Solid-state forms of dipalertinib and methods for preparing same

Abstract

The present disclosure encompasses solid-state forms of dipareltinib and dipareltinib complexes, in some embodiments, crystalline polymorphs of dipareltinib and dipareltinib complexes, methods for preparing the same, and pharmaceutical compositions thereof.

Description

[Technical Field]

[0001] The present disclosure encompasses solid state forms of dipalertinib and dipalertinib complexes, in some embodiments, crystalline polymorphs of dipalertinib and dipalertinib complexes, methods for preparing the same, and pharmaceutical compositions thereof. [Background technology]

[0002] Dipalertinib, N-[(8S)-4-amino-8,9-dihydro-6-methyl-5-(3-quinolinyl)pyrimido[5,4-b]indolizin-8-yl]-2-propenamide, is a compound having the following structure:

[0003] [ka]

[0004] It has the following structure.

[0005] Dipareltinib is a reversible EGFR inhibitor developed for the treatment of non-small cell lung cancer.

[0006] This compound is described in WO2015025936.

[0007] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. From a single molecule, distinct crystalline structures, as well as melting points, thermal behavior (e.g., as measured by thermogravimetric analysis ("TGA") or differential scanning calorimetry ("DSC")), X-ray diffraction (XRD) patterns, infrared absorption fingerprints, and solid-state ( 13 C) A wide variety of polymorphs can occur, with physical properties such as NMR spectra, etc. One or more of these techniques can be used to distinguish between different polymorphic forms of a compound.

[0008] Different salts and solid-state forms (including solvated forms) of an active pharmaceutical ingredient can have different properties. Such variations in the properties of different salts and solid-state forms and solvates can provide a basis for improving formulations, for example, by promoting better processing or handling characteristics, favorably altering the dissolution profile, or improving stability (polymorphic stability and chemical stability) and shelf life. These variations in the properties of different salts and solid-state forms can also lead to improvements in the final dosage form, for example, if they help improve bioavailability. Different salts and solid-state forms and solvates of an active pharmaceutical ingredient can also give rise to a wide variety of polymorphs or crystalline forms, which in turn can provide additional opportunities for evaluating variations in the properties and characteristics of the solid active pharmaceutical ingredient. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2015025936 [Patent Document 2] U.S. Patent No. 9,650,386 [Non-patent literature]

[0010] [Non-Patent Document 1] Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. Summary of the Invention [Problem to be solved by the invention]

[0011] The discovery of new salts, solid-state forms, and solvates of a pharmaceutical product can provide materials with desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification, or as desirable intermediate crystalline forms that facilitate conversion to other polymorphic forms. New solid-state forms of a pharmaceutically useful compound can also provide opportunities to improve the performance characteristics of a pharmaceutical product. For example, providing products with different properties, including a different crystal habit, greater crystallinity, or polymorphic stability, expands the repertoire of materials available to formulation scientists for formulation optimization, which may provide better processing or handling characteristics, an improved dissolution profile, or an improved shelf life (chemical / physical stability). For at least these reasons, additional salts and solid-state forms (including solvated forms) of dipalertinib are needed. [Means for solving the problem]

[0012] The present disclosure provides crystalline polymorphs of dipalertinib and dipalertinib complexes, such as dipalertinib salts and cocrystals, methods for preparing the same, and pharmaceutical compositions thereof, which can be used to prepare other solid-state forms of dipalertinib, other dipalertinib salts and cocrystals, and solid-state forms thereof.

[0013] The present disclosure also provides other solid state forms or other salts or co-crystals of dipalertinib, and uses of said solid state forms of dipalertinib and dipalertinib complexes in the preparation of these solid state forms.

[0014] The present disclosure provides crystalline polymorphs of dipareltinib and dipareltinib complexes for use in medicine, including the treatment of cancer, particularly non-small cell lung cancer ("NSCLC").

[0015] The present disclosure also encompasses the use of the crystalline polymorphs of dipalertinib and dipalertinib complexes of the present disclosure for the preparation of pharmaceutical compositions and / or pharmaceutical formulations, particularly pharmaceutical compositions or formulations for oral administration.

[0016] In another aspect, the present disclosure provides pharmaceutical compositions comprising crystalline polymorphs of dipalertinib and dipalertinib complexes according to the present disclosure. The pharmaceutical compositions according to any aspect of the present invention may include oral dosage forms.

[0017] The present disclosure also includes a method for preparing the pharmaceutical composition mentioned above.The method includes combining any one or a combination of crystalline polymorphs of dipalertinib and dipalertinib complex with at least one pharmaceutically acceptable excipient.In particular, the pharmaceutical composition can include a pharmaceutically acceptable excipient suitable for preparing an oral dosage form.

[0018] The crystalline polymorphs of diparertinib and diparertinib complexes, and pharmaceutical compositions or pharmaceutical formulations of crystalline polymorphs of diparertinib and diparertinib complexes defined herein, can be used as medicaments, such as for the treatment of cancer, particularly NSCLC.

[0019] The present disclosure also provides methods of treating cancer, particularly NSCLC, by administering a therapeutically effective amount of any one or combination of the crystalline polymorphs of dipareltinib and dipareltinib complexes of the present disclosure, or at least one of the pharmaceutical compositions described above, to a subject suffering from cancer, particularly NSCLC, or otherwise in need of treatment.

[0020] The present disclosure also provides the use of at least one of the crystalline polymorphs of dipalertinib and dipalertinib complexes of the present disclosure, or the pharmaceutical compositions described above, for the manufacture of a medicament for treating, for example, cancer, particularly NSCLC. The medicament can be administered in an intranasal dosage form or an oral dosage form.

[0021] According to any aspect or embodiment of the present disclosure, the pharmaceutical composition or pharmaceutical formulation for the treatment of cancer, particularly NSCLC, is preferably in the form of an oral dosage form. [Brief explanation of the drawings]

[0022] [Figure 1] 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of crystalline dipalertinib Form 1. [Figure 2] 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of amorphous dipalertinib. [Figure 3] FIG. 1 shows a characteristic XRPD of crystalline dipareltinib succinic acid form C1. [Figure 4] 1 shows a characteristic XRPD of crystalline dipareltinib succinic acid form C3. [Figure 5] 1 shows a characteristic XRPD of crystalline dipareltinib Form 2. [Figure 6a] 1 shows a characteristic solid-state 13C NMR spectrum (range 200-0 ppm) of dipalertinib Form 1. [Figure 6b] 1 shows a characteristic solid-state 13C NMR spectrum (range 200-100 ppm) of dipalertinib Form 1. [Figure 6c] 1 shows a characteristic solid-state 13C NMR spectrum (range 100-0 ppm) of dipalertinib Form 1. [Figure 7a] 1 shows a characteristic solid-state 13C NMR spectrum (range 200-0 ppm) of dipalertinib Form 2. [Figure 7b] 1 shows a characteristic solid-state 13C NMR spectrum (range 200-100 ppm) of dipalertinib Form 2. [Figure 7c] 1 shows a characteristic solid-state 13C NMR spectrum (range 100-0 ppm) of dipalertinib Form 2. [Figure 8a] FIG. 1 shows a characteristic solid-state C NMR spectrum (range 200-0 ppm) of crystalline dipalertinib succinate form C1. [Figure 8b] FIG. 1 shows a characteristic solid-state C NMR spectrum (range 200-100 ppm) of crystalline dipalertinib succinate form C1. [Figure 8c] FIG. 1 shows a characteristic solid-state C NMR spectrum (range 100-0 ppm) of crystalline dipalertinib succinate form C1. [Figure 9] FIG. 1 shows a characteristic XRPD of crystalline dipalertinib adipic acid form C6. [Figure 10a] Figure 1 shows a characteristic solid-state C NMR spectrum (range 200-0 ppm) of crystalline dipalertinib-adipic acid form C6. [Figure 10b] Figure 1 shows a characteristic solid-state C NMR spectrum (range 200-100 ppm) of crystalline dipalertinib-adipic acid form C6. [Figure 10c] Figure 1 shows a characteristic solid-state C NMR spectrum (range 100-0 ppm) of crystalline dipalertinib-adipic acid form C6. [Figure 11] 1 shows a characteristic XRPD of crystalline dipareltinib-fumarate form C2. [Figure 12] 1 shows a characteristic XRPD of crystalline dipalertinib Form 4. DETAILED DESCRIPTION OF THE INVENTION

[0023] The present disclosure encompasses solid-state forms of diparertinib and diparertinib complexes, including crystalline polymorphs of diparertinib and diparertinib complexes, methods for preparing the same, and pharmaceutical compositions thereof.

[0024] The solid-state properties of dipareltinib and dipareltinib complexes, and their crystalline polymorphs, can be influenced by controlling the conditions under which dipareltinib and its crystalline polymorphs are obtained in solid form.

[0025] As used herein, a solid-state form (or polymorph) may be referred to as being polymorphically pure or as being substantially free of any other solid-state (or polymorphic) forms. As used herein in this context, the phrase "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 dipareltinib or a dipareltinib complex described herein as being substantially free of any other solid-state forms can 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 dipareltinib or a dipareltinib complex. In some embodiments of the present disclosure, the described crystalline polymorph of dipareltinib or a dipareltinib complex may contain about 1% to about 20% (w / w), about 5% to about 20% (w / w), or about 5% to about 10% (w / w) of one or more other crystalline polymorphs of the same dipareltinib or a dipareltinib complex.

