WO2024121805A1

WO2024121805A1 - Solid state forms of zipalertinib and process for preparation thereof

Info

Publication number: WO2024121805A1
Application number: PCT/IB2023/062398
Authority: WO
Inventors: Pavel KOLESA; Jana ROMANOVÁ; Alexandr Jegorov
Original assignee: Assia Chemical Industries Ltd.
Priority date: 2022-12-08
Filing date: 2023-12-08
Publication date: 2024-06-13

Abstract

The present disclosure encompasses solid state forms of Zipalertinib, and of Zipalertinib complexes, in embodiments crystalline polymorphs of Zipalertinib and of Zipalertinib complexes, processes for preparation thereof, and pharmaceutical compositions thereof.

Description

SOLID STATE FORMS OF ZIPALERTINIB AND PROCESS FOR PREPARATION THEREOF

FIELD OF THE DISCLOSURE

[0001] The present disclosure encompasses solid state forms of Zipalertinib, and of Zipalertinib complexes, in embodiments crystalline polymorphs of Zipalertinib and of Zipalertinib complexes, processes for preparation thereof, and pharmaceutical compositions thereof.

BACKGROUND OF THE DISCLOSURE

[0002] Zipalertinib, N-[(8S)-4-Amino-8,9-dihydro-6-methyl-5-(3-quinolinyl)pyrimido[5,4- b]indolizin-8-yl]-2-propenamide, has the following structure:

[0003] Zipalertinib is a reversible EGFR inhibitor developed for the treatment of Non-Small Cell Lung Cancer.

[0004] The compound is described in International Publication No. WO 2015025936.

[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 solid state (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 salts, 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 salts and solid state forms (including solvated forms) of Zipalertinib.

SUMMARY OF THE DISCLOSURE

[0008] The present disclosure provides crystalline polymorphs of Zipalertinib and of Zipalertinib complexes, such as Zipalertinib salts and co-crystals; processes for preparation thereof, and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other solid state forms of Zipalertinib, other Zipalertinib salts and co-crystals and their solid state forms.

[0009] The present disclosure also provides uses of the said solid state forms of Zipalertinib and of Zipalertinib complexes in the preparation of other solid state forms of Zipalertinib or other salts or co-crystals and their solid state forms thereof. [0010] The present disclosure provides crystalline polymorphs of Zipalertinib and of Zipalertinib complexes for use in medicine, including for the treatment of cancer, particularly Non-Small Cell Lung Cancer (“NSCLC”).

[0011] The present disclosure also encompasses the use of crystalline polymorphs of Zipalertinib and of Zipalertinib complexes of the present disclosure for the preparation of pharmaceutical compositions and/or formulations, particularly pharmaceutical compositions or formulations for oral administration.

[0012] In another aspect, the present disclosure provides pharmaceutical compositions comprising crystalline polymorphs of Zipalertinib and of Zipalertinib complexes according to the present disclosure. Pharmaceutical compositions according to any aspect of the present disclosure may include oral dosage forms.

[0013] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorphs of Zipalertinib and of Zipalertinib complexes with at least one pharmaceutically acceptable excipient. Particularly, the pharmaceutical compositions may comprise pharmaceutically acceptable excipient suitable for preparing an oral dosage form.

[0014] The crystalline polymorph of Zipalertinib and of Zipalertinib complexes as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorph of Zipalertinib and of Zipalertinib complexes may be used as medicaments, such as for treatment of cancer, particularly NSCLC.

[0015] The present disclosure also provides methods of treating cancer, particularly NSCLC, by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Zipalertinib and of Zipalertinib complexes of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from cancer, particularly NSCLC, or otherwise in need of the treatment.

[0016] The present disclosure also provides uses of crystalline polymorphs of Zipalertinib and of Zipalertinib complexes of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g., cancer, particularly NSCLC. The medicament may be administered as an intranasal dosage form, or may be administered as an oral dosage form. [0017] According to any aspect or embodiment of the present disclosure, pharmaceutical compositions or formulations for the treatment of cancer, particularly NSCLC, are preferably in the form of oral dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of crystalline Zipalertinib Form 1.

[0019] Figure 2 shows a characteristic X-ray powder diffraction pattern (XRPD) of amorphous Zipalertinib.

[0020] Figure 3 shows a characteristic XRPD of crystalline Zipalertinib-succinic acid Form Cl.

[0021] Figure 4 shows a characteristic XRPD of crystalline Zipalertinib-succinic acid Form C3.

[0022] Figure 5 shows a characteristic XRPD of crystalline Zipalertinib Form 2.

[0023] Figure 6a shows a characteristic solid-state ¹³C NMR spectrum of Zipalertinib Form 1 (at the range from 200-0 ppm).

[0024] Figure 6b shows a characteristic solid-state ¹³C NMR spectrum of Zipalertinib Form 1 (at the range from 200-100 ppm).

[0025] Figure 6c shows a characteristic solid-state ¹³C NMR spectrum of Zipalertinib Form 1 (at the range from 100-0 ppm).

[0026] Figure 7a shows a characteristic solid-state ¹³C NMR spectrum of Zipalertinib Form 2 (at the range from 200-0 ppm).

[0027] Figure 7b shows a characteristic solid-state ¹³C NMR spectrum of Zipalertinib Form 2 (at the range from 200-100 ppm).

[0028] Figure 7c shows a characteristic solid-state ¹³C NMR spectrum of Zipalertinib Form 2 (at the range from 100-0 ppm).

[0029] Figure 8a shows a characteristic solid-state ¹³C NMR spectrum of crystalline Zipalertinib-succinic acid Form Cl (at the range from 200-0 ppm).

[0030] Figure 8b shows a characteristic solid-state ¹³C NMR spectrum of crystalline Zipalertinib-succinic acid Form Cl (at the range from 200-100 ppm).

[0031] Figure 8c shows a characteristic solid-state ¹³C NMR spectrum of crystalline Zipalertinib-succinic acid Form Cl (at the range from 100-0 ppm). [0032] Figure 9 shows a characteristic XRPD of crystalline Zipalertinib-adipic acid Form C6.

[0033] Figure 10a shows a characteristic solid-state ¹³C NMR spectrum of crystalline Zipalertinib- adipic acid Form C6 (at the range from 200-0 ppm).

[0034] Figure 10b shows a characteristic solid-state ¹³C NMR spectrum of crystalline Zipalertinib- adipic acid Form C6 (at the range from 200-100 ppm).

[0035] Figure 10c shows a characteristic solid-state ¹³C NMR spectrum of crystalline Zipalertinib- adipic acid Form C6 (at the range from 100-0 ppm).

[0036] Figure 11 shows a characteristic XRPD of crystalline Zipalertinib-fumaric acid Form C2.

[0037] Figure 12 shows a characteristic XRPD of crystalline Zipalertinib Form 4.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0038] The present disclosure encompasses solid state forms of Zipalertinib and of Zipalertinib complexes, including crystalline polymorphs of Zipalertinib and of Zipalertinib complexes, processes for preparation thereof, and pharmaceutical compositions thereof.

[0039] Solid state properties of Zipalertinib and of Zipalertinib complexes and crystalline polymorphs thereof can be influenced by controlling the conditions under which Zipalertinib and crystalline polymorphs thereof are obtained in solid form.

[0040] 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. Thus, a crystalline polymorph of Zipalertinib or of Zipalertinib complexes 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 Zipalertinib or of Zipalertinib complexes. In some embodiments of the disclosure, the described crystalline polymorph of Zipalertinib or of Zipalertinib complexes 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 Zipalertinib or of Zipalertinib complexes.

[0041] A compound may be referred to herein as chemically pure or purified compound or as substantially free of any other compounds. As used herein in this context, the expression "substantially free of any other compounds " will be understood to mean that the pure compound 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 compound as measured, for example, by HPLC. Thus, pure or purified Zipalertinib or of Zipalertinib complexes described herein as substantially free of any compounds 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 Zipalertinib or of Zipalertinib complexes. In some embodiments of the disclosure, the described pure or purified Zipalertinib or of Zipalertinib complexes 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 compounds.

[0042] In specific embodiments, the above described pure or purified Zipalertinib or of Zipalertinib complexes may relate to enantiomeric purity, i.e. pure or purified Zipalertinib or Zipalertinib complex refers to Zipalertinib that is substantially free of enantiomers of Zipalertinib.

[0043] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of Zipalertinib or of Zipalertinib complexes of the present disclosure may have advantageous properties 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.

[0044] 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 Zipalertinib 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 Zipalertinib characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0045] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline forms of Zipalertinib, relates to a crystalline form of Zipalertinib, which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, unless otherwise indicated, an “anhydrous” form would generally not contain more than 1% (w/w), of either water or organic solvents as measured for example by TGA. [0046] 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 is often referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0047] Co-Crystal" or "Co-crystal" as used herein is defined as a crystalline material including two or more molecules in the same crystalline lattice and associated by non-ionic and non-covalent bonds. In some embodiments, the co-crystal includes two molecules which are in natural state.

[0048] As used herein, crystalline Zipalertinib succinic acid or crystalline Zipalertinib succinic acid complex is a distinct molecular species. Crystalline Zipalertinib succinic acid may be a co-crystal of Zipalertinib and succinic acid. Alternatively crystalline Zipalertinib and succinic acid may be a salt, i.e. Zipalertinib succinate. [0049] As used herein, crystalline Zipalertinib adipic acid or crystalline Zipalertinib adipic acid complex is a distinct molecular species. Crystalline Zipalertinib adipic acid may be a cocrystal of Zipalertinib and adipic acid. Alternatively crystalline Zipalertinib and adipic acid may be a salt, i.e., Zipalertinib adipate. In some embodiments the molar ratio between the active pharmaceutical ingredient, Zipalertinib, and the conformer, adipic acid, is between 1: 1.5 and 1.5: 1, preferably between 1: 1.25 and 1.25: 1, in other embodiments about 1: 1.

[0050] As used herein, the term "isolated" in reference to crystalline polymorph of Zipalertinib of the present disclosure corresponds to a crystalline polymorph of Zipalertinib or of Zipalertinib complex that is physically separated from the reaction mixture in which it is formed. [0051] As used herein, unless stated otherwise, the XRPD measurements are taken using copper Ka radiation wavelength 1.54187 A. XRPD peaks reported herein are measured using CuK a radiation, X = 1.54187 A, typically at a temperature of 25 ± 3°C.

[0052] As used herein, unless stated otherwise, solid state ¹³C NMR data is obtained using ¹³C CP/MAS NMR method. Particularly, as used herein, unless stated otherwise, the ¹³C CP/MAS NMR reported herein are measured at 700 MHz, preferably at a temperature of at 293 K ± 3°C.

[0053] 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., the room 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.

[0054] 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. [0055] 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.

[0056] 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.

[0057] As used herein and unless indicated otherwise, the term "ambient conditions" refer to atmospheric pressure and a temperature of 22-24°C.

[0058] The present disclosure amorphous Zipalertinib. A characteristic XRPD pattern of amorphous Zipalertinib is shown in Figure 2.

