. 43.70a, 2023). A multi-scan absorption correction was performed using CrysAlisPro (Rigaku, VI.171. 43.70a, 2023) using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Using01ex2 [1], the structure was solved with the SHELXT [2] structure solution program using Intrinsic Phasing and refined with the SHELXL [3] refinement package using Least Squares minimization.Thermal gravimetric analysis (TGA)

[0117] Equipment: TA Discovery;Crucibles: Aluminum, 100 plHeating range: 20 - 200 °C;Heating rate: 10 °C / min;Purging gas: Nitrogen;Purging gas flow: 25 ml / min.Differential scanning calorimetry (DSC)

[0118] Equipment: TA Discovery;Crucibles: Aluminum Tzero pans with pin-holed Tzero hermetic lids, 40 pl;Heating range: 25 - 300 °C;Heating rate: 10 °C / min;Purging gas: Nitrogen;Purging gas flow: 50 ml / min.HPLC method used for purity analysis of the starting material [used for Procedures A andB of example 1, Example 2 and Procedures B, C and D of Example 3] and products ofExample 3 procedures D, E, F, G and HHPLC method used for purity analysis of example 3, procedures I and JEXAMPLESPreparation of starting materials

[0119] Pirtobrutinib and N-(4-(( 1 S)- 5-amino-4-cyano- 1 -( 1 , 1 , 1 -trifluoropropan-2-yl)- 1 H- pyrazol-3-yl)benzyl)-5-fluoro-2-methoxybenzamide can be prepared according to methods known from the literature, for example according to the disclosure in International Publication Nos. WO 2017 / 103611 or WO 2022 / 056100.

[0120] Unless indicated otherwise, purity of Pirtobrutinib used as starting material, in the examples was characterized by the HPLC chromatogram exhibited in Figure 8.Example 1: Preparation of Pirtobrutinib crystal Form 1Procedure A

[0121] Pirtobrutinib (80 mg) was suspended at room temperature in butyl acetate (1 mL) and dissolved while heating to a temperature at about 95°C. Clear solution was cooled down to 5°C over a period of about 2 hours. The solid was filtered and analyzed by XRPD, DSC and TGA. Form 1 was obtained. The XRPD pattern is shown in Figure 1. The TGA thermogram is shown in Figure 2. The DSC thermogram is shown in Figure 3.Procedure B

[0122] Pirtobrutinib (80 mg) was dissolved in ethanol (1 mL) by heating to 50°C during a period of about 45 min. Clear solution was cooled down to room temperature during a period of about 1 hour and stored at room temperature overnight. Monocrystals were formed and analyzed by scXRD.

[0123] Unit cell parameters of Pirtobrutinib Form 1Example 2: Preparation of amorphous Pirtobrutinib

[0124] Pirtobrutinib (10 grams) was dissolved in methanol (80 mL) at room temperature. Clear solution was filtered to remove foreign particles and evaporated to dryness on rotavapor at temperature of about 60°C. Obtained solid was analyzed by XRPD and the XRPD pattern is presented in Figure 4.Example 3: Preparation of Pirtobrutinib crystal Form 2Procedure A

[0125] Pirtobrutinib (amorphous) was suspended in water and slurried at room temperature for period of about 5 days. Solid matter was filtered, dried under vacuum and analyzed by XRPD, DSC and TGA. Form 2 was obtained. The XRPD pattern is shown in Figure 5. The TGA thermogram is shown in Figure 6. The DSC thermogram is shown in Figure 7.Procedure B

[0126] Pirtobrutinib (80 mg) was dissolved in dimethylacetamide (0.5 mL) at room temperature. Clear solution of Pirtobrutinib was quickly added into water (3 mL) at room temperature. Material precipitated immediately and obtained suspension was stirred at room temperature overnight. Solid matter was filtered, dried under vacuum, analyzed by XRPD and identified as Form 2 of Pirtobrutinib.Procedure C

[0127] 100 mg of Pirtobrutinib was dissolved in ethanol (4 mb) at room temperature.Obtained solution is added dropwise to water (28 mL). Crystallization occurred immediately, and suspension was obtained. Suspension was filtrated off over blue ribbon filter paper and analyzed by XRPD. Pirtobrutinib Form 2 was obtained.