[0026] Compounds may be referred to herein as chemically pure or purified compounds, or as being substantially free of any other compounds. As used herein in this context, the phrase "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 compounds, as measured, for example, by HPLC. Thus, a pure or purified dipalertinib or dipalertinib conjugate described herein as being substantially free of any compounds can 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 dipalertinib or dipalertinib conjugate. In some embodiments of the present disclosure, the described pure or purified dipalertinib or dipalertinib conjugate may contain about 1% to about 20% (w / w), about 5% to about 20% (w / w), or about 5% to about 10% (w / w) of one or more other compounds.

[0027] In certain embodiments, the pure or purified dipalertinib or dipalertinib conjugate described above may refer to enantiomeric purity, i.e., pure or purified dipalertinib or dipalertinib conjugate refers to dipalertinib that is substantially free of dipalertinib enantiomers.

[0028] Depending on which other crystalline polymorphs are compared, the crystalline polymorphs of dipalertinib or dipalertinib complex of the present disclosure can 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 and thermal and mechanical stability with respect to polymorphic transformation, stability towards dehydration and / or storage stability, low residual solvent content, low hygroscopicity, and advantageous processing and handling characteristics such as compressibility and bulk density.

[0029] Solid-state forms, such as crystalline or amorphous forms, may be referred to herein as being characterized by graphical data "depicted" or "substantially depicted" in the figures. Such data include, for example, powder X-ray diffraction patterns and solid-state NMR spectra. As is well known in the art, graphical data can potentially provide additional technical information (so-called "fingerprints") to further define each solid-state form, which cannot necessarily be described by reference to numerical values ​​or peak positions alone. In any event, those skilled in the art will understand that such graphical representations of data may be subject to minor variations, for example, in relative peak 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 those skilled in the art. Nevertheless, those skilled in the art can readily compare the graphical data in the figures herein with graphical data generated for an unknown crystalline form and determine whether the two sets of graphical data characterize the same crystalline form or two different crystalline forms. Thus, a crystalline form of dipalertinib referred to herein as being characterized by graphical data "as depicted" or "substantially as depicted" in a figure will be understood to include any crystalline form of dipalertinib characterized using graphical data having such minor variations compared to the figure, as would be known to one of skill in the art.

[0030] As used herein, unless otherwise stated, the term "anhydrous" with respect to a crystalline form of dipalertinib refers to a crystalline form of dipalertinib that does not contain any water of crystallization (or other solvent) in a stoichiometric amount defined within the crystal. Moreover, unless otherwise specified, the "anhydrous" form generally does not contain more than 1% (w / w) of either water or organic solvent, as measured, for example, by TGA.

[0031] The term "solvate," as used herein, unless otherwise specified, refers to a crystalline form in which a solvent is incorporated into the crystalline structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate can be present in either stoichiometric or non-stoichiometric amounts.

[0032] A "co-crystal" or "co-crystal," as used herein, is defined as a crystalline material comprising two or more molecules within the same crystal lattice, associated by non-ionic, non-covalent bonds. In some embodiments, a co-crystal comprises two molecules in their native state.

[0033] As used herein, crystalline dipalertinib succinic acid or crystalline dipalertinib succinic acid complex is a separate molecular species. Crystalline dipalertinib succinic acid can be a co-crystal of dipalertinib and succinic acid. Alternatively, crystalline dipalertinib and succinic acid can be a salt, i.e., dipalertinib succinate salt.

[0034] As used herein, crystalline dipalertinib adipic acid or crystalline dipalertinib adipic acid complex is a distinct molecular species. Crystalline dipalertinib adipic acid can be a cocrystal of dipalertinib and adipic acid. Alternatively, crystalline dipalertinib and adipic acid can be a salt, i.e., dipalertinib adipic acid salt. In some embodiments, the molar ratio between the active pharmaceutical ingredient dipalertinib and the conformer adipic acid is between 1:1.5 and 1.5:1, preferably between 1:1.25 and 1.25:1, and in other embodiments, about 1:1.

[0035] As used herein, the term "isolated" with reference to a crystalline polymorph of dipareltinib of the present disclosure corresponds to a crystalline polymorph of dipareltinib or a dipareltinib complex that is physically separated from the reaction mixture in which it is formed.

[0036] As used herein, unless otherwise stated, XRPD measurements are made using copper Kα radiation at a wavelength of 1.54187 Å. XRPD peaks reported herein are measured using Cu Kα radiation at λ=1.54187 Å, typically at a temperature of 25±3° C.

[0037] As used herein, unless otherwise specified, solid state 13 C NMR data is 13 C CP / MAS NMR methods. Specifically, as used herein, unless otherwise indicated, the 13 C CP / MAS NMR is measured at 700 MHz, preferably at a temperature of 293 K±3°C.

[0038] An object, such as a reaction mixture, may be characterized as being at or being brought to "room temperature" or "ambient temperature," often abbreviated herein as "RT." This means that the temperature of the object is close to or the same as the temperature of the space in which the object is located, e.g., a room or fume hood. Typically, room temperature is from about 20° C. to about 30° C., or from about 22° C. to about 27° C., or about 25° C.

[0039] The amount of solvent used in a chemical process, such as a reaction or crystallization, may be referred to herein as a "volume" or "vol" or "V" numerical value. For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10 V) of solvent. In this context, this expression may be understood to mean milliliters of solvent per gram of suspended material; thus, suspending 5 grams of material in 10 volumes of solvent means that a volume of 10 milliliters of solvent is used per gram of suspended material, i.e., 50 mL of solvent in this example. In other contexts, the term "v / v" may be used to indicate the numerical value of the volume of solvent added to a liquid mixture, based on the volume of the mixture. For example, adding solvent X (1.5 v / v) to 100 ml of a reaction mixture may indicate that 150 mL of solvent X has been added.

[0040] As used herein, a process or step may be referred to as occurring "overnight." This refers to, for example, a time period spanning overnight hours during which the process or step may not be actively observed. This time period may be from about 8 hours to about 20 hours, or from about 10 to 18 hours, or in some cases, about 16 hours.

[0041] As used herein, the term "reduced pressure" refers to a pressure below atmospheric pressure. For example, reduced pressure is from about 10 mbar to about 50 mbar.

[0042] As used herein, unless otherwise specified, the term "ambient conditions" refers to atmospheric pressure and a temperature of 22-24°C.

[0043] The present disclosure describes amorphous dipareltinib, the characteristic XRPD pattern of which is shown in Figure 2.

[0044] In some embodiments, the present disclosure includes a method for preparing amorphous dipalertinib. The method includes precipitating amorphous dipalertinib from a mixture containing 2-butanol and n-heptane. Typically, this method includes dissolving dipalertinib in 2-butanol and adding n-heptane. Dissolution is assisted 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 can be cooled, preferably at a cooling rate of 1°C / min. Typically, n-heptane is added to the cooled solution, thus forming a suspension from which the amorphous material can be isolated. Preferably, the 2-butanol-n-heptane suspension is further cooled, for example, to a temperature of about 0°C. The amorphous material can be isolated, for example, by filtration, or dried, for example, by vacuum drying, preferably at room temperature. The amorphous material can be used to prepare a crystalline form of dipalertinib, such as crystalline dipalertinib Form 1 described herein below.

[0045] The present disclosure includes a crystalline polymorph of dipalertinib designated as Form 1. Crystalline Form 1 can 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 an XRPD pattern as depicted in Figure 1, or a combination thereof. Crystalline Form 1 can be further described 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 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.

[0046] Crystalline Form 1 can 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 dipalertinib can be further characterized by an XRPD pattern as described in any of the embodiments herein, wherein the XRPD pattern is absent from a peak between 3.0 and 6.6 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to any aspect or embodiment of the present disclosure, crystalline Form 1 of dipalertinib can be further characterized by an X-ray powder diffraction pattern as described in any of the embodiments herein, wherein the XRPD pattern is absent from a peak between 8.4 and 9.8 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to any aspect or embodiment of the present disclosure, crystalline Form 1 of dipalertinib is as described in any of the embodiments herein and may be characterized by an X-ray powder diffraction pattern having no peaks at 12.5 to 13.2 degrees two-theta ± 0.2 degrees two-theta.

[0047] Alternatively, crystalline Form 1 of dipalertinib may be a solid-state crystalline form having characteristic peaks at the following: 164.7, 158.4, 154.4, 121.0, and 109.0 ppm±0.2 ppm. 13 C NMR spectrum, solid state as illustrated in either Figure 6a, Figure 6b or Figure 6c 13 C NMR spectrum, and combinations thereof. Crystalline Form 1 of dipalertinib may be characterized by data selected from one or more of the following solid-state absolute chemical shift differences from the reference peak at 103.7 ppm ± 1 ppm: 61.1, 54.7, 50.8, 17.3, and 5.3 ppm ± 0.1 ppm. 13 C NMR spectrum, solid state with 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 ppm13 C NMR, as well as combinations thereof.

[0048] According to any aspect or embodiment of the present disclosure, crystalline Form 1 of dipalertinib is preferably isolated.

[0049] In some embodiments, crystalline Form 1 of dipalertinib is an anhydrous form. Typically, the water content is less than 0.5%, as determined, for example, by TGA (temperature range 30° C. to 100° C.).