[0059] In some embodiments, the present disclosure includes a process for preparation of amorphous Zipalertinib. The process comprises precipitating amorphous Zipalertinib from a mixture comprising 2-butanol and n-heptane. Typically, the process comprises dissolving Zipalertinib in 2-butanol and adding n-heptane. The dissolution is aided by heating, for example to a temperature of about 80°C to about 100°C, preferably about 95°C. After a clear solution is formed, it may be cooled down, preferably at a cooling rate 1 °C/min. n-heptane is typically added to the cooled solution, thus forming a suspension, from which the amorphous can be isolated. Preferably, the 2-butanol n-heptane suspension is further cooled, for example to a temperature of about 0°C. The amorphous can be isolated, for example by filtration, and can be dried, for example by vacuum drying, preferably at room temperature. The amorphous can be used to prepare crystalline forms of Zipalertinib, for example crystalline Zipalertinib form 1, which is described herein below.

[0060] The present disclosure includes a crystalline polymorph of Zipalertinib, designated Form 1. Crystalline Form 1 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 7.9, 12.0, 15.8, 17.5 and 19.3 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 1; or by combinations thereof. Crystalline Form 1 may be further by an XRPD pattern having characteristic peaks at 7.9, 12.0, 15.8, 17.5 and 19.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks at 14.9, 21.7, 22.3, 24.0 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta. [0061] Crystalline Form 1 may be described by an XRPD pattern having characteristic peaks at 7.9, 12.0, 14.9, 15.8, 17.5, 19.3, 21.7, 22.3, 24.0 and 25.3 degrees 2-theta ± 0.2 degrees 2- theta. According to any aspect or embodiment, crystalline Form 1 of Zipalertinib may be further characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at: 3.0 to 6.6 degrees 2-theta ± 0.2 degrees 2- theta. Alternatively or additionally, according to aspect or embodiment of the present disclosure, crystalline Form 1 of Zipalertinib may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments herein, and wherein the X-ray powder diffraction pattern also has an absence of peaks at: 8.4 to 9.8 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to aspect or embodiment of the present disclosure, crystalline Form 1 of Zipalertinib may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments herein, and also having an absence of peaks at: 12.5 to 13.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0062] Alternatively, crystalline Form 1 of Zipalertinib may be characterized by data selected from one or more of the following: a solid state ¹³C NMR spectrum with characteristic peaks at 164.7, 158.4, 154.4, 121.0 and 109.0 ppm ± 0.2 ppm; a solid state ¹³C NMR spectrum as depicted in any of figures 6a, 6b or 6c; and combinations thereof. Crystalline Form 1 of Zipalertinib may be further characterized by a solid state ¹³C NMR spectrum having the following chemical shift absolute differences from reference peak at 103.7 ppm ± 1 ppm: 61.1,

54.7, 50.8, 17.3 and 5.3 ppm ± 0.1 ppm; a solid state ¹³C NMR having the following peak list:

164.7, 163.2, 158.4, 154.4, 152.2, 151.3, 146.5, 136.7, 132.3, 130.6, 128.7, 127.7, 126.7, 125.8, 121.0, 109.0 and 103.7 ppm ± 0.2 ppm; and combinations thereof.

[0063] According to any aspect or embodiment of the present disclosure, crystalline Form 1 of Zipalertinib is preferably isolated.

[0064] In some embodiments, Crystalline Form 1 of Zipalertinib is anhydrous form. Typically, the water content is of less than 0.5%, as determined for example by TGA (at a temperature range of 30°C-100°C).

[0065] Crystalline Form 1 of Zipalertinib may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.9, 12.0, 15.8, 17.5 and 19.3 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1, and combinations thereof. [0066] According to any aspect or embodiment of the disclosure, crystalline Form 1 of Zipalertinib may be polymorphically pure or may be substantially free of any other solid state forms of Zipalertinib.

[0067] The present disclosure further includes a crystalline polymorph of Zipalertinib, designated Form 2. Crystalline Form 2 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 7.8, 12.4, 13.0, 17.8, 19.3 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern showing no peaks (peak absence) at the areas of 14.9 - 15.4 degrees 2-theta, 20.4 - 21.2 degrees 2-theta and 22.2 - 22.4 degrees 2-theta; or by an XRPD pattern as depicted in Figure 5; or by combinations thereof.

[0068] Crystalline Form 2 may be described by an XRPD pattern having characteristic peaks at 7.8, 12.4, 13.0, 17.8, 19.3 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta and also not having any peaks (peak absence) at the areas of 14.9 - 15.4 degrees 2-theta, 20.4 - 21.2 degrees 2-theta and 22.2 - 22.4 degrees 2-theta.

[0069] According to any aspect or embodiment, crystalline Form 2 of Zipalertinib may be further characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at: 3.0 to 7.2 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to aspect or embodiment of the present disclosure, crystalline Form 2 of Zipalertinib may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments herein, and wherein the X-ray powder diffraction pattern also has an absence of peaks at: 8.4 to 9.2 degrees 2-theta ± 0.2 degrees 2- theta.

[0070] Alternatively, crystalline Form 2 of Zipalertinib may be characterized by data selected from one or more of the following: a solid state ¹³C NMR spectrum with characteristic peaks at 164.2, 146.1, 136.5, 129.0 and 120.9 ppm ± 0.2 ppm; a solid state ¹³C NMR spectrum as depicted in any of figures 7a, 7b or 7c; and combinations thereof. Crystalline Form 2 of Zipalertinib may be further characterized by a solid state ¹³C NMR spectrum having the following chemical shift absolute differences from reference peak at 103.5 ppm ± 1 ppm: 60.7, 42.6, 33.0, 25.5 and 17.4 ppm ± 0.1 ppm; a solid state ¹³C NMR having the following peak list:

164.2, 163.3, 158.3, 154.7, 154.2, 152.2, 146.1, 136.5, 132.4, 130.6, 129.0, 126.7, 125.7, 120.9,

109.2, 108.5 and 103.5 ppm ± 0.2 ppm; and combinations thereof. [0071] According to any aspect or embodiment of the present disclosure, crystalline Form 2 of Zipalertinib is preferably isolated.

[0072] In some embodiments, Crystalline Form 2 of Zipalertinib is anhydrous form.

Typically, the water content is of less than 0.5%, as determined for example by TGA (at a temperature range of 30°C-100°C).

[0073] Crystalline Form 2 of Zipalertinib may be characterized by each of the above characteristics alone/or by all possible combinations.

[0074] The present disclosure further includes a crystalline polymorph of Zipalertinib, designated Form 4. Crystalline Form 4 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 5.3, 15.8, 16.6, 19.7 and 22.0 degrees 2-theta ± 0.2 degrees 2-theta or by an XRPD pattern as depicted in Figure 12; or by combinations thereof.

[0075] Crystalline Form 4 may be described by an XRPD pattern having characteristic peaks at 5.3, 15.8, 16.6, 19.7 and 22.0 degrees 2-theta ± 0.2 degrees 2-theta and also having any one, two, three, four or five additional peaks at 9.1, 10.5, 13.8, 26.7 and 27.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0076] Crystalline Form 4 may be described by an XRPD pattern having characteristic peaks at 5.3, 9.1, 10.5, 13.8, 15.8, 16.6, 19.7, 22.0, 26.7 and 27.8 degrees 2-theta ± 0.2 degrees 2-theta. [0077] According to any aspect or embodiment, crystalline Form 4 of Zipalertinib may be further characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at: 3.0 to 4.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0078] According to any aspect or embodiment of the present disclosure, crystalline Form 4 of Zipalertinib is preferably isolated.

[0079] Crystalline Form 4 of Zipalertinib may be characterized by each of the above characteristics alone/or by all possible combinations.

[0080] According to any aspect or embodiment of the disclosure, crystalline Form 4 of Zipalertinib may be polymorphically pure or may be substantially free of any other solid state forms of Zipalertinib.

[0081] The present disclosure includes a crystalline Zipalertinib and succinic acid complex. [0082] Crystalline Zipalertinib succinic acid complex may be a co-crystal of Zipalertinib and succinic acid. Alternatively, crystalline Zipalertinib succinic acid may be a salt, i.e., Zipalertinib succinate. In preferred embodiments, Crystalline Zipalertinib succinic acid complex is a cocrystal of Zipalertinib and succinic acid.

[0083] The present disclosure further includes a crystalline polymorph of Zipalertinib succinic acid, designated form Cl.

[0084] In some embodiments the molar ratio between the active pharmaceutical ingredient, Zipalertinib, and the co-former, succinic acid in crystalline form Cl, is between 2: 1.5 and 2.5: 1, preferably between 2: 1.25 and 2.25: 1, in other embodiments about 2: 1.

[0085] Crystalline Zipalertinib succinic acid form Cl may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 7.5, 8.5, 9.3, 11.7 and 14.5 degrees 2-theta ± 0.2 degrees 2-theta, a XRPD, or by an XRPD pattern as depicted in Figure 3; or by combinations thereof. Crystalline Zipalertinib succinic acid Form Cl may be further by an XRPD pattern having characteristic peaks at 7.5, 8.5, 9.3, 11.7 and 14.5 degrees 2- theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks at 13.6, 15.9, 17.1, 17.8 and 21.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0086] Crystalline Zipalertinib succinic acid Form Cl may be described by an XRPD pattern having characteristic peaks at 7.5, 8.5, 9.3, 11.7, 13.6, 14.5, 15.9, 17.1, 17.8 and 21.1 degrees 2- theta ± 0.2 degrees 2-theta.

[0087] According to any aspect or embodiment, crystalline Form Cl of Zipalertinib succinic acid may be further characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at: 3.0 to 4.3 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to aspect or embodiment of the present disclosure, crystalline Form Cl of Zipalertinib succinic acid may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments herein, and wherein the X-ray powder diffraction pattern also has an absence of peaks at: 4.9 to 7.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0088] Alternatively, crystalline Zipalertinib succinic acid Form Cl may be characterized by data selected from one or more of the following: a solid state ¹³C NMR spectrum with characteristic peaks at 179.9, 165.6, 156.2, 146.8 and 126.5 ppm ± 0.2 ppm; a solid state ¹³C NMR spectrum as depicted in any of figures 8a, 8b or 8c; and combinations thereof. Crystalline Zipalertinib succinic acid Form Cl may be further characterized by a solid state ¹³C NMR spectrum having the following chemical shift absolute differences from reference peak at 102.82 ppm ± 1 ppm: 77.1, 62.7, 53.3, 44.0 and 23.7 ppm ± 0.1 ppm; a solid state ¹³C NMR having the following peak list: 179.9, 165.6, 156.2, 150.5, 149.8, 146.8, 133.8, 129.3 and 126.5 ppm ± 0.2 ppm; and combinations thereof.

[0089] According to any aspect or embodiment of the present disclosure, crystalline Zipalertinib succinic acid Form Cl is preferably isolated.

[0090] Crystalline Form Cl of Zipalertinib succinic acid may be an anhydrous form. Typically, the water content in crystalline form Cl of Zipalertinib succinic acid is not more than 1% (w/w), or not more than 0.5% (w/w), preferably not more than 0.3% (w/w), as determined by TGA.

[0091] Crystalline Form Cl of Zipalertinib succinic acid may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.5, 8.5, 9.3, 11.7 and 14.5 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 3, and combinations thereof.