[0128] Unit cell parameters of Pirtobrutinib Form 2:Procedure D

[0129] Pirtobrutinib (8 grams) was dissolved in dimethylacetamide (48 mL) at room temperature and clear solution was added dropwise into water (310 mL). Material started to precipitate immediately, obtained suspension was stirred for about 3 hours, filtered and dried under vacuum to constant weight to obtain Pirtobrutinib form 2 (HPLC purity 99.73%).Procedure E

[0130] N-(4-(( 1 S)-5 -amino-4-cyano- 1 -( 1 , 1 , 1 -trifluoropropan-2-y 1)- 1 H-pyrazol-3 -yl)benzy 1)-5-fluoro-2-methoxybenzamide (2.5 grams, 5.4 mmol) was charged in a 50 ml round bottom flask and suspended in methanesulfonic acid (10 ml, 4 V / w). The mixture was heated to 80 °C, the suspension dissolved and became a light brown solution. Distilled water (0.195 ml, 10.8 mmol) was then added and the mixture was stirred for 8 hours at 80 °C. The reaction mixture was cooled to room temperature and added dropwise into a previously prepared mixture of 7.3 M aqueous sodium hydroxide (37.5 ml, 15 V / w) and absolute ethanol (3.75 ml, 1.5 V / w) previously seeded with Pirtobrutinib form 2 obtained according to Example 3, Procedure D (50 mg, 2%w / w). The drop wise addition was performed for the duration of 30 minutes while maintaining the temperature below 10 °C. The off-white suspension that formed was stirred overnight at room temperature and then filtered. The off-white crystals were washed two times with distilled water (2 x 12.5 ml, 2 x 5 V / w). The off-white solids were collected and dried for 10 hours at 50 °C and 10 mbar, to obtain Pirtobrutinib form 2 (HPLC purity 98.71%).Procedure F (removal of residual sodium mesylate)

[0131] Pirtobrutinib obtained according to Example 3, Procedure E (3.5 grams, 7.7 mmol) was charged in a 50 ml round bottom flask and suspended in distilled water (25 ml, 7.1 V / w). After stirring one hour at room temperature, an additional quantity of distilled water (12.5 ml, 3.6 V / w) was added. The off-white suspension was stirred for another hour at room temperature and then filtered. The off white crystals were washed two times with distilled water (2 x 17.5 ml, 2 x 5 V / w). The solids were collected and dried for 10 hours at 50 °C and 10 mbar, to obtain Pirtobrutinib form 2 (HPLC purity 98.72%).Procedure G (MM / 4080 / 42 / T HPLC methodi)

[0132] N-(4-(( 1 S)-5 -amino-4-cyano- 1 -( 1 , 1 , 1 -trifluoropropan-2-y 1)- 1 H-pyrazol-3 -yl)benzy 1)-5-fluoro-2-methoxybenzamide (1.0 gram, 2.2 mmol) was charged in a 5 ml round bottom flask and suspended in methanesulfonic acid (4 ml, 4 V / w). The mixture was heated to 80 °C, the suspension dissolved and became a light brown solution. The mixture was stirred for 8 hours at 80 °C and distilled water (0.078 ml, 4.3 mmol) was then added and stirred for another 3 hours at 80 °C. The reaction mixture was cooled to room temperature and stirred overnight. The brown solution was then added dropwise into a previously prepared mixture of 7.3 M aqueous sodium hydroxide (15.0 ml, 15 V / w) and absolute ethanol (1.5 ml, 1.5 V / w) previously seeded with 5- amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-l -(1 , 1 , 1 -trifluoropropan-2-yl)- 1H- pyrazole-4-carboxamide Pirtobrutinib form 2 obtained according to Example 3, Procedure D (10 mg, 1% w / w). The dropwise addition was performed for the duration of 30 minutes while maintaining the temperature below 10 °C. The off-white suspension that formed was stirred overnight at room temperature and then filtered. The off-white crystals were washed two times with distilled water (2 x 5.0 ml, 2 x 5 V / w). The off-white solids were collected and dried for 10 hours at 50 °C and 10 mbar to obtain Pirtobrutinib form 2 (HPLC purity 99.02%).Procedure H

[0133] Pirtobrutinib obtained according to Example 3, Procedure F (1.0 gram, 2.2 mmol) was charged in a 50 ml round bottom flask and dissolved in absolute ethanol (15.0 ml, 15 V / w). The brown solution was added dropwise into a previously prepared mixture of distilled water (45.0 ml, 45 V / w) and absolute ethanol (4.5 ml, 4.5 V / w) previously seeded with Pirtobrutinib obtained according to Example 3, Procedure G (20 mg, 2% w / w). The dropwise addition was performed for the duration of 6 hours at room temperature. The off-white suspension that formed was stirred overnight at room temperature and then filtered. The off-white crystals were washed two times with distilled water (2 x 5 ml, 2 x 5 V / w). The off-white solids were collected and dried for 10 h at 50 °C and 10 mbar to obtain Pirtobrutinib form 2 (HPLC purity 99.45%).Procedure