[0050] Dipalertinib crystalline Form 1 may be characterized by each alone or all possible combinations of the above characteristics, for example, by an XRPD pattern having peaks at 7.9, 12.0, 15.8, 17.5, and 19.3 degrees two-theta ± 0.2 degrees two-theta, an XRPD pattern as depicted in Figure 1, and combinations thereof.

[0051] According to any aspect or embodiment of the present disclosure, crystalline Form 1 of dipalertinib may be polymorphically pure or may be substantially free of any other solid state forms of dipalertinib.

[0052] The present disclosure further includes a crystalline polymorph of dipalertinib designated as Form 2. Crystalline Form 2 can 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 an XRPD pattern that shows no peaks (absence of peaks) in the regions of 14.9-15.4 degrees 2-theta, 20.4-21.2 degrees 2-theta, and 22.2-22.4 degrees 2-theta, or an XRPD pattern as depicted in Figure 5, or a combination thereof.

[0053] Crystalline Form 2 can 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 no peaks (absence of peaks) in the regions of 14.9-15.4 degrees 2-theta, 20.4-21.2 degrees 2-theta, and 22.2-22.4 degrees 2-theta.

[0054] According to any aspect or embodiment, crystalline Form 2 of dipalertinib may be further characterized by an XRPD pattern as described in any of the embodiments herein, wherein the XRPD pattern is absent from a peak at 3.0 to 7.2 degrees two-theta ± 0.2 degrees two-theta. Alternatively or additionally, according to any aspect or embodiment of the present disclosure, crystalline Form 2 of dipalertinib may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments herein, wherein the X-ray powder diffraction pattern is absent from a peak at 8.4 to 9.2 degrees two-theta ± 0.2 degrees two-theta.

[0055] Alternatively, crystalline Form 2 of dipalertinib may be a solid-state crystalline form having characteristic peaks at the following: 164.2, 146.1, 136.5, 129.0, and 120.9 ppm±0.2 ppm. 13 C NMR spectrum, solid state as illustrated in either Figure 7a, Figure 7b or Figure 7c 13 C NMR spectrum, and combinations thereof. Crystalline Form 2 of dipalertinib may be characterized by data selected from one or more of the following solid-state absolute chemical shifts from the reference peak at 103.5 ppm ± 1 ppm: 60.7, 42.6, 33.0, 25.5, and 17.4 ppm ± 0.1 ppm. 13 C NMR spectrum, solid state with 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 13C NMR, as well as combinations thereof.

[0056] According to any aspect or embodiment of the present disclosure, crystalline Form 2 of dipalertinib is preferably isolated.

[0057] In some embodiments, crystalline Form 2 of dipalertinib is an anhydrous form. Typically, the water content is less than 0.5%, as determined, for example, by TGA (temperature range 30° C. to 100° C.).

[0058] Dipalertinib crystalline Form 2 may be characterized by each and every possible combination of the above characteristics.

[0059] The present disclosure further includes a crystalline polymorph of dipalertinib designated as Form 4. Crystalline Form 4 can 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 two-theta ± 0.2 degrees two-theta, or an XRPD pattern as depicted in Figure 12, or a combination thereof.

[0060] Crystalline Form 4 can 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 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.

[0061] Crystalline Form 4 can 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 two-theta ±0.2 degrees two-theta.

[0062] According to any aspect or embodiment, crystalline Form 4 of dipalertinib may be further characterized by an XRPD pattern as described in any of the embodiments herein, wherein the XRPD pattern is free of peaks at 3.0 to 4.2 degrees two-theta ± 0.2 degrees two-theta.

[0063] According to any aspect or embodiment of the present disclosure, crystalline Form 4 of dipalertinib is preferably isolated.

[0064] Dipalertinib crystalline Form 4 may be characterized by each and every possible combination of the above characteristics.

[0065] According to any aspect or embodiment of the present disclosure, crystalline Form 4 of dipalertinib may be polymorphically pure or may be substantially free of any other solid state forms of dipalertinib.

[0066] The present disclosure includes a complex of crystalline dipalertinib and succinic acid.

[0067] The crystalline dipalertinib succinic acid complex can be a co-crystal of dipalertinib and succinic acid. Alternatively, the crystalline dipalertinib succinic acid can be a salt, i.e., dipalertinib succinate salt. In a preferred embodiment, the crystalline dipalertinib succinic acid complex is a co-crystal of dipalertinib and succinic acid.

[0068] The present disclosure further includes a crystalline polymorph of dipalertinib succinic acid designated Form C1.

[0069] In some embodiments, the molar ratio between the active pharmaceutical ingredient dipalertinib and the co-former succinic acid in crystalline Form C1 is between 2:1.5 and 2.5:1, preferably between 2:1.25 and 2.25:1, and in other embodiments, about 2:1.

[0070] Crystalline dipareltinib succinic acid form C1 can 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, an XRPD, or an XRPD pattern as depicted in Figure 3, or a combination thereof. Crystalline dipareltinib succinic acid form C1 can be further described 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 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.

[0071] Crystalline dipareltinib succinic acid Form C1 can 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 two-theta ± 0.2 degrees two-theta.

[0072] According to any aspect or embodiment, dipalertinib succinic acid crystalline Form C1 may be further characterized by an XRPD pattern as described in any of the embodiments herein, wherein the XRPD pattern is absent from a peak at 3.0 to 4.3 degrees two-theta ± 0.2 degrees two-theta. Alternatively or additionally, according to any aspect or embodiment of the present disclosure, dipalertinib succinic acid crystalline Form C1 may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments herein, wherein the X-ray powder diffraction pattern is absent from a peak at 4.9 to 7.0 degrees two-theta ± 0.2 degrees two-theta.

[0073] Alternatively, crystalline dipareltinib succinic acid Form C1 may have a solid-state solubility in water having characteristic peaks at the following: 179.9, 165.6, 156.2, 146.8, and 126.5 ppm±0.2 ppm. 13 C NMR spectrum, solid state as illustrated in either Figure 8a, Figure 8b or Figure 8c 13C NMR spectrum, C NMR spectrum, and combinations thereof. Crystalline dipalertinib succinic acid Form C1 may be characterized by solid-state NMR spectra having the following absolute chemical shift differences from the reference peak at 102.82 ppm ± 1 ppm: 77.1, 62.7, 53.3, 44.0, and 23.7 ppm ± 0.1 ppm. 13 C NMR spectrum, solid state with 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 13 C NMR, as well as combinations thereof.

[0074] According to any aspect or embodiment of the present disclosure, the crystalline dipalertinib succinic acid Form C1 is preferably isolated.

[0075] Dipalertinib succinic acid crystalline Form C1 can be an anhydrous form. Typically, the water content in dipalertinib succinic acid crystalline Form C1 is 1% (w / w) or less, or 0.5% (w / w) or less, preferably 0.3% (w / w) or less, as determined by TGA.

[0076] Dipalertinib succinic acid crystalline Form C1 may be characterized by each and every possible combination of the above characteristics alone or in any combination, for example, an XRPD pattern having peaks at 7.5, 8.5, 9.3, 11.7, and 14.5 degrees two-theta ± 0.2 degrees two-theta, an XRPD pattern as depicted in FIG. 3, and combinations thereof.

[0077] According to any aspect or embodiment of the present disclosure, crystalline Form C1 of dipalertinib succinic acid may be polymorphically pure or may be substantially free of any other solid state forms of dipalertinib succinic acid.

[0078] The present disclosure further includes a crystalline polymorph of dipareltinib succinic acid designated Form C3. Crystalline dipareltinib succinic acid Form C3 can 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 an XRPD pattern as depicted in Figure 4, or a combination thereof. Crystalline dipareltinib succinic acid Form C3 can be further described 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 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.

[0079] Crystalline dipareltinib succinic acid Form C3 can 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 two-theta ± 0.2 degrees two-theta.

[0080] According to any aspect or embodiment, crystalline Form C3 of dipalertinib succinic acid may be further characterized by an XRPD pattern as described in any of the embodiments herein, wherein the XRPD pattern is absent from a peak at 3.0 to 6.0 degrees two-theta ± 0.2 degrees two-theta. Alternatively or additionally, according to any aspect or embodiment of the present disclosure, crystalline Form C3 of dipalertinib succinic acid may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments herein, wherein the XRPD pattern is absent from a peak at 9.3 to 10.3 degrees two-theta ± 0.2 degrees two-theta.

[0081] According to any aspect or embodiment of the present disclosure, the crystalline dipalertinib succinic acid Form C3 is preferably isolated.

[0082] Dipalertinib succinic acid crystalline form C3 may be characterized by each and every possible combination of the above characteristics, for example, an XRPD pattern having peaks at 6.9, 14.8, 21.2, 23.7, and 25.3 degrees two-theta ± 0.2 degrees two-theta, an XRPD pattern as depicted in FIG. 4, and combinations thereof.

[0083] According to any aspect or embodiment of the present disclosure, crystalline Form C3 of dipalertinib succinic acid may be polymorphically pure or may be substantially free of any other solid state forms of dipalertinib succinic acid.

[0084] The present disclosure includes a complex of crystalline dipalertinib and fumaric acid, or crystalline dipalertinib and fumaric acid.