[0092] According to any aspect or embodiment of the disclosure, crystalline Form Cl of Zipalertinib succinic acid may be polymorphically pure or may be substantially free of any other solid state forms of Zipalertinib succinic acid.

[0093] The present disclosure further includes a crystalline polymorph of Zipalertinib succinic acid, designated form C3. Crystalline Zipalertinib succinic acid form C3 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 6.9, 14.8, 21.2, 23.7 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 4; or by combinations thereof. Crystalline Zipalertinib succinic acid Form C3 may be further by an XRPD pattern having characteristic peaks at 6.9, 14.8, 21.2, 23.7 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks at 11.1, 19.4, 20.4, 22.9, and 27.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0094] Crystalline Zipalertinib succinic acid Form C3 may be described by an XRPD pattern having characteristic peaks at 6.9, 11.1, 14.8, 19.4, 20.4, 21.2, 22.9, 23.7, 25.3 and 27.7 degrees 2-theta ± 0.2 degrees 2-theta. [0095] According to any aspect or embodiment, crystalline Form C3 of Zipalertinib succinic acid may be further characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at: 3.0 to 6.0 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to aspect or embodiment of the present disclosure, crystalline Form C3 of Zipalertinib succinic acid may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments herein, and wherein the X-ray powder diffraction pattern also has an absence of peaks at: 9.3 to 10.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0096] According to any aspect or embodiment of the present disclosure, crystalline Zipalertinib succinic acid Form C3 is preferably isolated.

[0097] Crystalline Form C3 of Zipalertinib succinic acid may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 6.9, 14.8, 21.2, 23.7 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 4, and combinations thereof.

[0098] According to any aspect or embodiment of the disclosure, crystalline Form C3 of Zipalertinib succinic acid may be polymorphically pure or may be substantially free of any other solid state forms of Zipalertinib succinic acid.

[0099] The present disclosure includes a crystalline Zipalertinib and fumaric acid or crystalline Zipalertinib and fumaric acid complex.

[00100] Crystalline Zipalertinib fumaric acid or crystalline Zipalertinib and fumaric acid complex may be a co-crystal of Zipalertinib and fumaric acid. Alternatively, crystalline Zipalertinib fumaric acid may be a salt, i.e., Zipalertinib fumarate.

[00101] The present disclosure further includes a crystalline polymorph of Zipalertinib fumaric acid, designated form C2. Crystalline Zipalertinib fumaric acid form C2 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 5.5, 6.5, 8.8, 13.8 and 25.7 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 11; or by combinations thereof. Crystalline Zipalertinib fumaric acid Form C2 may be further by an XRPD pattern having characteristic peaks at 5.5, 6.5, 8.8, 13.8 and 25.7 degrees 2-theta ± 0.2 degrees 2-theta, and any one, two, three, four or five additional peaks at 11.1, 18.4, 20.4, 27.1 and 28.0 degrees 2-theta ± 0.2 degrees 2-theta. [00102] Crystalline Zipalertinib fumaric acid Form C2 may be described by an XRPD pattern having characteristic peaks at 5.5, 6.5, 8.8, 11.1, 13.8, 18.4, 20.4, 25.7, 27.1 and 28.0 degrees 2- theta ± 0.2 degrees 2-theta.

[00103] According to any aspect or embodiment, crystalline Form C2 of Zipalertinib fumaric acid may be further characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at: 3.0 to 4.0 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to aspect or embodiment of the present disclosure, crystalline Form C2 of Zipalertinib fumaric acid may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments herein, and wherein the X-ray powder diffraction pattern also has an absence of peaks at: 7.2 to 8.2 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to aspect or embodiment of the present disclosure, crystalline Form C2 of Zipalertinib fumaric acid may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments herein, and wherein the X-ray powder diffraction pattern also has an absence of peaks at: 9.5 to 10.2 degrees 2-theta ± 0.2 degrees 2-theta.

[00104] According to any aspect or embodiment of the present disclosure, crystalline Zipalertinib fumaric acid Form C2 is preferably isolated.

[00105] Crystalline Form C2 of Zipalertinib fumaric acid may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 5.5, 6.5, 8.8, 13.8 and 25.7 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 11, and combinations thereof.

[00106] According to any aspect or embodiment of the disclosure, crystalline Form C2 of Zipalertinib fumaric acid may be polymorphically pure or may be substantially free of any other solid state forms of Zipalertinib fumaric acid.

[00107] The present disclosure includes a crystalline Zipalertinib and adipic acid complex. [00108] Crystalline Zipalertinib adipic acid complex may be a co-crystal of Zipalertinib and adipic acid. Alternatively, crystalline Zipalertinib adipic acid may be a salt, i.e., Zipalertinib adipate. . In preferred embodiments, crystalline Zipalertinib adipic acid complex is a co-crystal of Zipalertinib and adipic acid.

[00109] The present disclosure further includes a crystalline polymorph of Zipalertinib adipic acid, designated form C6. Crystalline Zipalertinib adipic acid form C6 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 5.3, 5.9, 11.9, 14.3 and 17.8 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 9; or by combinations thereof. Crystalline Zipalertinib adipic acid Form C6 may be further by an XRPD pattern having characteristic peaks at 5.3, 5.9, 11.9, 14.3 and 17.8 degrees 2- theta ± 0.2 degrees 2-theta, and any one, two, three, four or five additional peaks at 7.5, 10.9, 13.3, 15.9 and 16.8 degrees 2-theta ± 0.2 degrees 2-theta.

[00110] Crystalline Zipalertinib adipic acid Form C6 may be described by an XRPD pattern having characteristic peaks at 5.3, 5.9, 7.5, 10.9, 11.9, 13.3, 14.3, 15.9, 16.8 and 17.8 degrees 2- theta ± 0.2 degrees 2-theta.

[00111] According to any aspect or embodiment, crystalline Form C6 of Zipalertinib adipic acid may be further characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at: 3.0 to 4.3 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to aspect or embodiment of the present disclosure, crystalline Form C6 of Zipalertinib adipic acid may be characterized by an X- ray powder diffraction pattern as described in any of the embodiments herein, and wherein the X-ray powder diffraction pattern also has an absence of peaks at: 6.5 to 6.8 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to aspect or embodiment of the present disclosure, crystalline Form C6 of Zipalertinib adipic acid may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments herein, and wherein the X-ray powder diffraction pattern also has an absence of peaks at: 8.0 to 9.2 degrees 2-theta ± 0.2 degrees 2-theta.

[00112] Alternatively, crystalline Zipalertinib adipic acid Form C6 may be characterized by data selected from one or more of the following: a solid state ¹³C NMR spectrum with characteristic peaks at 178.8, 174.1, 166.5, 156.7 and 107.9 ppm ± 0.2 ppm; a solid state ¹³C NMR spectrum as depicted in any of figures 10a, 10b or 10c; and combinations thereof. Crystalline Zipalertinib adipic acid Form C6 may be further characterized by a solid state ¹³C NMR spectrum having the following chemical shift absolute differences from reference peak at 101.8 ppm ± 1 ppm: 77.0, 72.3, 64.7, 54.9 and 6.1 ppm ± 0.1 ppm; a solid state ¹³C NMR having the following peak list: 178.8, 174.1, 166.5, 156.7, 149.9, 149.1, 148.4, 146.4, 139.9, 131.5, 130.2, 128.9, 128.0, 127.1, 125.9, 107.9 and 101.8 ppm ± 0.2 ppm; and combinations thereof. [00113] According to any aspect or embodiment of the present disclosure, crystalline Zipalertinib adipic acid Form C6 is preferably isolated.

[00114] Crystalline Form C6 of Zipalertinib adipic acid may be an anhydrous form. Typically, the water content in crystalline form C6 of Zipalertinib adipic acid is not more than 1% (w/w, as determined, for example by TGA.

[00115] Crystalline Form C6 of Zipalertinib adipic acid may be characterized by each of the above characteristics alone/or by all possible combinations, for example, an XRPD pattern having peaks at 5.3, 5.9, 11.9, 14.3 and 17.8 degrees 2-theta ± 0.2 degrees 2-theta; a solid state ¹³C NMR spectrum as depicted in Figure 10a, and combinations thereof.

[00116] According to any aspect or embodiment of the disclosure, crystalline Form C6 of Zipalertinib adipic acid may be polymorphically pure or may be substantially free of any other solid state forms of Zipalertinib adipic acid.

[00117] The above crystalline polymorphs and co-crystals can be used to prepare other crystalline polymorphs of Zipalertinib, other Zipalertinib salts or co-crystals and their solid state forms. Solid state forms may be crystalline polymorphs, co-crystals and complexes of Zipalertinib or of Zipalertinib salt.

[00118] The present disclosure encompasses a process for preparing other solid state forms of Zipalertinib or of Zipalertinib salts and co-crystals. The process includes preparing any one of the crystalline polymorphs of Zipalertinib by the processes of the present disclosure. The process may further comprise converting said crystalline polymorph of Zipalertinib to other crystalline polymorph of Zipalertinib or to other Zipalertinib salt or co-crystal.

[00119] The present disclosure provides the above described crystalline polymorphs of Zipalertinib and of Zipalertinib complexes for use in the preparation of pharmaceutical compositions comprising Zipalertinib or Zipalertinib complexes and/or crystalline polymorphs thereof.

[00120] The present disclosure also encompasses the use of crystalline polymorphs of Zipalertinib or of Zipalertinib complexes of the present disclosure for the preparation of pharmaceutical compositions of crystalline polymorph Zipalertinib and/or crystalline polymorphs thereof. Particularly, the pharmaceutical compositions may be used for oral administration. [00121] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorphs of Zipalertinib or of Zipalertinib complexes of the present disclosure with at least one pharmaceutically acceptable excipient. Particularly, the pharmaceutical compositions may comprise pharmaceutically acceptable excipient suitable for making formulations for oral administration. Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the solid state forms of Zipalertinib 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. For example, excipients may be added to assist in formation of formulation suitable for oral administration.

[00122] 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.

[00123] 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, hydroxy ethyl 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.

[00124] 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.

[00125] 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.

[00126] 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.

[00127] 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.

[00128] 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.

[00129] In liquid pharmaceutical compositions of the present invention, Zipalertinib 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.

[00130] 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. [00131] 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.

[00132] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[00133] 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.

[00134] 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.

[00135] 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, intranasal 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.

[00136] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs. [00137] 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. [00138] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[00139] 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.

[00140] 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.

[00141] 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.

[00142] 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.

[00143] A pharmaceutical formulation of Zipalertinib can be administered. For example, it can be administrated orally. Zipalertinib may be formulated for administration to a mammal, in embodiments to a human. Zipalertinib can be formulated, for example, as a viscous liquid solution or suspension, such as a 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 1 such as buffers, solubilizers, and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7^th ed.

[00144] The crystalline polymorphs of Zipalertinib and of Zipalertinib complexes and the pharmaceutical compositions and/or formulations of Zipalertinib of the present disclosure can be used as medicaments, in embodiments in the treatment of cancer, particularly NSCLC. The medicament may preferably be administrated in oral form.