[0134] N-(4-(( 1 S)-5 -amino-4-cyano- 1 -( 1 , 1 , 1 -trifluoropropan-2-y 1)- 1 H-pyrazol-3 -yl)benzy 1)-5-fluoro-2-methoxybenzamide (10.0 grams, 22 mmol) was charged in a 250 ml reactor and suspended in methanesulfonic acid (100 ml, 10 V / w). The mixture was heated to 80 °C, the suspension dissolved and became a light brown solution. Distilled water (0.78 ml, 43 mmol) was then added and the mixture was stirred for 4 hours at 80 °C. The reaction mixture was cooled to room temperature and added dropwise to 7.3 M aqueous sodium hydroxide (375.0 ml, 37.5 V / w) previously cooled to 0 °C and seeded with Pirtobrutinib obtained according to Example 3, Procedure H (200 mg, 2% w / w). The dropwise addition was performed for the duration of 60 minutes while maintaining the temperature below 10 °C. The off-white suspension that formed was stirred overnight at room temperature and then filtered. The off-white crystals were washed two times with distilled water (2 x 50 ml, 2 x 5 V / w). The off-white solids were collected and dried for 10 hours at 50 °C and 10 mbar to obtain Pirtobrutinib form 2 (HPLC purity 99.22%).Procedure J (removal or residual sodium mesylate)

[0135] Pirtobrutinib obtained according to Example 3, Procedure I (15.0 grams, 31 mmol) was charged in a 250 ml reactor and suspended in distilled water (150 ml, 10 V / w). The off- white suspension was stirred overnight at room temperature and then filtered. The off white crystals were washed two times with distilled water (2 x 75 ml, 2 x 5 V / w). The solids were collected and dried for 10 h at 50 °C and 10 mbar to obtain Pirtobrutinib form 2 (HPLC purity 98.77%).Procedure K

[0136] Pirtobrutinib (amorphous, about 150-200 mg), obtained according to example 3, Procedure A was suspended in water (about 1.5-2.5 ml) and slurried at room temperature for period of about 5 days. Solid matter was filtered, dried under vacuum and analyzed by XRPD, DSC and TGA. Form 2 was obtained.Example 4 - Compressibility Determination

[0137] A die and a flat-faced punch fitted on a TA-XTplus Texture analyser (FA 5029767, Stable Micro Systems Ltd., Godaiming, UK) was used. 200 mg of the test sample were compressed in a steel mould (with the rate of displacement 0.03 mm / s).

[0138] In addition, a cyclic procedure (similar to tapping) was performed in 10 compressive force steps of in increments of 1 kg, force relaxation for 10 s then retracting to zero, and then repeated compressive steps (altogether up to 10 steps). The data is presented in the table below:Carr index for Pirtobrutinib forms 2 and A

[0139] A high Carr’s Index is indicative of poorer flowability. In particular, a material having a Carr’s Index of 26 or greater is considered to show poor flowability, and a material having a Carr’s Index of 32-37 is classified as having a very poor flowability. Form A has a Carr’s Index of 34, which is classified as having very poor flowability. In contrast, the Form 2 has a significantly lower Carr’s Index (17.84) and hence has a superior flowability compared to Form A.Example 5 - Solubility

[0140] The solubilities of Pirtobrutinib forms 2 and Pirtobrutinib form A were determined in water, pH 4.5 buffer, pH 6.8 buffer and pH 1.2 solution as follows:Buffers and solutions were prepared as follows:HC1 solution, pH= 1.2

[0141] 16.6 mL of cone. Hydrochloric acid (12 M) was added to 2 L of water.Acetate buffer, pH 4.5

[0142] 2.99 grams of sodium acetate trihydrate buffer was weighed in 1000 mL beaker, dissolved in about 500 ml of purified water, and 14 mL of 2.0 N Acetic acid solution in 1000 mLbeaker was added, then diluted to lOOOmL with purified water. pH value 4.50 ± 0.05 is measured or adjusted using 2.0 N acetic acid solution.Phosphate buffer, pH=6.80

[0143] 250 mL of 0.2M Potassium phosphate buffer and 112 mb of 0.2M Sodium hydroxide solution were mixed in 1000 mL beaker, diluted up-to mark with purified water. pH value 6.80 ± 0.05 is measured or adjusted with 0.2 M Sodium hydroxide solution.