[0085] The crystalline dipalertinib fumarate or the complex of crystalline dipalertinib and fumaric acid may be a co-crystal of dipalertinib and fumaric acid. Alternatively, the crystalline dipalertinib fumarate may be a salt, i.e., dipalertinib fumarate.

[0086] The present disclosure further includes a crystalline polymorph of dipalertinib fumarate designated as Form C2. Crystalline dipalertinib fumarate Form C2 can 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 an XRPD pattern as depicted in Figure 11, or a combination thereof. Crystalline dipalertinib fumarate Form C2 can be further described 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.

[0087] Crystalline dipalertinib fumarate Form C2 can 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 two-theta ± 0.2 degrees two-theta.

[0088] According to any aspect or embodiment, crystalline form C2 of dipalertinib fumarate can be further characterized by an XRPD pattern as described in any of the embodiments herein, wherein the XRPD pattern is absent from a peak at 3.0 to 4.0 degrees two-theta ± 0.2 degrees two-theta. Alternatively or additionally, according to any aspect or embodiment of the present disclosure, crystalline form C2 of dipalertinib fumarate can be characterized by an X-ray powder diffraction pattern as described in any of the embodiments herein, wherein the X-ray powder diffraction pattern is absent from a peak at 7.2 to 8.2 degrees two-theta ± 0.2 degrees two-theta. Alternatively or additionally, according to any aspect or embodiment of the present disclosure, crystalline form C2 of dipalertinib fumarate can be characterized by an X-ray powder diffraction pattern as described in any of the embodiments herein, wherein the X-ray powder diffraction pattern is absent from a peak at 9.5 to 10.2 degrees two-theta ± 0.2 degrees two-theta.

[0089] According to any aspect or embodiment of the present disclosure, the crystalline dipalertinib fumarate Form C2 is preferably isolated.

[0090] Dipalertinib fumarate crystalline form C2 may be characterized by each and every possible combination of the above characteristics alone or in any combination, for example, an XRPD pattern having peaks at 5.5, 6.5, 8.8, 13.8, and 25.7 degrees two-theta ± 0.2 degrees two-theta, an XRPD pattern as depicted in FIG. 11, and combinations thereof.

[0091] According to any aspect or embodiment of the present disclosure, crystalline Form C2 of dipalertinib fumarate may be polymorphically pure or may be substantially free of any other solid state forms of dipalertinib fumarate.

[0092] The present disclosure includes a complex of crystalline dipalertinib and adipic acid.

[0093] The crystalline dipalertinib adipic acid complex can be a co-crystal of dipalertinib and adipic acid. Alternatively, the crystalline dipalertinib adipic acid can be a salt, i.e., dipalertinib adipic acid salt. In a preferred embodiment, the crystalline dipalertinib adipic acid complex is a co-crystal of dipalertinib and adipic acid.

[0094] The present disclosure further includes a crystalline polymorph of dipalertinib adipic acid designated Form C6. Crystalline dipalertinib adipic acid Form C6 can 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 an XRPD pattern as depicted in Figure 9, or a combination thereof. Crystalline dipalertinib adipic acid Form C6 can be further described 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.

[0095] Crystalline dipalertinib adipic acid Form C6 can 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 two-theta ± 0.2 degrees two-theta.

[0096] According to any aspect or embodiment, crystalline Form C6 of dipalertinib adipic acid can be further characterized by an XRPD pattern as described in any of the embodiments herein, wherein the XRPD pattern is absent from a peak at 3.0 to 4.3 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to any aspect or embodiment of the present disclosure, crystalline Form C6 of dipalertinib adipic acid can be characterized by an X-ray powder diffraction pattern as described in any of the embodiments herein, wherein the X-ray powder diffraction pattern is absent from a peak at 6.5 to 6.8 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to any aspect or embodiment of the present disclosure, crystalline Form C6 of dipalertinib adipic acid can be characterized by an X-ray powder diffraction pattern as described in any of the embodiments herein, wherein the X-ray powder diffraction pattern is absent from a peak at 8.0 to 9.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0097] Alternatively, crystalline dipalertinib adipic acid Form C6 has a solid-state solubility profile having characteristic peaks at the following: 178.8, 174.1, 166.5, 156.7, and 107.9 ppm±0.2 ppm. 13 C NMR spectrum, solid state as illustrated in either Figure 10a, Figure 10b or Figure 10c 13 C NMR spectrum, C NMR spectrum, and combinations thereof. Crystalline dipalertinib adipic acid Form C6 has a solid-state NMR spectrum with the following absolute chemical shifts from the reference peak of 101.8 ppm ± 1 ppm: 77.0, 72.3, 64.7, 54.9, and 6.1 ppm ± 0.1 ppm. 13 C NMR spectrum, solid state with 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 13 C NMR, as well as combinations thereof.

[0098] According to any aspect or embodiment of the present disclosure, the crystalline dipalertinib adipic acid Form C6 is preferably isolated.

[0099] Dipalertinib adipic acid crystalline form C6 can be anhydrous. Typically, the water content of dipalertinib adipic acid crystalline form C6 is 1% (w / w) or less, as determined by, for example, TGA.

[0100] Dipalertinib adipic acid crystalline Form C6 exhibits each and every possible combination of the above characteristics, for example, an XRPD pattern having peaks at 5.3, 5.9, 11.9, 14.3, and 17.8 degrees two-theta ± 0.2 degrees two-theta; a solid-state XRPD pattern as illustrated in Figure 10a; 13 C NMR spectra, as well as combinations of these.

[0101] According to any aspect or embodiment of the present disclosure, crystalline Form C6 of dipalertinib adipic acid may be polymorphically pure or may be substantially free of any other solid state forms of dipalertinib adipic acid.

[0102] The above crystalline polymorphs and co-crystals can be used to prepare other crystalline polymorphs of dipalertinib, other salts or co-crystals of dipalertinib, and solid-state forms thereof. The solid-state forms can be crystalline polymorphs, co-crystals, and complexes of dipalertinib or dipalertinib salts.

[0103] The present disclosure encompasses methods for preparing other solid-state forms of dipalertinib or dipalertinib salts and co-crystals. The methods include preparing any one of the crystalline polymorphs of dipalertinib by the methods of the present disclosure. The methods can further include converting the crystalline polymorph of dipalertinib to another crystalline polymorph of dipalertinib or another dipalertinib salt or co-crystal.

[0104] The present disclosure provides the above crystalline polymorphs of dipalertinib and dipalertinib complexes for use in preparing pharmaceutical compositions comprising dipalertinib or dipalertinib complexes and / or these crystalline polymorphs.

[0105] The present disclosure also encompasses the use of the crystalline polymorphs of dipalertinib or dipalertinib complex of the present disclosure for the preparation of pharmaceutical compositions of crystalline polymorphs of dipalertinib and / or these crystalline polymorphs. In particular, the pharmaceutical compositions can be used for oral administration.

[0106] The present disclosure includes methods for preparing the pharmaceutical compositions mentioned above. These methods include combining any one or a combination of the crystalline polymorphs of dipalertinib or dipalertinib complex of the present disclosure with at least one pharmaceutically acceptable excipient. In particular, the pharmaceutical composition can include a pharmaceutically acceptable excipient suitable for preparing a formulation for oral administration. The pharmaceutical combination or pharmaceutical preparation of the present disclosure contains any one or a combination of the solid-state forms of dipalertinib of the present disclosure. In addition to the active ingredient, the pharmaceutical preparation of the present disclosure may contain one or more excipients. Excipients are added to the formulation for a variety of purposes. For example, excipients can be added to help form a formulation suitable for oral administration.

[0107] Diluents can increase the bulk of a solid pharmaceutical composition and make it easier for patients and caregivers to handle pharmaceutical dosage forms containing the composition. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugars, 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.

[0108] Solid pharmaceutical compositions that are compressed into dosage forms such as tablets can contain 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, carbomers (e.g., Carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), hydroxypropylmethylcellulose (e.g., Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0109] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by adding a disintegrant to the composition, including 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, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[0110] Glidants can be added to improve the flowability of non-compacted solid compositions and 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.

[0111] When a dosage form such as a tablet is produced by compressing a powdered composition, the composition is subjected to pressure from a punch and a die. Some excipients and active ingredients tend to stick to the surface of the punch and die, which can cause holes and other surface irregularities in the product. A lubricant can be added to the composition to reduce adhesion and facilitate the release of the product from the die. 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.

[0112] Flavoring and flavor enhancers make the dosage form more palatable to the patient. Common flavoring and flavor enhancers for pharmaceutical products that can be included in the compositions of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0113] Solid and liquid compositions may also be dyed using any pharmaceutically acceptable coloring agent to improve their appearance and / or facilitate identification of the product and unit dosage level by the patient.

[0114] In liquid pharmaceutical compositions of the present invention, dipalertinib and any other solid excipients may be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0115] Liquid pharmaceutical compositions may contain emulsifying agents to uniformly disperse active ingredients or other excipients that are insoluble in the liquid carrier throughout the composition. Emulsifying agents that may be useful in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methylcellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0116] The liquid pharmaceutical compositions of the present invention may also contain thickening agents to improve the mouthfeel of the product and / or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid, bentonite, carbomer, calcium or sodium carboxymethylcellulose, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum, and combinations thereof.

[0117] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve taste.