[00145] The present disclosure also provides methods of treating cancer, particularly NSCLC by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Zipalertinib or of Zipalertinib complexes of the present disclosure, or at least one of the above pharmaceutical compositions and/or formulations, to a subject in need of the treatment.

[00146] 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

[00147] Zipalertinib Form 1 and amorphous Zipalertinib: The Powder X-ray Diffraction was performed on an X-Ray powder diffractometer PanAlytical X’pert Pro; CuKa radiation (A. = 1.54187 A); X’Celerator detector with active length 2.122 degrees 2-theta.

[00148] Zipalertinib Form 1, Zipalertinib succinic acid Form Cl and C3, Zipalertinib adipic acid Form C6, Zipalertinib fumaric acid Form C2 and Zipalertinib Form 4: The Powder X-ray Diffraction was performed on an X-Ray powder diffractometer PanAlytical EMPYREAN; CuKa radiation (X = 1.54187 A); pixCel detector with active length 2.140 degrees 2-theta.

[00149] In both methods, the 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-theta

Scan mode: continuous Step size: 0.0167 degrees (X’Pert Pro); 0.0131 degrees (EMPYREAN)

Step size: 42 s (X’Pert Pro); 41 s (EMPYREAN)

Sample spin: 60 rpm

Sample holder: zero background silicon plate

Solid state ¹³C-NMR ( ¹³C CP/MAS NMR) method

[00150] Spectra were measured at 16.4 T using a Bruker Avance NEO 700 SB NMR spectrometer (Karlsruhe, Germany, 2021) with 3.2 mm probehead. The ¹³C CP/MAS NMR spectra were recorded at room temperature and the frictional heating of the spinning samples was compensated. The ¹³C CP/MAS NMR spectra employing cross-polarization were acquired using the standard cross-polarization pulse scheme at spinning frequency of 20 kHz. The spinning frequency can be at the range of 18 kHz to 20 kHz. The duration of cross-polarization spin-lock pulse was 7 ms, and the spectral width was 600 ppm with the resonance frequency offset 100 ppm. The dipolar decoupling SPINAL64 is applied during the data acquisition. The number of scans is set for the signal-to-noise ratio SINO reaches at least the value ca. 50. The ¹³C scales are referenced to glycine (176.03 ppm for ¹³C).

[00151] The NMR spectrometer was 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 adamantine sample (resulting line-width at half-height A v 1/2 was less than 3.5 Hz at 250 ms of acquisition time).

EXAMPLES

Preparation of starting materials

[00152] Zipalertinib can be prepared according to methods known from the literature, for example International Publication No. WO 2015025936 (and the corresponding U.S. counterpart, U.S. Patent No. 9,650,386).

Example 1: Preparation of amorphous Zipalertinib

[00153] Zipalertinib (60 mg) was suspended in 2-butanol (1.5 mL) at RT and heated to a temperature of about 95°C at a heating rate of 0.5 °C /minute, and a clear solution was formed. The solution was cooled down to a temperature of about 10 °C at a cooling rate of 1 °C / minute. Then, n-heptane (2.5 mL) was added at a temperature of about 10 °C and the solution became cloudy. The obtained suspension was stirred for 100 minutes and cooled down to a temperature of about 0 °C over a period of about 1 hour. An additional volume of n-heptane (1 mL) was added at a temperature of about 0 °C. The suspension was filtered and dried under the vacuum at room temperature for a period of about 15 minutes. An XRPD pattern is shown in Figure 2.

Example 2: Preparation of Zipalertinib Form 1

[00154] Zipalertinib (100 mg) was suspended in dimethylformamide (“DMF”, 600 pl) at room temperature and the suspension was heated to a temperature of about 70°C over a period of about 30 minutes, and a clear solution formed. The solution was stirred at a temperature of about 70 °C for a period of about 20 minutes. The clear solution was cooled down to a temperature of about 0 °C over a period of about 2 hours. During the cooling period, water (400 pl) was added at a temperature of about 18 °C, and additional volume of water (200 pl) was added at a temperature of about 0 °C, and a suspension formed. The suspension was stirred at a temperature of about 0 °C for about 17.5 hours. The suspension was filtered and the solid was dried under the vacuum at room temperature for about 1 hour. The solid was analyzed by XRPD; Form 1 was obtained. An XRPD pattern is shown in Figure 1.

Example 3: Preparation of Zipalertinib Form 1

[00155] Zipalertinib (6 grams) was dissolved in ethanol (55 mL) at room temperature. The sample was heated to 70 °C over a period of about 30 minutes. Zipalertinib crystallized during heating and the obtained suspension was stirred at 70 °C for an additional 10 minutes. The suspension was cooled down to about 5 °C over a period of about 3 hours. The suspension was stirred at 5 °C for 18 hours. The suspension was filtered and dried under the nitrogen flow at room temperature for about 75 minutes. The solid was analyzed by XRPD; Form 1 was obtained.

Example 4: Preparation of amorphous Zipalertinib

[00156] Zipalertinib (5 grams) was dissolved in the mixture of dichloromethane (100 mL) and methanol (200 mL) at room temperature. The obtained clear solution was filtrated to remove foreign particles. The solvent was evaporated to dryness on rotavapor at temperature of about 60 °C. The solid was analyzed by XRPD; Amorphous form of Zipalertinib was obtained.

Example 5: Preparation of crystalline Zipalertinib succinic acid form Cl

[00157] Zipalertinib (100 mg) and succinic acid (15 mg) were suspended in ethanol (1 mL) at room temperature. The sample was heated to 70 °C over a period of about 30 minutes, during this time the compounds dissolved and crystallized. The obtained suspension was stirred at 70 °C for 20 minutes. The suspension was cooled down to about 10 °C over a period of about 3 hours. The suspension was stirred at about 10 °C for 30 minutes. The suspension was filtered and dried under the vacuum at room temperature for about 30 minutes. The solid was analyzed by XRPD; Form Cl was obtained. An XRPD pattern is shown in Figure 3.

Example 6: Preparation of crystalline Zipalertinib succinic acid form C3

[00158] Zipalertinib (200 mg) and succinic acid (120 mg) were suspended in ethanol (3 mL) at room temperature. The sample was heated to a temperature of about 70 °C over a period of about 30 minutes in which the sample dissolved and crystallized. The suspension was stirred at a temperature of about 70 °C for 20 minutes. The suspension was cooled down to a temperature of about 10 °C over a period of about 3 hours. The suspension was stirred at 10 °C for 30 minutes. The suspension was filtered and dried under the vacuum at room temperature for about 30 minutes. The solid was analyzed by XRPD; Form C3 was obtained. An XRPD pattern is shown in Figure 4.

Example 7: Preparation of crystalline Zipalertinib form 2

[00159] Zipalertinib amorphous form (80 mg) was suspended in ethylal (1 ml) at room temperature. The obtained suspension was heated to a temperature of about 75 °C by a heating rate 0.5 °C/min. The suspension was stirred at a temperature of about 75 °C for 30 minutes and then cooled down to 5 °C by cooling rate 1 °C/min and stirred at a temperature of about 5 °C for 20 hours and 30 minutes. The sample was filtrated and dried under the vacuum at room temperature for 15 minutes. The solid was analyzed by XRPD; Form 2 was obtained.

Example 8: Preparation of crystalline Zipalertinib form 2

[00160] Zipalertinib amorphous form (200 mg) was slurried in ethylal (3 ml) at room temperature for a period of at least 2 days. The sample was filtered and dried under the vacuum at room temperature for 15 minutes. The solid was analyzed by XRPD; Form 2 was obtained.

Example 9: Preparation of crystalline Zipalertinib form 2

[00161] Zipalertinib amorphous form (200 mg) was slurried in ethylal (3 ml) at a temperature of about 40 °C for a period of at least 2 days. The sample was filtered and dried under the vacuum at room temperature for 15 minutes. An XRPD pattern is shown in Figure 5. [00162] Further aspects and embodiments of the present disclosure are set out in the numbered clauses below, presented in List A and List B.

Example 10: Preparation of crystalline Zipalertinib adipic acid form C6

[00163] Zipalertinib (60 mg) and adipic acid (23 mg) were suspended in ethanol (1 mL) at about room temperature. The suspension was heated to 75 °C by a heating rate 0.5 °C/min, and then stirred at 75 °C for 30 minutes to obtain clear solution. Then, the solution was cooled down to a temperature of about 20 °C at a cooling rate 1 °C/min. The suspension was filtered and dried under the vacuum at room temperature for about 30 minutes. The solid was analyzed by XRPD; Form C6 was obtained. An XRPD pattern is shown in Figure 9.

Example 11: Preparation of crystalline Zipalertinib adipic acid form C6

[00164] Zipalertinib (1 gram) and adipic acid (188 mg) were suspended in ethanol (34 mL) at room temperature. The suspension was heated to a temperature of about 74 °C over a period of about 30 minutes to obtain a clear solution. The solution was stirred at a temperature of about 74 °C for 15 minutes. The solution was cooled down to a temperature of about 5 °C over a period of about 4 hours. The sample crystallized during the cooling period. The suspension was stirred at a temperature of about 5 °C for 1 hour. The suspension was filtered and dried under the vacuum at room temperature for about 2 hours. The solid was analyzed by XRPD; Form C6 was obtained.

Example 12; Preparation of crystalline Zipalertinib fumaric acid form C2

[00165] Zipalertinib (20 mg) and fumaric acid (12 mg) were dissolved in ethanol (1.2 mL) at a temperature of about 60 °C. The solvent was slowly evaporated and the solid was analyzed by XRPD. Zipalertinib fumaric acid form C2 was obtained; An XRPD pattern is shown in Figure 11.

Example 13; Preparation of crystalline Zipalertinib fumaric acid form C2

[00166] Zipalertinib (200 mg) and fumaric acid (120 mg) were suspended in ethanol (3 mL) at room temperature. The suspension was heated to a temperature of about 70 °C over a period of about 30 minutes. Additional volume of ethanol (6 ml) was added to obtain clear solution. The solution was stirred at a temperature of about 70 °C for 5 minutes. The solution was cooled down to a temperature of about 10 °C over a period of about 3 hours. The sample crystallized during the cooling period. The suspension was filtered and dried under the vacuum at room temperature for 12 hours. The solid was analyzed by XRPD; Form C2 was obtained. Example 14: Preparation of amorphous Zipalertinib - higher scale

[00167] Zipalertinib (10 grams) was dissolved in dichloromethane (200 ml) and methanol (400 ml) at room temperature. The solution was filtered to remove foreign particles. The solvent was evaporated to dryness on rotavapor at 60 °C within 1 hour. The solid was analyzed by XRPD; amorphous form was obtained.

Example 15: Preparation of crystalline Zipalertinib Form 4

[00168] Amorphous Zipalertinib (300 mg) was suspended water (2 ml) and stirred at a temperature of about 40 °C for seven days. The sample was filtered, dried under the vacuum and nitrogen flow for 30 minutes. The solid was analyzed by XRPD; form 4 was obtained. An XRPD pattern is shown in Figure 12.

Example 16; Preparation of crystalline Zipalertinib succinic acid form Cl (2:1) - Higher scale

[00169] Zipalertinib (6 g) and succinic acid (902 mg) were suspended in ethanol (130 ml).