[0144] Pirtobrutinib samples (around 50 mg) were weighed into 15 ml TPP centrifuge tubes (Sigma) and 11 ml of solvent was added. Solvents used were water, phosphate buffer (pH=6.8), acetate buffer (pH= 4.5) and hydrochloric acid solution (pH= 1.2).

[0145] Tubes were stoppered and shaken at 160 rpm for 24 hours at 37±0.2 °C in incubator shaker (Innova 4080, New Brunswick Scientific). Suspensions were filtered through 0.45 pm PTFE syringe filter and Pirtobrutinib concentrations were determined by HPLC. Obtained results are shown in the table below:Solubility comparison of form A and Form 2 after 1 hour.

[0146] The results show that the Pirtobrutinib form 2 has a significantly higher solubility in all the tested media compared with Form A. The higher solubility is particularly advantageous from the point of view of processing the active agent to prepare a pharmaceutical composition or formulation. Moreover, a higher solubility is associated with better pharmacokinetic characteristics and drug absorption.

[0147] Further aspects and embodiments of the present disclosure are set out in the numbered clauses below:1. A crystalline form of Pirtobrutinib designated form 2, which is characterized by data selected from:(a) an X-ray powder diffraction pattern having peaks at 11.4, 16.7 and 25.1 degrees 2- theta ± 0.2 degrees 2-theta;(b) an X-ray powder diffraction pattern substantially as depicted in Figure 5;(c) a solid state13C NMR spectrum having characteristic peaks at 55.82, 110.13, 120.20 and 162.82 ppm ± 0.2 ppm;(d) a solid state13C NMR spectrum having the following chemical shift absolute differences from reference peak at 94.91 ppm ± 0.2 ppm: 39.09, 15.22, 25.29 and 67.91 ppm ± 0.1 ppm;(e) a solid state13C NMR spectrum substantially as depicted in Figure 16, 17 or 18;(f) the following unit cell data: cell length a 7.25 A cell length b 17.28 A cell length c 34.66 A cell angle alpha 90 ° cell angle beta 90 ° cell angle gamma 90 ° cell volume 4342.2 A3symmetry space group name_ 2 / 2 / 2y; and(g) combination of any two or more of (a)-(f).2. A crystalline form of Pirtobrutinib according to Clause 1, which is characterized by an X- ray powder diffraction pattern having peaks at 11.4, 16.7 and 25.1 degrees 2-theta ± 0.2 degrees 2-theta.3. A crystalline form of Pirtobrutinib according to Clause 1 or Clause 2, which is characterized by an X-ray powder diffraction pattern having peaks at 11.4, 16.7 and 25.1 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one or two peaks selected from 10.2 and 21.1 degrees 2-theta ± 0.2 degrees 2-theta.A crystalline form of Pirtobrutinib according to any of Clauses 1, 2, or 3, which is characterized by an X-ray powder diffraction pattern having peaks at 10.2, 11.4, 16.7, 21.1 and 25.1 degrees 2-theta ± 0.2 degrees 2-theta; or an X-ray powder diffraction pattern substantially as depicted in Figure 5. A crystalline form of Pirtobrutinib according to any of Clauses 1, 2, 3, or 4, which is characterized by an X-ray powder diffraction pattern having peaks at 10.2, 11.4, 16.7, 21.1 and 25.1 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks selected from 14.4, 15.3, 18.4, 22.0 and 24.5 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Pirtobrutinib according to any of Clauses 1, 2, 3 4, or 5, which is characterized by an X-ray powder diffraction pattern having peaks at 10.2, 11.4, 14.4, 15.3, 16.7, 18.4, 21.1, 22.0, 24.5 and 25.1 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Pirtobrutinib according to any of Clauses 1, 2, 3, 4, 5, or 6, which is characterized by an X-ray powder diffraction pattern having an absence of peaks at 3.0 to 4.5 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Pirtobrutinib according to any of Clauses 1, 2, 3, 4, 5, 6, or 7, which is characterized by an X-ray powder diffraction pattern having an absence of peaks at 5.5 to 6.0 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Pirtobrutinib according to any of Clauses 1, 2, 3, 4, 5, 6, 7, or 8, which is characterized by an X-ray powder diffraction pattern having an absence of peaks at 7.7 to 8.7 degrees 2-theta ± 0.2 degrees 2-theta. A form of Pirtobrutinib according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, or 9, which is characterized by an X-ray powder diffraction pattern having an absence of peaks at 11.9 to 12.2 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Pirtobrutinib according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, which is characterized by an X-ray powder diffraction pattern having an absence of peaks at 18.9 to 19.1 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Pirtobrutinib according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, which is characterized by an X-ray powder diffraction pattern having an absence of peaks at 22.7 to 23.0 degrees 2-theta ± 0.2 degrees 2-theta.A crystalline form of Pirtobrutinib