[0118] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid can be added at ingestible levels to improve storage stability.

[0119] According to the present disclosure, the liquid composition may also contain a buffering agent such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. The choice of excipients and the amounts to be used can be readily determined by a formulation scientist empirically and with consideration of standard procedures and references in the field.

[0120] The solid compositions of the present disclosure include powders, granules, aggregates, and compressed compositions. Dosages include those suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, intranasal, and ophthalmic administration. The most suitable administration in a given case will depend on the nature and severity of the condition being treated, but in some embodiments, the route of administration is oral. Dosages are conveniently presented in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical arts.

[0121] Dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs.

[0122] The dosage form of the present disclosure may be a capsule containing a composition, such as a powdered or granulated solid composition of the present disclosure, within a hard or soft shell. The shell may be made from gelatin and may optionally contain a plasticizer such as glycerin and / or sorbitol, an opacifying agent, and / or a colorant.

[0123] The active ingredients and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0124] Compositions for tablet 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 granules are sieved and / or milled, dried, and then sieved and / or milled to the desired particle size. The granules may then be compressed into tablets, or other excipients such as glidants and / or lubricants may be added before compression.

[0125] Tableting compositions can be prepared by dry blending in a conventional manner. For example, the blended composition of the actives and excipients can be compressed into a slug or a sheet and then comminuted into compacted granules. The compacted granules can then be compressed into tablets.

[0126] As an alternative to dry granulation, the blended composition can be directly compressed into a compressed dosage form using direct compression technology.Direct compression produces more uniform tablets 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 appropriate use of these and other excipients in direct compression tableting is known to those skilled in the art who have experience and skill in the specific formulation challenges of direct compression tableting.

[0127] The capsule filling of the present disclosure may include any of the above blends and granules described with respect to tableting, but is not subjected to a final tableting step.

[0128] A pharmaceutical formulation of dipalertinib can be administered. The pharmaceutical formulation of dipalertinib can be administered, for example, orally. Dipalertinib can be formulated for administration to mammals, in some embodiments, humans. Dipalertinib can be formulated for injection, for example, as a viscous liquid solution or suspension, such as a clear solution. The formulation may 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 (allowing for syringeability), flowability, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and castor oil USP. Additional substances, such as buffers, solubilizers, and antioxidants, among others, can be added to the formulation. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7 th ed.

[0129] The crystalline polymorphs of dipalertinib and dipalertinib complexes disclosed herein, as well as pharmaceutical compositions and / or pharmaceutical formulations of dipalertinib, can be used as medicines in embodiments for the treatment of cancer, particularly NSCLC.The medicines can be preferably administered in oral form.

[0130] The present disclosure also provides a method of treating cancer, particularly NSCLC, by administering to a subject in need thereof a therapeutically effective amount of any one or combination of the crystalline polymorphs of dipalertinib or dipalertinib complex of the present disclosure, or at least one of the pharmaceutical compositions and / or pharmaceutical formulations described above.

[0131] Thus, while the present disclosure has been described with reference to certain preferred embodiments and illustrative examples, those skilled in the art will recognize that modifications are possible to the disclosure as described and illustrated without departing from the spirit and scope of the disclosure disclosed herein. The examples are set forth to aid in the understanding of the disclosure, but are not intended to, and should not be construed to, limit the scope of the disclosure in any way.

[0132] X-ray Powder Diffraction ("XRPD") Method Dipareltinib Form 1 and amorphous dipareltinib: Powder X-ray diffraction was performed on a PanAlytical X'pertPro X-ray powder diffractometer, CuKα radiation (λ=1.54187 Å), X'Celerator detector, with an effective length of 2.122 degrees 2-theta.

[0133] Dipareltinib Form 1, Dipareltinib succinate Forms C1 and C3, Dipareltinib adipic acid Form C6, Dipareltinib fumarate Form C2, and Dipareltinib Form 4: Powder X-ray diffraction was performed on a PanAlytical EMPYREAN X-ray powder diffractometer, CuKα radiation (λ=1.54187 Å), pixCel detector, with an effective length of 2.140 degrees 2-theta.

[0134] For both methods, the laboratory temperature was 25±3°C and the sample holder was background zero. Prior to analysis, the samples were lightly ground using a mortar and pestle to obtain a fine powder. The ground sample was adjusted into the cavity of the sample holder, and a cover glass was used to smooth the sample surface. Measurement parameters: Scan range: 3 to 40 degrees 2-theta Scan Mode: Continuous Process size: 0.0167 degrees (X'Pert Pro), 0.0131 degrees (EMPYREAN) Process size: 42 seconds (X'Pert Pro), 41 seconds (EMPYREAN) Sample spin: 60 rpm Sample holder: Zero background silicon plate

[0135] solid state 13 C-NMR( 13 C CP / MAS NMR) method Spectra were measured at 16.4 T using a Bruker Avance NEO 700 SB NMR spectrometer (Karlsruhe, Germany, 2021) equipped with a 3.2 mm probehead. 13 C CP / MAS NMR spectra were recorded at room temperature and corrected for frictional heating of the spinning sample. 13 C CP / MAS NMR spectra were acquired using a standard cross-polarization pulse scheme at a spin frequency of 20 kHz. The spin frequency can range from 18 kHz to 20 kHz. The cross-polarization spin-lock pulse duration was 7 ms, the spectral width was 600 ppm, and the resonance frequency offset was 100 ppm. Dipolar decoupling (SPINAL64) was applied during data acquisition. The scan number was set to reach a signal-to-noise ratio (SINO) of at least approximately 50. 13 The C scale is glycine ( 13 The standard is 176.03 ppm for C.

[0136] The NMR spectrometer was calibrated, and all experimental parameters were carefully optimized before recording the spectrum. The magic angle was set using KBr during standard optimization procedures, and the field homogeneity was optimized using an adamantine sample (resulting in a half-maximum linewidth Δν of less than 3.5 Hz with an acquisition time of 250 ms). [Example]

[0137] Preparation of starting materials Dipalertinib can be prepared according to methods known from the literature, for example WO2015025936 (and its corresponding US counterpart US Pat. No. 9,650,386).

[0138] Example 1 Preparation of amorphous dipalertinib Dipalertinib (60 mg) was suspended in 2-butanol (1.5 mL) at room temperature and heated to a temperature of approximately 95°C at a heating rate of 0.5°C / min, forming a clear solution. The solution was cooled to a temperature of approximately 10°C at a cooling rate of 1°C / min. Next, n-heptane (2.5 mL) was added at a temperature of approximately 10°C, causing the solution to become cloudy. The resulting suspension was stirred for 100 minutes and cooled to a temperature of approximately 0°C over approximately 1 hour. An additional volume of n-heptane (1 mL) was added at a temperature of approximately 0°C. The suspension was filtered and dried under vacuum at room temperature for approximately 15 minutes. The XRPD pattern is shown in Figure 2.

[0139] Example 2 Preparation of dipareltinib form 1 Dipalertinib (100 mg) was suspended in dimethylformamide ("DMF", 600 μl) at room temperature, and the suspension was heated to a temperature of about 70° C. for about 30 minutes, forming a clear solution. The solution was stirred at a temperature of about 70° C. for about 20 minutes. The clear solution was cooled to a temperature of about 0° C. for about 2 hours. During the cooling period, water (400 μl) was added at a temperature of about 18° C., and an additional volume of water (200 μl) was added at a temperature of about 0° C., forming a suspension. 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 vacuum at room temperature for about 1 hour. The solid was analyzed by XRPD, and Form 1 was obtained. The XRPD pattern is shown in FIG. 1.

[0140] Example 3 Preparation of dipareltinib form 1 Dipalertinib (6 grams) was dissolved in ethanol (55 mL) at room temperature. The sample was heated to 70°C for approximately 30 minutes. Dipalertinib crystallized during heating, and the resulting suspension was stirred at 70°C for an additional 10 minutes. The suspension was cooled to approximately 5°C over approximately 3 hours. The suspension was stirred at 5°C for 18 hours. The suspension was filtered and dried under a nitrogen stream at room temperature for approximately 75 minutes. The solid was analyzed by XRPD to obtain Form 1.

[0141] Example 4 Preparation of amorphous dipalertinib Dipalertinib (5 grams) was dissolved in a mixture of dichloromethane (100 mL) and methanol (200 mL) at room temperature. The resulting clear solution was filtered to remove foreign particles. The solvent was evaporated to dryness in a rotary evaporator at a temperature of about 60°C. The solid was analyzed by XRPD, and an amorphous form of dipalertinib was obtained.

[0142] Example 5 Preparation of Crystalline Dipareltinib Succinic Acid Form C1 Dipalertinib (100 mg) and succinic acid (15 mg) were suspended in ethanol (1 mL) at room temperature. The sample was heated to 70°C for approximately 30 minutes, during which time the compound dissolved and crystallized. The resulting suspension was stirred at 70°C for 20 minutes. The suspension was cooled to approximately 10°C over approximately 3 hours. The suspension was stirred at approximately 10°C for 30 minutes. The suspension was filtered and dried under vacuum at room temperature for approximately 30 minutes. The solid was analyzed by XRPD to obtain Form C1. The XRPD pattern is shown in Figure 3.