The suspension was heated to a temperature of about 74 °C over a period of about 30 minutes to obtain clear solution. The volume of the solvent was reduced to 90 ml on rotavapor, and small crystals appeared. The suspension was stirred again at a temperature of about 74 °C and was cooled down to 5 °C over a period of about 8 hours. The suspension was stirred at a temperature of about 5 °C for 24 hours and was filtered and dried under the vacuum for 1 hour at room temperature. The solid was analyzed by XRPD; form Cl was obtained.

Example 17; Preparation of crystalline Zipalertinib fumaric acid form C2

[00170] Zipalertinib (20 mg) and fumaric acid (12 mg) were dissolved in ethanol (1.2 mb) at a temperature of about 60 °C. The solvent was slowly evaporated to dryness. The resulting solid was analysed by XRPD and confirmed to be Zipalertinib fumaric acid form C2.

Stability Testing

[00171] Samples of Zipalertinib Form 1 and Zipalertinib succinic acid Form Cl were subjected to conditions of different relative humidities at different temperatures. XRPD analysis was performed on the samples after 6 months. A sample of Zipalertinib adipic acid Form C6 was subjected to conditions of different relative humidities at different temperatures and XRPD analysis was carried out after 4 months. The results are shown in Table 1 below:

Table 1

[00172] The results demonstrate that Zipalertinib Form 1, Zipalertinib succinic acid Form Cl and Zipalertinib adipic acid Form C6 are stable after exposure to high and low relative humidity at different temperatures, indicating that these crystalline forms have excellent storage stability.

[00173] Further aspects and embodiments of the present disclosure are set out in the numbered clauses 1 A to 22A below:

1A. Crystalline Zipalertinib succinic acid.

2A. Crystalline Zipalertinib succinic acid which is a co-crystal.

3A. Crystalline Zipalertinib succinate.

4A. A crystalline product according to Clause 1A, 2A, or 3A, designated form Cl, which is characterized by data selected from one or more of the following:

(a) an XRPD pattern having peaks at 7.5, 8.5, 9.3, 11.7 and 14.5 degrees 2-theta ± 0.2 degrees 2-theta;

(b) an XRPD pattern as depicted in Figure 3;

(c) a solid state ¹³C NMR spectrum with characteristic peaks at 179.9, 165.6, 156.2, 146.8 and 126.5 ppm ± 0.2 ppm;

(d) a solid state ¹³C NMR spectrum as depicted in any of figures 8a, 8b or 8c; and

(e) combinations of these data.

5A. A crystalline product according to any of Clauses 1A, 2A, 3 A or 4A, designated form Cl, characterized by the XRPD pattern having peaks at 7.5, 8.5, 9.3, 11.7 and 14.5 degrees 2- theta ± 0.2 degrees 2-theta, and also having one, two, three or four additional peaks selected from 13.6, 15.9, 17.1, 17.8 and 21.1 degrees two theta ± 0.2 degrees two theta.

6A. A crystalline product according to any of Clauses 1A, 2A, 3 A, 4A, or 5 A, designated form C 1 , characterized by the XRPD pattern having peaks at 7.5, 8.5, 9.3, 11.7, 13.6, 14.5, 15.9, 17.1, 17.8 and 21.1 degrees two theta ± 0.2 degrees two theta.

7A. A crystalline product according to any of Clauses 1A, 2A, 3 A, 4A, 5 A, or 6A, which is further characterized by an XRPD pattern having an absence of peaks at: 3.0 to 4.3 degrees 2-theta ± 0.2 degrees 2-theta.

8A. A crystalline product according to any of Clauses 1A, 2A, 3 A, 4A, 5 A, 6A, or 7A, which is further characterized by an XRPD pattern having an absence of peaks at: 4.9 to 7.0 degrees 2-theta ± 0.2 degrees 2-theta.

9A. A crystalline product according to any of Clauses 1A, 2A, 3 A, 4A, 5 A, 6A, 7A, or 8A, designated form Cl, characterized by a solid state ¹³C NMR spectrum with characteristic peaks at 179.9, 165.6, 156.2, 146.8 and 126.5 ppm ± 0.2 ppm and a solid state ¹³C NMR spectrum having the following chemical shift absolute differences from reference peak at 102.82 ppm ± 1 ppm: 77.1, 62.7, 53.3, 44.0 and 23.7 ppm ± 0.1 ppm. A. A crystalline product according to any of Clauses 1A, 2A, 3 A, 4A, 5 A, 6A, 7A, 8 A, or 9A, designated form Cl, characterized by a solid state ¹³C NMR spectrum having the following peak list: 179.9, 165.6, 156.2, 150.5, 149.8, 146.8, 133.8, 129.3 and 126.5 ppm ± 0.2 ppm. A. A crystalline product according to any of Clauses 1A, 2A, 3 A, 4A, 5 A, 6A, 7A, 8 A, 9A, or 10A, designated form Cl, wherein the crystalline form is an anhydrous form. A. A crystalline product according to any of Clauses 1A, 2A, 3 A, 4A, 5 A, 6A, 7A, 8 A, 9A, 10A, or 11A, designated form Cl which contains not more than 1% (w/w), or not more than 0.5% (w/w), and preferably not more than 0.3% (w/w), as determined by TGA.A. A crystalline product according to any of Clauses 1A, 2A, 3 A, 4A, 5 A, 6A, 7A, 8 A, 9A, 10 A, 11 A, or 12A, designated form Cl, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Zipalertinib succinic acid or crystalline Zipalertinib succinate. A. A crystalline product according to any of Clauses 1A, 2A, 3 A, 4A, 5 A, 6A, 7A, 8 A, 9A, 10A, 11 A, 12A, or 13A, designated form Cl, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Zipalertinib succinic acid or crystalline Zipalertinib succinate. A. A pharmaceutical composition comprising a crystalline product according to any of Clauses 1 A-14A, and at least one pharmaceutically acceptable excipient. A. Use of a crystalline product according to any of Clauses 1 A-14A for the preparation of a pharmaceutical composition and/or formulation, preferably wherein the pharmaceutical formulation is a tablet, capsule, etc. A. A process for preparing the pharmaceutical composition according to Clause 15A, comprising combining a crystalline product according to any of Clauses 1 A-14A with at least one pharmaceutically acceptable excipient. A. A crystalline product according to any of Clauses 1A-14A, or a pharmaceutical composition according to Clause 15 A, for use as a medicament. A. A crystalline product according to any of Claims 1A-14A, or a pharmaceutical composition according to Claim 15A, for use in the treatment of cancer, particularly NonSmall Cell Lung Cancer. A. A method of treating cancer, for example, Non-Small Cell Lung Cancer, comprising administering a therapeutically effective amount of a crystalline product according to any of Clauses 1A-14A, or a pharmaceutical composition according to Clause 15 A, to a subject in need of the treatment. A. Use of a crystalline product according to any of Clauses 1 A-14A in the preparation of another solid state form Zipalertinib succinic acid or Zipalertinib succinate. A. A process for preparing a solid state form of Zipalertinib succinic acid or Zipalertinib succinate comprising preparing any one or a combination of a crystalline product according to any one of Clauses 1 A-14A, and converting it to another a solid state form thereof.

[00174] Further aspects and embodiments of the present disclosure are set out in the numbered clauses IB to 18B below:

IB. Crystalline Zipalertinib succinic acid.

2B. Crystalline Zipalertinib succinic acid which is a co-crystal.

3B. Crystalline Zipalertinib succinate.

4B. A crystalline product according to Clause IB, 2B, or 3B, designated form C3, which is characterized by data selected from one or more of the following:

(a) an XRPD pattern having peaks at 6.9, 14.8, 21.2, 23.7 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta;

(b) an XRPD pattern as depicted in Figure 4; and

(c) combinations of these data.

5B. A crystalline product according to any of Clauses IB, 2B, 3B or 4B, designated form C3, characterized by the XRPD pattern having peaks at 6.9, 14.8, 21.2, 23.7 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three or four additional peaks selected from 11.1, 19.4, 20.4, 22.9 and 27.7 degrees two theta ± 0.2 degrees two theta.

6B. A crystalline product according to any of Clauses IB, 2B, 3B, 4B or 5B, designated form C3, characterized by the XRPD pattern having peaks at 6.9, 11.1, 14.8, 19.4, 20.4, 21.2, 22.9, 23.7, 25.3 and 27.7 degrees two theta ± 0.2 degrees two theta.

7B. A crystalline product according to any of Clauses IB, 2B, 3B, 4B, 5B, or 6B, which is further characterized by an XRPD pattern having an absence of peaks at: 3.0 to 6.0 degrees 2-theta ± 0.2 degrees 2-theta.

8B. A crystalline product according to any of Clauses IB, 2B, 3B, 4B, 5B, 6B, or 7B, which is further characterized by an XRPD pattern having an absence of peaks at: 9.3 to 10.3 degrees 2-theta ± 0.2 degrees 2-theta.

9B. A crystalline product according to any of Clauses IB, 2B, 3B, 4B, 5B, 6B, 7B, or 8B, designated form C3, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Zipalertinib succinic acid or crystalline Zipalertinib succinate.

10B. A crystalline product according to any of Clauses IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, or 9B, designated form C3, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Zipalertinib succinic acid or crystalline Zipalertinib succinate. B. A pharmaceutical composition comprising a crystalline product according to any of Clauses 1B-10B, and at least one pharmaceutically acceptable excipient. B. Use of a crystalline product according to any of Clauses 1B-10B for the preparation of a pharmaceutical composition and/or formulation, preferably wherein the pharmaceutical formulation is a tablet, capsule, etc. B. A process for preparing the pharmaceutical composition according to Clause 1 IB, comprising combining a crystalline product according to any of Clauses 1B-10B with at least one pharmaceutically acceptable excipient. B. A crystalline product according to any of Clauses 1B-10B, or a pharmaceutical composition according to Clause 1 IB, for use as a medicament. B. A crystalline product according to any of Claims 1B-10B, or a pharmaceutical composition according to Claim 1 IB, for use in the treatment of cancer, particularly NonSmall Cell Lung Cancer. B. A method of treating cancer, for example, Non-Small Cell Lung Cancer, comprising administering a therapeutically effective amount of a crystalline product according to any of Clauses 1B-10B, or a pharmaceutical composition according to Clause 1 IB, to a subject in need of the treatment. B. Use of a crystalline product according to any of Clauses 1B-10B in the preparation of another solid state form Zipalertinib succinic acid or Zipalertinib succinate. B. A process for preparing a solid state form of Zipalertinib succinic acid or Zipalertinib succinate comprising preparing any one or a combination of a crystalline product according to any one of Clauses 1B-10B, and converting it to another a solid state form thereof.

[00175] Further aspects and embodiments of the present disclosure are set out in the numbered clauses 1C to 23C below:

1C. Crystalline Zipalertinib adipic acid.

2C. Crystalline Zipalertinib adipic acid which is a co-crystal.

3C. Crystalline Zipalertinib adipate.

4C. A crystalline product according to Clause 1C, 2C, or 3C, designated form C6, which is characterized by data selected from one or more of the following:

(a) an XRPD pattern having peaks at 5.3, 5.9, 11.9, 14.3 and 17.8 degrees 2-theta ± 0.2 degrees 2-theta;

(b) an XRPD pattern as depicted in Figure 9; and

(c) combinations of these data.