according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, or 12, which is characterized by an X-ray powder diffraction pattern X-ray powder diffraction pattern substantially as depicted in Figure 5; A crystalline form of Pirtobrutinib according to Clause 1, which is characterized by a solid state13C NMR spectrum having characteristic peaks at 55.82, 110.13, 120.20 and 162.82 ppm ± 0.2 ppm. A crystalline form of Pirtobrutinib according to Clause 1, or Clause 14 which is characterized by a solid state13C NMR spectrum having the following chemical shift absolute differences from reference peak at 94.91 ppm ± 0.2 ppm: 39.09, 15.22, 25.29 and 67.91sppm ± 0.1 ppm. A crystalline form of Pirtobrutinib according to Clause 1, which is characterized by a solid state13C NMR spectrum substantially as depicted in any of Figures 16, 17 or 18. A crystalline form of Pirtobrutinib according to any of Clauses 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, or 13, which is further characterized by a solid state13C NMR spectrum having characteristic peaks at 55.82, 110.13, 120.20 and 162.82 ppm ± 0.2 ppm. A crystalline form of Pirtobrutinib according to any of Clauses 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 17, which is further characterized by a solid state13C NMR spectrum having the following chemical shift absolute differences from reference peak at 94.91 ppm ± 0.2 ppm: 39.09, 15.22, 25.29 and 67.91sppm ± 0.1 ppm. A crystalline form of Pirtobrutinib according to any of Clauses 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, which is further characterized by a solid state13C NMR spectrum substantially as depicted in any of Figures 16, 17 or 18. A crystalline form of Pirtobrutinib according to Clause 1, which is characterized by the following unit cell data: cell length a 7.25 A cell length b 17.28 A cell length c 34.66 A cell angle alpha 90 ° cell angle_beta 90 ° cell angle gamma 90 ° cell volume 4342.2 A3symmetry space group name_P2 / 2 / 2 / .A crystalline form of Pirtobrutinib according to any of Clause 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, or 19, which is characterized by the following unit cell data: cell length a 7.25 A cell length b 17.28 A cell length c 34.66 A cell angle alpha 90 ° cell angle beta 90 ° cell angle gamma 90 ° cell volume 4342.2 A3symmetry space group name_ 2 / 2 / 2 / . A crystalline form of Pirtobrutinib according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21, which is anhydrous. A crystalline form of Pirtobrutinib according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, which is isolated. A crystalline form of Pirtobrutinib according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23, which is substantially free of any other solid state forms; preferably containing about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Pirtobrutinib. Use of a crystalline form of Pirtobrutinib according to any of Clauses 1 to 24 for the preparation of a pharmaceutical composition and / or pharmaceutical formulation. Use of Pirtobrutinib according to any one of Clauses 1 to 24, for the preparation of other solid state forms of Pirtobrutinib, or Pirtobrutinib solid dispersion or premix, preferably wherein the solid dispersion is a spray-dried dispersion. Crystalline Pirtobrutinib according to any one of Clauses 1 to 24, for use in the preparation of other solid state forms of Pirtobrutinib, or Pirtobrutinib premix, preferably a solid dispersion, and more preferably wherein the solid dispersion is a spray-dried dispersion. A process for preparing a premix or a solid dispersion comprising mixing Pirtobrutinib form 2 according to any one of Clauses 1 to 24, a carrier, and optionally one or more otherpharmaceutically acceptable excipients, and one or more solvents to form a mixture; and removing the solvent(s) from the mixture. A process for preparing a spray dried dispersion comprising mixing Pirtobrutinib form 2 according to any one of Clauses 1 to 24, a carrier, and optionally one or more other pharmaceutically acceptable excipients and one or more solvents to form a mixture and spray-drying the mixture. A process according to Clause 28 or Clause 29, wherein the carrier is a pharmaceutically acceptable carrier which is preferably selected from the group consisting of: polyvinylpyrrolidone (PVP), copovidone (copolymer of 1 -vinyl-2-pyrrolidone and vinyl acetate), polyethylene glycol, hydroxypropylmethyl cellulose (hypromellose, HPMC), or hydroxylpropylmethyl cellulose acetate succinate, HPMCAS); and more particularly wherein the pharmaceutically acceptable carrier is a hydroxypropylmethyl cellulose acetate succinate (HPMCAS). A process according to any of Clause 28, 29 or 31, wherein the solvent comprises one or more solvents, which can be one or more organic or aqueous solvent, preferably wherein the one or more solvents is capable of dissolving Pirtobrutinib and the