[0143] Example 6 Preparation of crystalline dipareltinib succinate form C3 Dipalertinib (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 for about 30 minutes, during which time the sample dissolved and crystallized. The suspension was stirred at a temperature of about 70°C for 20 minutes. The suspension was cooled to a temperature of about 10°C over about 3 hours. The suspension was stirred at 10°C for 30 minutes. The suspension was filtered and dried under vacuum at room temperature for about 30 minutes. The solid was analyzed by XRPD to obtain Form C3. The XRPD pattern is shown in Figure 4.

[0144] Example 7 Preparation of crystalline dipalertinib Form 2 Dipalertinib amorphous form (80 mg) was suspended in ethylal (1 ml) at room temperature. The resulting suspension was heated to a temperature of about 75°C at a heating rate of 0.5°C / min. The suspension was stirred at a temperature of about 75°C for 30 minutes, then cooled to 5°C at a cooling rate of 1°C / min, and stirred at a temperature of about 5°C for 20 hours and 30 minutes. The sample was filtered and dried under vacuum at room temperature for 15 minutes. The solid was analyzed by XRPD to obtain Form 2.

[0145] Example 8 Preparation of crystalline dipalertinib Form 2 Dipalertinib amorphous form (200 mg) was slurried in ethylal (3 ml) at room temperature for at least 2 days. The sample was filtered and dried under vacuum at room temperature for 15 minutes. The solid was analyzed by XRPD and Form 2 was obtained.

[0146] Example 9 Preparation of crystalline dipalertinib Form 2 Dipalertinib amorphous form (200 mg) was slurried in ethylal (3 ml) at a temperature of about 40° C. for at least 2 days. The sample was filtered and dried under vacuum at room temperature for 15 minutes. The XRPD pattern is shown in FIG. 5.

[0147] Further aspects and embodiments of the present disclosure are described in the numbered clauses presented in Lists A and B below.

[0148] Example 10 Preparation of crystalline dipalertinib adipic acid form C6 Dipalertinib (60 mg) and adipic acid (23 mg) were suspended in ethanol (1 mL) at room temperature. The suspension was heated to 75°C at a heating rate of 0.5°C / min and then stirred at 75°C for 30 minutes to obtain a clear solution. The solution was then cooled to a temperature of about 20°C at a cooling rate of 1°C / min. The suspension was filtered and dried under vacuum at room temperature for about 30 minutes. The solid was analyzed by XRPD to obtain Form C6. The XRPD pattern is shown in Figure 9.

[0149] Example 11 Preparation of crystalline dipalertinib adipic acid form C6 Dipalertinib (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 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 vacuum at room temperature for about 2 hours. The solid was analyzed by XRPD to obtain Form C6.

[0150] Example 12 Preparation of Crystalline Dipalertinib Fumarate Form C2 Dipalertinib (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. Dipalertinib fumaric acid Form C2 was obtained. The XRPD pattern is shown in FIG. 11.

[0151] Example 13 Preparation of Crystalline Dipalertinib Fumarate Form C2 Dipalertinib (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 for about 30 minutes. An additional volume of ethanol (6 ml) was added to obtain a clear solution. The solution was stirred at a temperature of about 70°C for 5 minutes. The solution was cooled to a temperature of about 10°C over about 3 hours. The sample crystallized during the cooling period. The suspension was filtered and dried under vacuum at room temperature for 12 hours. The solid was analyzed by XRPD and Form C2 was obtained.

[0152] Example 14 Preparation of amorphous dipalertinib - high scale Dipalertinib (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 in a rotary evaporator at 60° C. within 1 hour. The solid was analyzed by XRPD, and an amorphous form was obtained.

[0153] Example 15 Preparation of crystalline dipalertinib Form 4 Amorphous dipalertinib (300 mg) was suspended in water (2 ml) and stirred at a temperature of about 40° C. for 7 days. The sample was filtered and dried under vacuum and a nitrogen stream for 30 minutes. The solid was analyzed by XRPD to give Form 4. The XRPD pattern is shown in FIG.

[0154] Example 16 Preparation of crystalline dipareltinib succinate form C1 (2:1) - high scale Dipalertinib (6 g) and succinic acid (902 mg) were suspended in ethanol (130 ml). The suspension was heated to a temperature of about 74°C for about 30 minutes to obtain a clear solution. The volume of the solvent was reduced to 90 ml on a rotary evaporator, resulting in the appearance of small crystals. The suspension was again stirred at a temperature of about 74°C and cooled to 5°C over a period of about 8 hours. The suspension was stirred at a temperature of about 5°C for 24 hours, filtered, and dried under vacuum at room temperature for 1 hour. The solid was analyzed by XRPD to obtain Form C1.

[0155] Example 17 Preparation of Crystalline Dipalertinib Fumarate Form C2 Dipalertinib (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 to dryness. The resulting solid was analyzed by XRPD and confirmed to be dipalertinib fumaric acid Form C2.

[0156] Stability testing Samples of dipalertinib Form 1 and dipalertinib succinic acid Form C1 were conditioned at different temperatures and relative humidities. XRPD analysis was performed on the samples after 6 months. Samples of dipalertinib adipic acid Form C6 were conditioned at different temperatures and relative humidities and XRPD analysis was performed after 4 months. The results are shown in Table 1 below.

[0157] [Table 1]

[0158] The results demonstrate that dipalertinib Form 1, dipalertinib succinate Form C1, and dipalertinib 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.

[0159] Further aspects and embodiments of the present disclosure are described below in numbered clauses 1A to 22A. 1A. Crystalline dipareltinib succinate. 2A. Cocrystal, crystalline dipalertinib succinate. 3A. Crystalline dipareltinib succinate. 4A. Below: (a) an XRPD pattern with peaks at 7.5, 8.5, 9.3, 11.7 and 14.5 degrees 2-theta ± 0.2 degrees 2-theta; (b) XRPD pattern as illustrated in Figure 3; (c) A solid-state compound having characteristic peaks at 179.9, 165.6, 156.2, 146.8, and 126.5 ppm ± 0.2 ppm. 13 C NMR spectrum, (d) In solid state as illustrated in any of Figures 8a, 8b or 8c. 13 C NMR spectrum, and (e) Combination of these data A crystalline product according to clause 1A, 2A, or 3A, designated as Form C1, characterized by data selected from one or more of: 5A. A crystalline product according to any of clauses 1A, 2A, 3A or 4A designated as Form C1, characterized by 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, and one, two, three or four additional peaks selected from 13.6, 15.9, 17.1, 17.8 and 21.1 degrees 2-theta ± 0.2 degrees 2-theta. 6A. A crystalline product according to any of clauses 1A, 2A, 3A, 4A, or 5A designated as Form C1, characterized by an 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. The crystalline product according to any of clauses 1A, 2A, 3A, 4A, 5A, or 6A, further characterized by an XRPD pattern having no peaks present at 3.0 to 4.3 degrees two-theta ± 0.2 degrees two-theta. 8A. A crystalline product according to any of clauses 1A, 2A, 3A, 4A, 5A, 6A, or 7A, further characterized by an XRPD pattern having no peaks present at 4.9 to 7.0 degrees two-theta ± 0.2 degrees two-theta. 9A. Solid-state fluoride with characteristic peaks at 179.9, 165.6, 156.2, 146.8 and 126.5 ppm ± 0.2 ppm 13 C NMR spectrum and the solid-state C NMR spectrum with the following absolute chemical shift differences from the reference peak at 102.82 ppm ± 1 ppm: 77.1, 62.7, 53.3, 44.0, and 23.7 ppm ± 0.1 ppm. 13 A crystalline product according to any of Article 1A, 2A, 3A, 4A, 5A, 6A, 7A, or 8A designated as Form C1, characterized by a C NMR spectrum. 10A. Solid-state chromatographic analysis with 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 13 A crystalline product according to any of Article 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, or 9A designated as Form C1, characterized by a C NMR spectrum. 11A. A crystalline product according to any of clauses 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, or 10A designated as Form C1, wherein the crystalline form is an anhydrous form. 12A. A crystalline product according to any of clauses 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, or 11A designated as Form C1, containing no more than 1% (w / w) or no more than 0.5% (w / w), preferably no more than 0.3% (w / w), as determined by TGA. 13A. The crystalline product according to any of clauses 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, or 12A designated as Form C1, containing about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% of dipareltinib succinic acid or any other crystalline form of crystalline dipareltinib succinate. 14A. The crystalline product according to any of clauses 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, or 13A designated as Form C1, containing about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% amorphous dipareltinib succinic acid or crystalline dipareltinib succinate. 15A. A pharmaceutical composition comprising a crystalline product according to any of clauses 1A to 14A and at least one pharmaceutically acceptable excipient. 16A. Use of a crystalline product according to any of clauses 1A to 14A for the preparation of a pharmaceutical composition and / or pharmaceutical formulation, preferably wherein the pharmaceutical formulation is a tablet, capsule, etc. 17A. A method for preparing a pharmaceutical composition according to clause 15A, comprising combining a crystalline product according to any of clauses 1A-14A with at least one pharmaceutically acceptable excipient. 18A. A crystalline product according to any of clauses 1A to 14A or a pharmaceutical composition according to clause 15A for use as a medicament. 19A. A crystalline product according to any of clauses 1A to 14A or a pharmaceutical composition according to clause 15A for use in the treatment of cancer, in particular non-small cell lung cancer. 20A. A method for treating cancer, such as non-small cell lung cancer, comprising administering to a subject in need of treatment a therapeutically effective amount of a crystalline product according to any of clauses 1A to 14A or a pharmaceutical composition according to clause 15A. 21A. Use of a crystalline product according to any of clauses 1A to 14A in the preparation of another solid-state form of dipareltinib succinic acid or dipareltinib succinate. 22A. A method for preparing a solid-state form of dipalertinib succinic acid or dipalertinib succinate salt, comprising preparing any one or combination of crystalline products according to any one of clauses 1A-14A and converting it to another solid-state form thereof.