5C. A crystalline product according to any of Clauses 1C, 2C, 3C or 4C, designated form C6, characterized by the XRPD pattern having peaks at 5.3, 5.9, 11.9, 14.3 and 17.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three or four additional peaks selected from 7.5, 10.9, 13.3, 15.9 and 16.8 degrees two theta ± 0.2 degrees two theta.

6C. A crystalline product according to any of Clauses 1C, 2C, 3C, 4C or 5C, designated form C6, characterized by the XRPD pattern having peaks 5.3, 5.9, 7.5, 10.9, 11.9, 13.3, 14.3, 15.9, 16.8 and 17.8 degrees two theta ± 0.2 degrees two theta.

7C. A crystalline product according to any of Clauses 1C, 2C, 3C, 4C 5C, or 6C, which is further characterized by an XRPD pattern having an absence of peaks at: 3.0 to 4.3 degrees 2-theta ± 0.2 degrees 2-theta.

8C. A crystalline product according to any of Clauses 1C, 2C, 3C, 4C 5C, 6C, or 7C, which is further characterized by an XRPD pattern having an absence of peaks at: 6.5 to 6.8 degrees 2-theta ± 0.2 degrees 2-theta.

9C. A crystalline product according to any of Clauses 1C, 2C, 3C, 4C 5C, 6C, 7C or 8C, which is further characterized by an XRPD pattern having an absence of peaks at: 8.0 to 9.2 degrees 2-theta ± 0.2 degrees 2-theta.

10C. A crystalline product according to any of Clauses 1C, 2C, 3C, 4C 5C, 6C, 7C, 8C, or 9C, which is characterized by data selected from one or more of the following:

(a) a solid state ¹³C NMR spectrum with characteristic peaks at 178.8, 174.1, 166.5, 156.7 and 107.9 ppm ± 0.2 ppm; (b) a solid state ¹³C NMR spectrum as depicted in any of figures 10a, 10b or 10c; and

(c) combinations of these data. C. A crystalline product according to any of Clauses 1C, 2C, 3C, 4C 5C, 6C, 7C, 8C, 9C, or 10C, designated form C6, characterized by a solid state ¹³C NMR spectrum having the following chemical shift absolute differences from reference peak at 101.8 ppm ± 1 ppm: 77.0, 72.3, 64.7, 54.9 and 6.1 ppm ± 0.1 ppm. C. A crystalline product according to any of Clauses 1C, 2C, 3C, 4C 5C, 6C, 7C, 8C, 9C, 10C, or 11C, designated form C6, characterized by a solid state ¹³C NMR having the following peak list: 178.8, 174.1, 166.5, 156.7, 149.9, 149.1, 148.4, 146.4, 139.9, 131.5, 130.2, 128.9, 128.0, 127.1, 125.9, 107.9 and 101.8 ppm ± 0.2 ppm. C. A crystalline product according to any of Clauses 1C, 2C, 3C, 4C 5C, 6C, 7C, 8C, 9C, 10C, 11C, or 12C, designated form C6, wherein the crystalline product is anhydrous form. C. A crystalline product according to any of Clauses 1C, 2C, 3C, 4C 5C, 6C, 7C, 8C, 9C, 10C, 11C, 12C, or 13C, wherein the water content is not more than 1% (w/w). C. A crystalline product according to any of Clauses 1C, 2C, 3C, 4C 5C, 6C, 7C, 8C, 9C, 10C, 11C, 12C, 13C, or 14C, designated form C6, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Zipalertinib adipic acid or crystalline Zipalertinib adipate. C. A pharmaceutical composition comprising a crystalline product according to any of Clauses 1C-15C, and at least one pharmaceutically acceptable excipient. C. Use of a crystalline product according to any of Clauses 1C-15C for the preparation of a pharmaceutical composition and/or formulation, preferably wherein the pharmaceutical formulation is a tablet, capsule, etc. C. A process for preparing the pharmaceutical composition according to Clause 16C, comprising combining a crystalline product according to any of Clauses 1A-15C with at least one pharmaceutically acceptable excipient. C. A crystalline product according to any of Clauses 1C-15C, or a pharmaceutical composition according to Clause 16C, for use as a medicament. C. A crystalline product according to any of Claims 1C-15C, or a pharmaceutical composition according to Claim 16C, for use in the treatment of cancer, particularly NonSmall Cell Lung Cancer. C. A method of treating cancer, for example, Non-Small Cell Lung Cancer, comprising administering a therapeutically effective amount of a crystalline product according to any of Clauses 1C-15C, or a pharmaceutical composition according to Clause 16C, to a subject in need of the treatment. C. Use of a crystalline product according to any of Clauses 1C-15C in the preparation of another solid state form Zipalertinib adipic acid or Zipalertinib adipate. C. A process for preparing a solid state form of Zipalertinib adipic acid or Zipalertinib adipate comprising preparing any one or a combination of a crystalline product according to any one of Clauses 1C-15C, and converting it to another a solid state form thereof.

[00176] Further aspects and embodiments of the present disclosure are set out in the numbered clauses ID to 18D below:

ID. Crystalline Zipalertinib fumaric acid.

2D. Crystalline Zipalertinib fumaric acid which is a co-crystal.

3D. Crystalline Zipalertinib fumarate.

4D. A crystalline product according to Clause ID, 2D, or 3D, designated form C2, which is characterized by data selected from one or more of the following:

(a) an XRPD pattern having peaks at 5.5, 6.5, 8.8, 13.8 and 25.7 degrees 2-theta ± 0.2 degrees 2-theta;

(b) an XRPD pattern as depicted in Figure 11 ; and

(c) combinations of these data.

5D. A crystalline product according to any of Clauses ID, 2D, 3D or 4D, designated form C2, characterized by the XRPD pattern having peaks at 5.5, 6.5, 8.8, 13.8 and 25.7 degrees 2- theta ± 0.2 degrees 2-theta, and also having one, two, three or four additional peaks selected from 11.1, 18.4, 20.4, 27.1 and 28.0 degrees two theta ± 0.2 degrees two theta.

6D. A crystalline product according to any of Clauses ID, 2D, 3D, 4D or 5D, designated form C2, characterized by the XRPD pattern having peaks at 5.5, 6.5, 8.8, 11.1, 13.8, 18.4, 20.4, 25.7, 27.1 and 28.0 degrees two theta ± 0.2 degrees two theta.

7D. A crystalline product according to any of Clauses ID, 2D, 3D, 4D, 5D, or 6D, which is further characterized by an XRPD pattern having an absence of peaks at: 3.0 to 4.0 degrees 2-theta ± 0.2 degrees 2-theta.

8D. A crystalline product according to any of Clauses ID, 2D, 3D, 4D, 5D, 6D, or 7D, which is further characterized by an XRPD pattern having an absence of peaks at: 7.2 to 8.2 degrees 2-theta ± 0.2 degrees 2-theta.

9D. A crystalline product according to any of Clauses ID, 2D, 3D, 4D, 5D, 6D, 7D, or 8D, which is further characterized by an XRPD pattern having an absence of peaks at: 9.5 to 10.2 degrees 2-theta ± 0.2 degrees 2-theta.

10D. A crystalline product according to any of Clauses ID, 2D, 3D, 4D, 5D, 6D, 7D, 8D, or 9D, designated form C2, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Zipalertinib fumaric acid or crystalline Zipalertinib fumarate. D. A pharmaceutical composition comprising a crystalline product according to any of Clauses 1D-10D, and at least one pharmaceutically acceptable excipient. D. Use of a crystalline product according to any of Clauses 1D-10D for the preparation of a pharmaceutical composition and/or formulation, preferably wherein the pharmaceutical formulation is a tablet, capsule, etc. D. A process for preparing the pharmaceutical composition according to Clause 1 ID, comprising combining a crystalline product according to any of Clauses 1D-10D with at least one pharmaceutically acceptable excipient. D. A crystalline product according to any of Clauses 1D-10D, or a pharmaceutical composition according to Clause 1 ID, for use as a medicament. D. A crystalline product according to any of Claims 1D-10D, or a pharmaceutical composition according to Claim 1 ID, for use in the treatment of cancer, particularly NonSmall Cell Lung Cancer. D. A method of treating cancer, for example, Non-Small Cell Lung Cancer, comprising administering a therapeutically effective amount of a crystalline product according to any of Clauses 1D-10D, or a pharmaceutical composition according to Clause 1 ID, to a subject in need of the treatment. D. Use of a crystalline product according to any of Clauses 1D-10D in the preparation of another solid state form Zipalertinib fumaric acid or Zipalertinib fumarate. D. A process for preparing a solid state form of Zipalertinib fumaric acid or Zipalertinib fumarate comprising preparing any one or a combination of a crystalline product according to any one of Clauses 1D-10D, and converting it to another a solid state form thereof.

[00177] Further aspects and embodiments of the present disclosure are set out in the numbered clauses IE to 17E below:

IE. Crystalline Zipalertinib Form 2, which is characterized by data selected from one or more of the following:

(a) an XRPD pattern having characteristic peaks at 7.8, 12.4, 13.0, 17.8, 19.3 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta,

(b) an XRPD pattern showing no peaks (peak absence) at the areas of 14.9 - 15.4 degrees 2-theta, 20.4 - 21.2 degrees 2-theta and 22.2 - 22.4 degrees 2-theta; or

(c) an XRPD pattern as depicted in Figure 5; and

(d) combinations thereof.

2E. Crystalline Form 2 according to Clause IE, which is characterized by an XRPD pattern having characteristic peaks at 7.8, 12.4, 13.0, 17.8, 19.3 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta and also not having any peaks (peak absence) at the areas of 14.9 - 15.4 degrees 2-theta, 20.4 - 21.2 degrees 2-theta and 22.2 - 22.4 degrees 2-theta.

3E. Crystalline Form 2 according to Clause IE or Clause 2E, which is characterized by an XRPD pattern having an absence of peaks at: 3.0 to 7.2 degrees 2-theta ± 0.2 degrees 2- theta.

4E. Crystalline Form 2 according to any of Clauses IE, 2E or 3E, which is characterized by an XRPD pattern having an absence of peaks at: 8.4 to 9.2 degrees 2-theta ± 0.2 degrees 2-theta.

5E. Crystalline Form 2 of Zipalertinib according to any of Clauses IE, 2E, 3E, or 4E, which is characterized by any one or more of the following:

(a) a solid state ¹³C NMR spectrum with characteristic peaks at 164.2, 146.1, 136.5, 129.0 and 120.9 ppm ± 0.2 ppm;

(b) a solid state ¹³C NMR spectrum as depicted in any of figures 7a, 7b or 7c;

(c) a solid state ¹³C NMR spectrum having the following chemical shift absolute differences from reference peak at 103.5 ppm ± 1 ppm: 60.7, 42.6, 33.0, 25.5 and 17.4 ppm ± 0.1 ppm;

(d) a solid state ¹³C NMR having the following peak list: 164.2, 163.3, 158.3, 154.7, 154.2, 152.2, 146.1, 136.5, 132.4, 130.6, 129.0, 126.7, 125.7, 120.9, 109.2, 108.5 and 103.5 ppm ± 0.2 ppm; and (e) combinations thereof.