carrier; optionally wherein the solvent is an aliphatic alcohol (particularly methanol, ethanol, or isopropanol), an ether (particularly diethyl ether or tetrahydrofuran), a ketone (particularly acetone), or an ester (particularly ethylacetate) solvents, or a mixture thereof. A process according to any of Clauses 28, 29, 30, or 31, further comprising blending the premix, solid dispersion, or the spray dried dispersion with one or more pharmaceutically acceptable excipients. A premix, solid dispersion, a spray-dried dispersion, preferably a spray-dried dispersion, which is obtainable by a process according to any of Clauses 28, 29, 30, 31, or 32. A pharmaceutical composition or pharmaceutical formulation comprising crystalline Pirtobrutinib according to any of Clauses 1 to 24, or a premix, solid dispersion, or a spray- dried suspension, preferably a spray-dried dispersion according to Clause 33. A pharmaceutical composition or pharmaceutical formulation comprising crystalline Pirtobrutinib according to any of Clauses 1 to 24, or a premix, solid dispersion, or a spray- dried suspension, preferably a spray-dried dispersion according to Clause 33, and one or more pharmaceutically acceptable excipients.Use of crystalline Pirtobrutinib as defined in any of Clauses 1 to 24, or a premix, a solid dispersion, or a spray-dried dispersion or premix according to Clause 33, for the preparation of a pharmaceutical composition, or pharmaceutical formulation, preferably wherein the pharmaceutical composition or pharmaceutical formulation comprises amorphous Pirtobrutinib. Crystalline Pirtobrutinib according to any of Clauses 1 to 24, or a premix, solid dispersion, or a spray-dried dispersion, preferably a spray-dried dispersion, according to Clause 33, for use in the preparation of a pharmaceutical composition or pharmaceutical formulation, preferably wherein the pharmaceutical composition or pharmaceutical formulation comprises amorphous Pirtobrutinib. A pharmaceutical composition or pharmaceutical formulation comprising crystalline Pirtobrutinib according to any of Clauses 1 to 24; or a premix, solid dispersion, or a spray- dried dispersion according to Clause 33. A process for preparing a pharmaceutical composition or pharmaceutical formulation according to Clause38, comprising combining crystalline Pirtobrutinib according to any of Clause 1 to 24; or premix, solid dispersion, or a spray-dried dispersion, preferably a spray- dried dispersion, according to Clause 33, or a combination thereof, with at least one pharmaceutically acceptable excipient. Crystalline Pirtobrutinib according to any of Clauses 1 to 24; or a premix, solid dispersion, or spray-dried dispersion, preferably a spray-dried dispersion, according to Clause 33, or a pharmaceutical composition or pharmaceutical formulation according to Clause 38, for use as a medicament. Crystalline Pirtobrutinib according to any of Clauses 1 to 24; or a premix, solid dispersion, or spray-dried dispersion, preferably a spray-dried dispersion, according to Clause 33, or a pharmaceutical composition or pharmaceutical formulation according to Clause 38, for use in the treatment of B-cell malignancies, preferably B-cell lymphomas and B-cell leukemias; preferably for use in the treatment of relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, Richter’s transformation (Richter’s syndrome), and marginal zone lymphoma; and more preferably relapsed or refractory mantle celllymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, and marginal zone lymphoma. A method of treating B-cell malignancies, preferably B-cell lymphomas and B-cell leukemias; preferably treating: relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, Richter’s transformation (Richter’s syndrome), and marginal zone lymphoma; and more preferably treating: relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, and marginal zone lymphoma: comprising administering a therapeutically effective amount of crystalline Pirtobrutinib according to any of Clauses 1 to 24, or a premix, solid dispersion, or spray-dried dispersion, preferably a spray-dried dispersion according to Clause 33, or the pharmaceutical composition according to Clause 38, to a subject in need of the treatment. Crystalline Pirtobrutinib according to any of Clauses 1 to 24, or a premix, solid dispersion, or spray-dried dispersion, preferably a spray-dried dispersion according to Clause 33, or the pharmaceutical composition according to Clause 38; for use in the manufacture of a medicament for treating: B-cell malignancies, preferably B-cell lymphomas and B-cell leukemias; preferably for treating: relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, Richter’s transformation (Richter’s syndrome), and marginal zone lymphoma; and more preferably for treating: relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, and marginal zone lymphoma.