[0160] Further aspects and embodiments of the present disclosure are described below in numbered clauses 1B to 18B. 1B. Crystalline dipareltinib succinate. 2B. Cocrystal, crystalline dipalertinib succinate. 3B. Crystalline dipareltinib succinate. 4B. Below: (a) an XRPD pattern with peaks at 6.9, 14.8, 21.2, 23.7 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta; (b) XRPD pattern as illustrated in Figure 4, and (c) Combination of these data A crystalline product according to clause 1B, 2B, or 3B designated as Form C3, characterized by data selected from one or more of: 5B. A crystalline product according to any of clauses 1B, 2B, 3B or 4B designated as Form C3, characterized by 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, and one, two, three or four additional peaks selected from 11.1, 19.4, 20.4, 22.9 and 27.7 degrees 2-theta ± 0.2 degrees 2-theta. 6B. A crystalline product according to any of clauses 1B, 2B, 3B, 4B or 5B designated as Form C3, characterized by an 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. The crystalline product according to any of clauses 1B, 2B, 3B, 4B, 5B, or 6B, further characterized by an XRPD pattern that is free of peaks at 3.0 to 6.0 degrees two-theta ± 0.2 degrees two-theta. 8B. The crystalline product according to any of clauses 1B, 2B, 3B, 4B, 5B, 6B, or 7B, further characterized by an XRPD pattern that is free of peaks at 9.3 to 10.3 degrees two-theta ± 0.2 degrees two-theta. 9B. The crystalline product according to any of clauses 1B, 2B, 3B, 4B, 5B, 6B, 7B, or 8B designated as Form C3, containing about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% of dipareltinib succinic acid or any other crystalline form of crystalline dipareltinib succinate. 10B. A crystalline product according to any of clauses 1B, 2B, 3B, 4B, 5B, 6B, 7B, 8B, or 9B designated as Form C3, containing about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% amorphous dipareltinib succinic acid or crystalline dipareltinib succinate. 11B. A pharmaceutical composition comprising a crystalline product according to any of clauses 1B-10B and at least one pharmaceutically acceptable excipient. 12B. Use of a crystalline product according to any of clauses 1B to 10B for the preparation of a pharmaceutical composition and / or pharmaceutical formulation, preferably wherein the pharmaceutical formulation is a tablet, capsule, etc. 13B. A method for preparing a pharmaceutical composition according to clause 11B, comprising combining a crystalline product according to any of clauses 1B-10B with at least one pharmaceutically acceptable excipient. 14B. A crystalline product according to any of clauses 1B to 10B or a pharmaceutical composition according to clause 11B for use as a medicament. 15B. A crystalline product according to any of clauses 1B to 10B or a pharmaceutical composition according to clause 11B for use in the treatment of cancer, in particular non-small cell lung cancer. 16B. A method of treating cancer, such as non-small cell lung cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline product according to any of clauses 1B to 10B or a pharmaceutical composition according to clause 11B. 17B. Use of a crystalline product according to any of clauses 1B to 10B in the preparation of another solid-state form of dipareltinib succinic acid or dipareltinib succinate. 18B. A method for preparing a solid-state form of dipalertinib succinic acid or dipalertinib succinate salt, comprising preparing any one or combination of crystalline products according to any one of clauses 1B-10B and converting it to another solid-state form thereof.

[0161] Further aspects and embodiments of the present disclosure are described below in numbered clauses 1C to 23C. 1C. Crystalline dipalertinib adipic acid. 2C. Cocrystal, crystalline dipalertinib adipic acid. 3C. Crystalline dipalertinib adipate. 4C. Below: (a) an XRPD pattern with peaks at 5.3, 5.9, 11.9, 14.3 and 17.8 degrees 2-theta ± 0.2 degrees 2-theta; (b) XRPD pattern as illustrated in Figure 9, and (c) Combination of these data A crystalline product according to clause 1C, 2C, or 3C designated as Form C6, characterized by data selected from one or more of: 5C. A crystalline product according to any of clauses 1C, 2C, 3C or 4C designated as Form C6, characterized by 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, and one, two, three or four additional peaks selected from 7.5, 10.9, 13.3, 15.9 and 16.8 degrees 2-theta ± 0.2 degrees 2-theta. 6C. A crystalline product according to any of clauses 1C, 2C, 3C, 4C or 5C designated as Form C6, characterized by an XRPD pattern having peaks at 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. The crystalline product according to any of clauses 1C, 2C, 3C, 4C, 5C, or 6C, further characterized by an XRPD pattern that is free of peaks at 3.0 to 4.3 degrees two-theta ± 0.2 degrees two-theta. 8C. The crystalline product according to any of clauses 1C, 2C, 3C, 4C, 5C, 6C, or 7C, further characterized by an XRPD pattern lacking a peak at 6.5 to 6.8 degrees two-theta ± 0.2 degrees two-theta. 9C. The crystalline product according to any of clauses 1C, 2C, 3C, 4C, 5C, 6C, 7C or 8C, further characterized by an XRPD pattern having no peaks present at 8.0 to 9.2 degrees two-theta ± 0.2 degrees two-theta. 10C. or less: (a) A solid-state ionomer having characteristic peaks at 178.8, 174.1, 166.5, 156.7, and 107.9 ppm ± 0.2 ppm. 13 C NMR spectrum, (b) In solid state as illustrated in either Figure 10a, Figure 10b or Figure 10c 13 C NMR spectrum, and (c) Combination of these data The crystalline product according to any of clauses 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, or 9C, characterized by data selected from one or more of: 11C. Solid-state 101.8 ppm ± 1 ppm reference peak with the following absolute chemical shift differences: 77.0, 72.3, 64.7, 54.9, and 6.1 ppm ± 0.1 ppm. 13 A crystalline product according to any of Article 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, or 10C designated as Form C6, characterized by a C NMR spectrum. 12C. Solid state chromatogram with 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 13 A crystalline product according to any of clauses 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, 10C, or 11C designated as Form C6, characterized by C NMR. 13C. A crystalline product according to any of clauses 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, 10C, 11C, or 12C designated as Form C6, which is an anhydrous form. 14C. A crystalline product according to any of clauses 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, 10C, 11C, 12C, or 13C, having a water content of 1% (w / w) or less. 15C. The crystalline product according to any of clauses 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, 10C, 11C, 12C, 13C, or 14C designated as Form C6, containing about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% of dipalertinib adipic acid or any other crystalline form of crystalline dipalertinib adipic acid salt. 16C. A pharmaceutical composition comprising a crystalline product according to any of clauses 1C to 15C and at least one pharmaceutically acceptable excipient. 17C. Use of a crystalline product according to any of clauses 1C to 15C for the preparation of a pharmaceutical composition and / or pharmaceutical formulation, preferably wherein the pharmaceutical formulation is a tablet, capsule, or the like. 18C. A method for preparing a pharmaceutical composition according to clause 16C, comprising combining a crystalline product according to any of clauses 1C to 15C with at least one pharmaceutically acceptable excipient. 19C. A crystalline product according to any of clauses 1C to 15C or a pharmaceutical composition according to clause 16C for use as a medicament. 20C. A crystalline product according to any of clauses 1C to 15C or a pharmaceutical composition according to clause 16C for use in the treatment of cancer, in particular non-small cell lung cancer. 21C. A method for treating cancer, such as non-small cell lung cancer, comprising administering to a subject in need of treatment a therapeutically effective amount of a crystalline product according to any of clauses 1C to 15C or a pharmaceutical composition according to clause 16C. 22C. Use of a crystalline product according to any of clauses 1C to 15C in the preparation of another solid-state form of dipalertinib adipic acid or dipalertinib adipic acid salt. 23C. A method for preparing a solid-state form of dipalertinib adipic acid or dipalertinib adipic acid salt, comprising preparing any one or combination of crystalline products according to any one of clauses 1C to 15C and converting it to another solid-state form thereof.