6E. Crystalline Zipalertinib Form 2 according to any of Clauses IE, 2E, 3E, 4E or 5E, which is isolated

7E. Crystalline Form 2 of Zipalertinib according to any of Clauses IE, 2E, 3E, 4E, 5E, or 6E, which is anhydrous form.

8E. Crystalline Form 2 of Zipalertinib according to any of Clauses IE, 2E, 3E, 4E, 5E, 6E, or 7E, having a water content of less than 0.5%.

9E. A crystalline product according to any of Clauses IE, 2E, 3E, 4E, 5E, 6E, 7E, or 8E, designated form 2, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Zipalertinib.

10E. A pharmaceutical composition comprising a crystalline product according to any of Clauses 1E-9E, and at least one pharmaceutically acceptable excipient.

HE. Use of a crystalline product according to any of Clauses 1E-9E for the preparation of a pharmaceutical composition and/or formulation, preferably wherein the pharmaceutical formulation is a tablet, capsule, etc.

12E. A process for preparing the pharmaceutical composition according to Clause 10E, comprising combining a crystalline product according to any of Clauses 1E-9E with at least one pharmaceutically acceptable excipient.

13E. A crystalline product according to any of Clauses 1E-9E, or a pharmaceutical composition according to Clause 10E, for use as a medicament.

14E. A crystalline product according to any of Claims 1E-9E, or a pharmaceutical composition according to Claim 10E, for use in the treatment of cancer, particularly Non-Small Cell Lung Cancer.

15E. A method of treating cancer, for example, Non-Small Cell Lung Cancer, comprising administering a therapeutically effective amount of a crystalline product according to any of Clauses 1E-9E, or a pharmaceutical composition according to Clause 10E, to a subject in need of the treatment.

16E. Use of a crystalline product according to any of Clauses 1E-9E in the preparation of another solid state form of Zipalertinib, Zipalertinib succinic acid or Zipalertinib succinate, Zipalertinib adipic acid or Zipalertinib adipate, Zipalertinib fumaric acid, or Zipalertinib fumarate, particularly Zipalertinib succinic acid or Zipalertinib succcinate. E. A process for preparing a solid state form of Zipalertinib, Zipalertinib succinic acid or Zipalertinib succinate, Zipalertinib adipic acid or Zipalertinib adipate, Zipalertinib fumaric acid, or Zipalertinib fumarate, particularly Zipalertinib succinic acid or Zipalertinib succinate, comprising preparing any one or a combination of a crystalline product according to any one of Clauses 1E-9E, and converting it to another a solid state form thereof.

[00178] Further aspects and embodiments of the present disclosure are set out in the numbered clauses IF to 21F below:

IF. Crystalline Zipalertinib Form 1, which is characterized by data selected from one or more of the following:

(a) an XRPD pattern having characteristic peaks at 7.9, 12.0, 15.8, 17.5 and 19.3 degrees 2-theta ± 0.2 degrees 2-theta;

(b) an XRPD pattern as depicted in Figure 1; and

(c) any combinations thereof.

2F. Crystalline Zipalertinib Form 1 according to Clause IF, which is characterised by an X-ray powder diffraction pattern having peaks at 7.9, 12.0, 15.8, 17.5 and 19.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks at 14.9, 21.7, 22.3, 24.0 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta.

3F. Crystalline Zipalertinib Form 1 according to Clause IF or Clause 2F, which is characterized by an XRPD pattern having characteristic peaks at 7.9, 12.0, 14.9, 15.8, 17.5, 19.3, 21.7, 22.3, 24.0 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta.

4F. Crystalline Form 1 of Zipalertinib according to any of Clauses IF, 2F or 3F, which is further characterized an XRPD pattern having an absence of peaks at: 3.0 to 6.6 degrees 2- theta ± 0.2 degrees 2-theta.

5F. Crystalline Form 1 of Zipalertinib according to any of Clause IF, 2F, 3F or 4F, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at: 8.4 to 9.8 degrees 2-theta ± 0.2 degrees 2-theta.

6F. Crystalline Form 1 of Zipalertinib according to any of Clause IF, 2F, 3F 4F, or 5F, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at: 12.5 to 13.2 degrees 2-theta ± 0.2 degrees 2-theta.

7F. Crystalline Form 1 of Zipalertinib according to any of Clause IF, 2F, 3F, 4F, 5F, or 6F, which is characterized by:

(a) a solid state ¹³C NMR spectrum with characteristic peaks at 164.7, 158.4, 154.4, 121.0 and 109.0 ppm ± 0.2 ppm; or

(b) a solid state ¹³C NMR spectrum as depicted in any of figures 6a, 6b or 6c.

8F. Crystalline Zipalertinib Form 1 according to any of Clauses IF, 2F, 3F, 4F, 5F, 6F, or 7F, which is characterized by data selected from one or more of the following: (a) a solid state ¹³C NMR spectrum having the following chemical shift absolute differences from reference peak at 103.7 ppm ± 1 ppm: 61.1, 54.7, 50.8, 17.3 and 5.3 ppm ± 0.1 ppm;

(b) a solid state ¹³C NMR having the following peak list: 164.7, 163.2, 158.4, 154.4, 152.2, 151.3, 146.5, 136.7, 132.3, 130.6, 128.7, 127.7, 126.7, 125.8, 121.0, 109.0 and 103.7 ppm ± 0.2 ppm; and

(c) any combinations thereof. F. Crystalline Zipalertinib Form 1 according to any of clauses IF to 8F, which is isolated. 0F. Crystalline Zipalertinib Form 1 according to any of clauses IF to 9F, which is anhydrous form. 1F. Crystalline Zipalertinib Form 1 according to any of clauses IF to 10F, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Zipalertinib. 2F. Crystalline Zipalertinib Form 1 according to any of clauses IF to 1 IF, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Zipalertinib. 3F. A crystalline product according to any of clauses IF to 12F, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Zipalertinib. 4F. A pharmaceutical composition comprising a crystalline product according to any of Clauses 1F-13F, and at least one pharmaceutically acceptable excipient. 5F. Use of a crystalline product according to any of Clauses 1F-13F for the preparation of a pharmaceutical composition and/or formulation, preferably wherein the pharmaceutical formulation is a tablet, capsule, etc. 6F. A process for preparing the pharmaceutical composition according to Clause 14F, comprising combining a crystalline product according to any of Clauses 1F-13F with at least one pharmaceutically acceptable excipient. 7F. A crystalline product according to any of Clauses 1F-13F, or a pharmaceutical composition according to Clause 14F, for use as a medicament. F. A crystalline product according to any of Claims 1F-13F, or a pharmaceutical composition according to Claim 14F, for use in the treatment of cancer, particularly NonSmall Cell Lung Cancer. F. A method of treating cancer, for example, Non-Small Cell Lung Cancer, comprising administering a therapeutically effective amount of a crystalline product according to any of Clauses 1F-13F, or a pharmaceutical composition according to Clause 14F, to a subject in need of the treatment. F. Use of a crystalline product according to any of Clauses 1F-13F, in the preparation of another solid state form of Zipalertinib, Zipalertinib succinic acid or Zipalertinib succinate, Zipalertinib adipic acid or Zipalertinib adipate, Zipalertinib fumaric acid, or Zipalertinib fumarate, particularly Zipalertinib succinic acid or Zipalertinib succcinate. F. A process for preparing a solid state form of Zipalertinib, Zipalertinib succinic acid or Zipalertinib succinate, Zipalertinib adipic acid or Zipalertinib adipate, Zipalertinib fumaric acid, or Zipalertinib fumarate, particularly Zipalertinib succinic acid or Zipalertinib succinate, comprising preparing any one or a combination of a crystalline product according to any one of Clauses 1F-13F, and converting it to another a solid state form thereof.

[00179] Further aspects and embodiments of the present disclosure are set out in the numbered clauses IGto 15G below:

1G. A crystalline form of Zipalertinib, designated Form 4, which is characterized by data selected from one or more of the following:

(a) an XRPD pattern having characteristic peaks at 5.3, 15.8, 16.6, 19.7 and 22.0 degrees 2-theta ± 0.2 degrees 2-theta; or

(b) an XRPD pattern as depicted in Figure 12.

2G. A crystalline form of Zipalertinib according to Clause 1G, which is characterized by an XRPD pattern having characteristic peaks at 5.3, 15.8, 16.6, 19.7 and 22.0 degrees 2-theta ± 0.2 degrees 2-theta and also having any one, two, three, four or five additional peaks at 9.1, 10.5, 13.8, 26.7 and 27.8 degrees 2-theta ± 0.2 degrees 2-theta.

3G. A crystalline form of Zipalertinib according to Clause 1G or Clause 2G, which is described by an XRPD pattern having characteristic peaks at 5.3, 910.5, 13.8, 15.8, 16.6, 19.7, 22.0, 26.7 and 27.8 degrees 2-theta ± 0.2 degrees 2-theta.

4G. Crystalline Form 4 of Zipalertinib according to any of Clauses 1G, 2G or 3G, which is further characterized an XRPD pattern having an absence of peaks at: 3.0 to 4.2 degrees 2-theta ± 0.2 degrees 2-theta.

5G. Crystalline Form 4 of Zipalertinib according to any of Clauses 1G, 2G, 3G, or 4G, which is isolated.

6G. Crystalline Zipalertinib Form 4 according to any of clauses IGto 5G, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Zipalertinib.

7G. A crystalline product according to any of clauses 1 G to 6G, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Zipalertinib.

8G. A pharmaceutical composition comprising a crystalline product according to any of Clauses 1G-7G, and at least one pharmaceutically acceptable excipient.

9G. Use of a crystalline product according to any of Clauses 1G-7G for the preparation of a pharmaceutical composition and/or formulation, preferably wherein the pharmaceutical formulation is a tablet, or capsule. G. A process for preparing the pharmaceutical composition according to Clause 8G, comprising combining a crystalline product according to any of Clauses 1G-7G with at least one pharmaceutically acceptable excipient. G. A crystalline product according to any of Clauses 1G-7G, or a pharmaceutical composition according to Clause 8G, for use as a medicament. G. A crystalline product according to any of Claims 1G-7G, or a pharmaceutical composition according to Claim 8G, for use in the treatment of cancer, particularly NonSmall Cell Lung Cancer. G. A method of treating cancer, for example, Non-Small Cell Lung Cancer, comprising administering a therapeutically effective amount of a crystalline product according to any of Clauses 1G-7G or a pharmaceutical composition according to Clause 8G, to a subject in need of the treatment. G. Use of a crystalline product according to any of Clauses 1G-7G, in the preparation of another solid state form of Zipalertinib, Zipalertinib succinic acid or Zipalertinib succinate, Zipalertinib adipic acid or Zipalertinib adipate, Zipalertinib fumaric acid, or Zipalertinib fumarate, particularly Zipalertinib succinic acid or Zipalertinib succcinate. G. A process for preparing a solid state form of Zipalertinib, Zipalertinib succinic acid or Zipalertinib succinate, Zipalertinib adipic acid or Zipalertinib adipate, Zipalertinib fumaric acid, or Zipalertinib fumarate, particularly Zipalertinib succinic acid or Zipalertinib succinate, comprising preparing any one or a combination of a crystalline product according to any one of Clauses 1G-7G, and converting it to another a solid state form thereof.