Claims

CLAIMS1. A crystalline form of Pirtobrutinib designated form 2, which is characterized by data selected from:(a) an X-ray powder diffraction pattern having peaks at 11.4, 16.7 and 25.1 degrees 2- theta ± 0.2 degrees 2-theta;(b) an X-ray powder diffraction pattern substantially as depicted in Figure 5;(c) a solid state13C NMR spectrum having characteristic peaks at 55.82, 110.13, 120.20 and 162.82 ppm ± 0.2 ppm;(d) a solid state13C NMR spectrum having the following chemical shift absolute differences from reference peak at 94.91 ppm ± 0.2 ppm: 39.09, 15.22, 25.29 and 67.91 ppm ± 0.1 ppm;(e) a solid state13C NMR spectrum substantially as depicted in Figure 16, 17 or 18;(f) the following unit cell data: cell length a 7.25 A cell length b 17.28 A cell length c 34.66 A cell angle alpha 90 ° cell angle beta 90 ° cell angle gamma 90 ° cell volume 4342.2 A3symmetry space group name 2 / 2 / 2y; and(g) combination of any two or more of (a)-(f).

2. A crystalline form of Pirtobrutinib according to Claim 1, which is characterized by an X- ray powder diffraction pattern having peaks at 11.4, 16.7 and 25.1 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one or two peaks selected from 10.2 and 21.1 degrees 2-theta ± 0.2 degrees 2-theta.

3. A crystalline form of Pirtobrutinib according to Claim 1 or Claim 2, which is characterized by an X-ray powder diffraction pattern having peaks at 10.2, 11.4, 16.7, 21.1 and 25.1 degrees 2-theta ± 0.2 degrees 2-theta.

4. A crystalline form of Pirtobrutinib according to any of Claims 1, 2 or 3, which is characterized by an X-ray powder diffraction pattern having peaks at 10.2, 11.4, 16.7, 21.1 and 25.1 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks selected from 14.4, 15.3, 18.4, 22.0 and 24.5 degrees 2-theta ± 0.2 degrees 2-theta.

5. A crystalline form of Pirtobrutinib according to any of Claims 1, 2, 3, or 4, which is characterized by an X-ray powder diffraction pattern having peaks at 10.2, 11.4, 14.4, 15.3, 16.7, 18.4, 21.1, 22.0, 24.5 and 25.1 degrees 2-theta ± 0.2 degrees 2-theta; or an X-ray powder diffraction pattern substantially as depicted in Figure 5.

6. A crystalline form of Pirtobrutinib according to any of Claims 1, 2, 3, 4, or 5, which is anhydrous.

7. A crystalline form of Pirtobrutinib according to any of Claims 1, 2, 3, 4, 5 or 6, which is isolated.

8. A crystalline form of Pirtobrutinib according to any of Claims 1, 2, 3, 4, 5, 6, or 7, which is substantially free of any other solid state forms; preferably containing about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Pirtobrutinib.

9. Use of a crystalline form of Pirtobrutinib according to any of Claims 1 to 8, for the preparation of a pharmaceutical composition and / or pharmaceutical formulation.10 Use of a crystalline form of Pirtobrutinib according to any of claims 1 to 8, for the preparation of other solid state forms of Pirtobrutinib, or Pirtobrutinib solid dispersion or premix, preferably wherein the solid dispersion is a spray-dried dispersion.

11. Crystalline form 2 of Pirtobrutinib according to any of claims 1-8, for use in the preparation of other solid state forms of Pirtobrutinib, or Pirtobrutinib solid dispersion or premix, preferably wherein the solid dispersion is a spray-dried dispersion.

12. A process for preparing a premix or a solid dispersion comprising mixing Pirtobrutinib form 2 according to any one of claims 1-8, a carrier, and optionally one or more other pharmaceutically acceptable excipients, and one or more solvents to form a mixture; and removing the solvent(s) from the mixture.