Claims

1. Crystalline Zipalertinib Form 1, which is characterized by data selected from one or more of the following:

(b) an XRPD pattern as depicted in Figure 1 ;

(c) a solid state ¹³C NMR spectrum with characteristic peaks at 164.7, 158.4, 154.4, 121.0 and 109.0 ppm ± 0.2 ppm;

(d) a solid state ¹³C NMR spectrum as depicted in any of figures 6a, 6b or 6c; and

(e) any combinations thereof.

2. Crystalline Zipalertinib Form 1 according to Claim 1, which is characterised by an X-ray powder diffraction pattern having peaks at 7.9, 12.0, 15.8, 17.5 and 19.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks at 14.9, 21.7, 22.3, 24.0 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta.

3. Crystalline Zipalertinib Form 1 according to Claim 1 or Claim 2, which is characterized by an XRPD pattern having characteristic peaks at 7.9, 12.0, 14.9, 15.8, 17.5, 19.3, 21.7, 22.3, 24.0 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta.

4. Crystalline Form 1 of Zipalertinib according to any of Claims 1, 2 or 3, which is further characterized an XRPD pattern having an absence of peaks at: 3.0 to 6.6 degrees 2-theta ± 0.2 degrees 2-theta; and/or an absence of peaks at: 8.4 to 9.8 degrees 2-theta ± 0.2 degrees 2-theta; and/or an absence of peaks at: 12.5 to 13.2 degrees 2-theta ± 0.2 degrees 2-theta.

5. Crystalline Zipalertinib Form 1 according to Claim 1 or Claim 2 or Claim 3, or Claim 4, which is characterized by data selected from one or more of the following:

(a) a solid state ¹³C NMR spectrum having the following chemical shift absolute differences from reference peak at 103.7 ppm ± 1 ppm: 61.1, 54.7, 50.8, 17.3 and 5.3 ppm ± 0.1 ppm;

(c) any combinations thereof.

6. Crystalline Zipalertinib Form 1 according to any preceding claim, which is isolated. Crystalline Zipalertinib Form 1 according to any preceding claim, which is anhydrous form. Crystalline Zipalertinib Form 1 according to any preceding claim, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Zipalertinib. Crystalline Zipalertinib Form 1 according to any preceding claim, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Zipalertinib. Crystalline Zipalertinib Form 4, which is characterized by data selected from one or more of the following:

(a) an XRPD pattern having characteristic peaks at 5.3, 15.8, 16.6, 19.7 and 22.0 degrees 2-theta ± 0.2 degrees 2-theta;

(b) an XRPD pattern as depicted in Figure 12; and

(c) any combinations thereof. Crystalline Zipalertinib Form 4 according to Claim 10, which is characterised by an X-ray powder diffraction pattern having peaks at 5.3, 15.8, 16.6, 19.7 and 22.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks at 9.1, 10.5, 13.8, 26.7 and 27.8 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Zipalertinib Form 4 according to Claim 10 or Claim 11 which is characterized by an XRPD pattern having characteristic peaks at 5.3, 9.1, 10.5, 13.8, 15.8, 16.6, 19.7, 22.0, 26.7 and 27.8 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form 4 of Zipalertinib according to any of Claims 10, 11 or 12, which is further characterized an XRPD pattern having an absence of peaks at: 3.0 to 4.2 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Zipalertinib Form 4 according to any of Claims 10, 11, 12, or 13, which is isolated. Crystalline Zipalertinib Form 4 according to any of Claims 10, 11, 12, 13, or 14, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Zipalertinib. Crystalline Zipalertinib Form 4 according to any of Claims 10, 11, 12, 13, 14, or 15, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Zipalertinib. Crystalline Zipalertinib succinic acid. Crystalline Zipalertinib succinic acid which is a co-crystal. A crystalline product according to Claim 17 or Claim 18, designated form Cl, which is characterized by data selected from one or more of the following:

(b) an XRPD pattern as depicted in Figure 3;

(c) a solid state 13C NMR spectrum with characteristic peaks at 179.9, 165.6, 156.2, 146.8 and 126.5 ppm ± 0.2 ppm;

(d) a solid state 13C NMR spectrum as depicted in any of figures 8a, 8b or 8c; and

(e) any combinations of these data. A crystalline product according to any of Claim 17, 18 or 19, designated form Cl, characterized by the XRPD pattern having peaks at 7.5, 8.5, 9.3, 11.7 and 14.5 degrees 2- theta ± 0.2 degrees 2-theta, and also having one, two, three or four additional peaks selected from 13.6, 15.9, 17.1, 17.8 and 21.1 degrees two theta ± 0.2 degrees two theta. A crystalline product according to any of Claim 17, 18, 19, or 20, designated form Cl, characterized by the XRPD pattern having peaks at 7.5, 8.5, 9.3, 11.7, 13.6, 14.5, 15.9, 17.1 , 17.8 and 21.1 degrees two theta ± 0.2 degrees two theta. A crystalline product according to any of Claims 17, 18, 19, 20, or 21, which is further characterized by an XRPD pattern having an absence of peaks at: 3.0 to 4.3 degrees 2- theta ± 0.2 degrees 2-theta; and/or having an absence of peaks at: 4.9 to 7.0 degrees 2- theta ± 0.2 degrees 2-theta. A crystalline product according to any of Claim 17, 18, 19, 20, 21, or 22, designated form Cl, characterized by a solid state 13C NMR spectrum with characteristic peaks at 179.9, 165.6, 156.2, 146.8 and 126.5 ppm ± 0.2 ppm and a solid state 13C NMR spectrum having the following chemical shift absolute differences from reference peak at

102.82 ppm ± 1 ppm: 77.1, 62.7, 53.3, 44.0 and 23.7 ppm ± 0.1 ppm. A crystalline product according to any of Claim 17, 18, 19, 20, 21, 22, or 23, designated form Cl, characterized by a solid state 13C NMR spectrum having the following peak list: 179.9, 165.6, 156.2, 150.5, 149.8, 146.8, 133.8, 129.3 and 126.5 ppm ± 0.2 ppm. A crystalline product according to any of Claim 17, 18, 19, 20, 21, 22, 23, or 24, designated form Cl, wherein the crystalline form is an anhydrous form. A crystalline product according to any Claim 17, 18, 19, 20, 21, 22, 23, 24, or 25, designated form Cl, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Zipalertinib succinic acid or crystalline Zipalertinib succinate. A crystalline product according to any of Claim 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, designated form Cl, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Zipalertinib succinic acid or crystalline Zipalertinib succinate. Crystalline Zipalertinib adipic acid. Crystalline Zipalertinib adipic acid which is a co-crystal. A crystalline product according to Claim 28 or Claim 29, designated form C6, which is characterized by data selected from one or more of the following:

(b) an XRPD pattern as depicted in Figure 9; and

(c) any combinations of these data. A crystalline product according to any of Claims 28, 29 or 30, designated form C6, characterized by the XRPD pattern having peaks at 5.3 , 5.9, 11.9, 14.3 and 17.8 degrees 2- theta ± 0.2 degrees 2-theta, and also having one, two, three or four additional peaks selected from 7.5, 10.9, 13.3, 15.9 and 16.8 degrees two theta ± 0.2 degrees two theta. A crystalline product according to any of Claims 28, 29, 30 or 31, designated form C6, characterized by the XRPD pattern having peaks 5.3, 5.9, 7.5, 10.9, 11.9, 13.3, 14.3, 15.9, 16.8 and 17.8 degrees two theta ± 0.2 degrees two theta. A crystalline product according to any of Claims 28, 29, 30, 31, or 32, which is further characterized by an XRPD pattern having an absence of peaks at: 3.0 to 4.3 degrees 2- theta ± 0.2 degrees 2-theta; and/or having an absence of peaks at: 6.5 to 6.8 degrees 2- theta ± 0.2 degrees 2-theta; and/or having an absence of peaks at: 8.0 to 9.2 degrees 2- theta ± 0.2 degrees 2-theta. A crystalline product according to any of Claims 28, 29, 30, 31, 32, or 33, designated form C6, characterized by data selected from one or more of the following:

(a) a solid state ¹³C NMR spectrum with characteristic peaks at 178.8, 174.1, 166.5, 156.7 and 107.9 ppm ± 0.2 ppm;

(b) a solid state ¹³C NMR spectrum as depicted in any of figures 10a, 10b or 10c; and

(c) any combinations of these data. A crystalline product according to any of Claims 28, 29, 30, 31, 32, 33, or 34, designated form C6, characterized by a solid state ¹³C NMR spectrum having the following chemical shift absolute differences from reference peak at 101.8 ppm ± 1 ppm: 77.0, 72.3, 64.7, 54.9 and 6.1 ppm ± 0.1 ppm. A crystalline product according to any of Claims 28, 29, 30, 31, 32, 33, 34, or 35, designated form C6, characterized by a solid state ¹³C NMR having the following peak list: 178.8, 174.1, 166.5, 156.7, 149.9, 149.1, 148.4, 146.4, 139.9, 131.5, 130.2, 128.9, 128.0, 127.1, 125.9, 107.9 and 101.8 ppm ± 0.2 ppm. A crystalline product according to any of Claims 28, 29, 30, 31, 32, 33, 34, 35, or 36, designated form C6, wherein the crystalline product is anhydrous form. A crystalline product according to any of Claims 28, 29, 30, 31, 32, 33, 34, 35, 36, or 37, designated form C6, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Zipalertinib adipic acid or crystalline Zipalertinib adipate. A pharmaceutical composition comprising a crystalline product according to any of Claims 1-38, and at least one pharmaceutically acceptable excipient. Use of a crystalline product according to any of Claims 1-38 for the preparation of a pharmaceutical composition and/or formulation, preferably wherein the pharmaceutical formulation is a tablet, capsule, etc. A process for preparing the pharmaceutical composition according to Claim 39, comprising combining a crystalline product according to any of Claims 1-38 with at least one pharmaceutically acceptable excipient. A crystalline product according to any of Claims 1-38, or a pharmaceutical composition according to Claim 39, for use as a medicament. A crystalline product according to any of Claims 1-38, or a pharmaceutical composition according to Claim 39, for use in the treatment of cancer, particularly Non-Small Cell Lung Cancer. A method of treating cancer, particularly Non-Small Cell Lung Cancer, comprising administering a therapeutically effective amount of a crystalline product according to any of Claims 1-38, or a pharmaceutical composition according to Claim 39, to a subject in need of the treatment. Use of a crystalline product according to any of Claims 1-38 in the preparation of another solid state form of Zipalertinib, Zipalertinib succinic acid or Zipalertinib succinate, Zipalertinib adipic acid or Zipalertinib adipate, Zipalertinib fumaric acid, or Zipalertinib fumarate, particularly Zipalertinib succinic acid or Zipalertinib succcinate. A process for preparing a solid state form of Zipalertinib or Zipalertinib salt or Zipalertinib co-crystal comprising preparing any one or a combination of a crystalline product according to any one of Claims 1-38, and converting it to another a solid state form thereof.