13. A process according to claim 12, for preparing a spray dried dispersion comprising mixing Pirtobrutinib form 2 according to any one of claims 1-8, a carrier, and optionallyone or more other pharmaceutically acceptable excipients, and one or more solvents to form a mixture; and spray-drying the mixture.

14. A process according to claim 12 or claim 13, further comprising blending the premix, solid dispersion or the spray dried dispersion with one or more pharmaceutically acceptable excipients.

15. A premix, solid dispersion, or spray-dried dispersion, preferably a spray-dried dispersion, which is obtainable by a process according to any of Claims 12, 13 or 14.

16. A pharmaceutical composition or formulation comprising a crystalline form of Pirtobrutinib according to any of Claims 1-8, or a premix, solid dispersion, or a spray- dried dispersion; preferably a spray-dried dispersion, according to claim 15.

17. A pharmaceutical formulation comprising a crystalline form of Pirtobrutinib according to any of Claims 1-8, or a premix, a solid dispersion, or a spray-dried dispersion, preferably a spray-dried dispersion, according to claim 15, and one or more pharmaceutically acceptable excipients.

18. Use of crystalline Pirtobrutinib as defined in any of claims 1-8 or a premix, solid dispersion, or a spray-dried suspension, preferably a spray-dried dispersion, according to claim 15, for the preparation of a pharmaceutical composition, preferably wherein the pharmaceutical composition comprises amorphous Pirtobrutinib.

19. Crystalline Pirtobrutinib according to any one of claims 1-8, or a premix, solid dispersion, or a spray-dried dispersion, preferably a spray-dried dispersion, according to claim 15, for use in the preparation of a pharmaceutical composition, preferably wherein the pharmaceutical composition comprises amorphous Pirtobrutinib.

20. A pharmaceutical composition or pharmaceutical formulation comprising crystalline Pirtobrutinib according to any of claims 1-8, or a premix, solid dispersion, or spray-dried dispersion, preferably a spray-dried dispersion, according to claim 15.

21. A process for preparation of a pharmaceutical composition or pharmaceutical formulation according to claim 20, comprising combining crystalline Pirtobrutinib according to any one of claims 1-8, or a premix, solid dispersion, or spray-dried dispersion, preferably a spray-dried dispersion, according to claim 15, with at least one pharmaceutically acceptable excipient.

22. Crystalline Pirtobrutinib according to any one of claims 1-8, or a premix, solid dispersion, or spray-dried dispersion, preferably a spray-dried dispersion, according to claim 15, or the pharmaceutical composition or pharmaceutical formulation according to claim 20, for use as a medicament.

23. Crystalline Pirtobrutinib according to any one of claims 1-8, or a premix, solid dispersion, or spray-dried dispersion, preferably a spray-dried dispersion, to claim 15, or the pharmaceutical composition or pharmaceutical formulation according to claim 20, for use in the treatment of B-cell malignancies, preferably B-cell lymphomas and B-cell leukemias; preferably for use in the treatment of relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, Richter’s transformation (Richter’s syndrome), and marginal zone lymphoma; and more preferably relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, and marginal zone lymphoma.

24. A method of treating B-cell malignancies, preferably B-cell lymphomas and B-cell leukemias; preferably treating: relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, Richter’s transformation (Richter’s syndrome), and marginal zone lymphoma; and more preferably treating: relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, and marginal zone lymphoma: comprising administering a therapeutically effective amount of crystalline Pirtobrutinib according to any of claims 1 to 8, or a premix, solid dispersion, or spray-dried dispersion, preferably a spray-dried dispersion according to claim 15, or the pharmaceutical composition or pharmaceutical formulation according to claim 20, to a subject in need of the treatment.

25. A crystalline form of Pirtobrutinib according to any of claims 1-8, or a premix, solid dispersion, or spray-dried dispersion, preferably a spray-dried dispersion, according to claim 15, or a pharmaceutical composition or pharmaceutical formulation according to claim 20, for use in the manufacture of a medicament for the treatment of: B-cell malignancies, preferably B-cell lymphomas and B-cell leukemias; preferably for treating: relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia,small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, Richter’s transformation (Richter’s syndrome), and marginal zone lymphoma; and more preferably for treating: relapsed or refractory mantle cell lymphoma (MCL), chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, and marginal zone lymphoma.

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