[0162] Further aspects and embodiments of the present disclosure are described in numbered clauses 1D to 18D below. 1D. Crystalline dipareltinib fumarate. 2D. Crystalline dipalertinib fumarate, a cocrystal. 3D. Crystalline dipalertinib fumarate. 4D. Below: (a) an XRPD pattern with peaks at 5.5, 6.5, 8.8, 13.8 and 25.7 degrees 2-theta ± 0.2 degrees 2-theta; (b) XRPD pattern as illustrated in Figure 11, and (c) Combination of these data A crystalline product according to clause 1D, 2D, or 3D, designated C2, characterized by data selected from one or more of: 5D. A crystalline product according to any of Clauses 1D, 2D, 3D or 4D designated as Form C2, characterized by 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, and also having one, two, three or four additional peaks selected from 11.1, 18.4, 20.4, 27.1 and 28.0 degrees 2-theta ± 0.2 degrees 2-theta. 6D. A crystalline product according to any of Articles 1D, 2D, 3D, 4D or 5D designated as Form C2, characterized by an 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 2-theta ± 0.2 degrees 2-theta. 7D. The crystalline product according to any of clauses 1D, 2D, 3D, 4D, 5D, or 6D, further characterized by an XRPD pattern having no peaks present at 3.0 to 4.0 degrees two-theta ± 0.2 degrees two-theta. 8D. The crystalline product according to any of clauses 1D, 2D, 3D, 4D, 5D, 6D, or 7D, further characterized by an XRPD pattern having no peaks present at 7.2 to 8.2 degrees two-theta ± 0.2 degrees two-theta. 9D. The crystalline product according to any of clauses 1D, 2D, 3D, 4D, 5D, 6D, 7D, or 8D, further characterized by an XRPD pattern having no peaks present at 9.5 to 10.2 degrees two-theta ± 0.2 degrees two-theta. 10D. A crystalline product according to any of clauses 1D, 2D, 3D, 4D, 5D, 6D, 7D, 8D, or 9D designated as Form C2, containing about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% of dipalertinib fumarate or any other crystalline form of crystalline dipalertinib fumarate. 11D. A pharmaceutical composition comprising a crystalline product according to any of clauses 1D-10D and at least one pharmaceutically acceptable excipient. 12D. Use of a crystalline product according to any of clauses 1D to 10D for the preparation of a pharmaceutical composition and / or pharmaceutical formulation, preferably wherein the pharmaceutical formulation is a tablet, capsule, etc. 13D. A method for preparing a pharmaceutical composition according to clause 11D, comprising combining a crystalline product according to any of clauses 1D-10D with at least one pharmaceutically acceptable excipient. 14D. A crystalline product according to any of clauses 1D to 10D or a pharmaceutical composition according to clause 11D for use as a medicament. 15D. A crystalline product according to any of clauses 1D to 10D or a pharmaceutical composition according to clause 11D for use in the treatment of cancer, in particular non-small cell lung cancer. 16D. A method for treating cancer, such as non-small cell lung cancer, comprising administering to a subject in need of treatment a therapeutically effective amount of a crystalline product according to any of clauses 1D to 10D or a pharmaceutical composition according to clause 11D. 17D. Use of a crystalline product according to any of clauses 1D to 10D in the preparation of another solid-state form of dipareltinib fumarate or dipareltinib fumarate salt. 18D. A method for preparing a solid-state form of dipalertinib fumarate or dipalertinib fumarate salt, comprising preparing any one or combination of crystalline products according to any one of clauses 1D-10D and converting it to another solid-state form thereof.

[0163] Further aspects and embodiments of the present disclosure are described below in numbered clauses 1E to 17E. 1E. Below: (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 that does not exhibit peaks (no peaks) in the regions of 14.9 to 15.4 degrees 2-theta, 20.4 to 21.2 degrees 2-theta, and 22.2 to 22.4 degrees 2-theta; or (c) XRPD pattern as illustrated in Figure 5, and (d) Combinations of these 1. Crystalline dipalertinib Form 2, characterized by data selected from one or more of: 2E. Crystalline Form 2 according to clause 1E, 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 no peaks (absence of peaks) in the regions of 14.9 to 15.4 degrees 2-theta, 20.4 to 21.2 degrees 2-theta and 22.2 to 22.4 degrees 2-theta. 3E. Crystalline Form 2 according to Clause 1E or Clause 2E characterized by an XRPD pattern that is absent a peak at 3.0 to 7.2 degrees two-theta ± 0.2 degrees two-theta. 4E. Crystalline Form 2 according to any of clauses 1E, 2E or 3E, characterized by an XRPD pattern that is absent a peak at 8.4 to 9.2 degrees 2-theta ± 0.2 degrees 2-theta. 5E. Crystalline Form 2 of dipalertinib according to any of clauses 1E, 2E, 3E, or 4E, characterized by any one or more of the following: (a) A solid-state ionomer having characteristic peaks at 164.2, 146.1, 136.5, 129.0, and 120.9 ppm ± 0.2 ppm. 13 C NMR spectrum, (b) In solid state as illustrated in any of Figures 7a, 7b or 7c 13 C NMR spectrum, (c) solid-state chromatograms with the following absolute chemical shift differences from the reference peak of 103.5 ppm ± 1 ppm: 60.7, 42.6, 33.0, 25.5, and 17.4 ppm ± 0.1 ppm 13 C NMR spectrum, (d) A solid state ion concentration of 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. 13 C NMR spectrum, and (e) Combinations of these. 6E. Crystalline dipalertinib Form 2 according to any of clauses 1E, 2E, 3E, 4E or 5E, isolated. 7E. Crystalline Form 2 of dipalertinib according to any of clauses 1E, 2E, 3E, 4E, 5E or 6E, which is an anhydrous form. 8E. Crystalline Form 2 of dipalertinib according to any of clauses 1E, 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 1E, 2E, 3E, 4E, 5E, 6E, 7E, or 8E designated as Form 2, containing less than about 20%, less than about 10%, less than about 5%, less than about 2%, less than about 1%, or less than about 0% of any other crystalline form of dipalertinib. 10E. A pharmaceutical composition comprising a crystalline product according to any of clauses 1E-9E and at least one pharmaceutically acceptable excipient. 11E. Use of a crystalline product according to any of clauses 1E to 9E for the preparation of a pharmaceutical composition and / or pharmaceutical formulation, preferably wherein the pharmaceutical formulation is a tablet, capsule, etc. 12E. A method for preparing a 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 to 9E or a pharmaceutical composition according to clause 10E for use as a medicament. 14E. A crystalline product according to any of clauses 1E to 9E or a pharmaceutical composition according to clause 10E for use in the treatment of cancer, in particular non-small cell lung cancer. 15E. A method of treating cancer, such as non-small cell lung cancer, comprising administering to a subject in need of treatment a therapeutically effective amount of a crystalline product according to any of clauses 1E to 9E or a pharmaceutical composition according to clause 10E. 16E. Use of a crystalline product according to any of clauses 1E to 9E in the preparation of another solid-state form of dipareltinib, dipareltinib succinic acid or dipareltinib succinate, dipareltinib adipic acid or dipareltinib adipic acid salt, dipareltinib fumaric acid or dipareltinib fumarate, in particular dipareltinib succinic acid or dipareltinib succinate. 17E. A process for preparing a solid-state form of dipareltinib, dipareltinib succinate or dipareltinib succinate, dipareltinib adipic acid or dipareltinib adipic acid salt, dipareltinib fumarate or dipareltinib fumarate, particularly dipareltinib succinate or dipareltinib succinate, comprising preparing any one or combination of crystalline products according to any one of clauses 1E to 9E and converting it to another solid-state form thereof.

[0164] Further aspects and embodiments of the present disclosure are described below in numbered clauses 1F to 21F. 1F. Below: (a) an XRPD pattern with characteristic peaks at 7.9, 12.0, 15.8, 17.5, and 19.3 degrees 2-theta ± 0.2 degrees 2-theta; (b) the XRPD pattern as illustrated in Figure 1, and (c) any combination of these 1. Crystalline dipalertinib Form 1, characterized by data selected from one or more of: 2F. The crystalline dipalertinib Form 1 according to clause 1F, characterized 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 dipalertinib Form 1 according to Clause 1F or Clause 2F, 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 two-theta ± 0.2 degrees two-theta. 4F. Crystalline Form 1 of dipalertinib according to any of clauses 1F, 2F or 3F, further characterized by an XRPD pattern having no peaks present at 3.0 to 6.6 degrees two-theta ± 0.2 degrees two-theta. 5F. The crystalline Form 1 of dipalertinib according to any of clauses 1F, 2F, 3F or 4F, further characterized by an X-ray powder diffraction pattern having no peaks at 8.4 to 9.8 degrees two-theta ± 0.2 degrees two-theta. 6F. Crystalline Form 1 of dipalertinib according to any of clauses 1F, 2F, 3F, 4F, or 5F, further characterized by an X-ray powder diffraction pattern having no peaks at 12.5 to 13.2 degrees two-theta ± 0.2 degrees two-theta. 7F. A crystalline Form 1 of dipalertinib according to any of clauses 1F, 2F, 3F, 4F, 5F, or 6F, characterized by: (a) A solid-state sample having characteristic peaks at 164.7, 158.4, 154.4, 121.0, and 109.0 ppm ± 0.2 ppm. 13 C NMR spectrum, or (b) In solid state as illustrated in either Figure 6a, Figure 6b or Figure 6c 13 C NMR spectrum. 8F. Below: (a) Solid-state chromatograms with the following absolute chemical shift differences from the reference peak at 103.7 ppm ± 1 ppm: 61.1, 54.7, 50.8, 17.3, and 5.3 ppm ± 0.1 ppm 13 C NMR spectrum, (b) A solid-state ion concentration of 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. 13 C NMR, and (c) any combination of these 1F, 2F, 3F, 4F, 5F, 6F, or 7F, characterized by data selected from one or more of: 9F. An isolated crystalline dipalertinib form 1 according to any of clauses 1F to 8F. 10F. Crystalline dipalertinib Form 1 according to any of clauses 1F to 9F, which is an anhydrous form. 11F. Crystalline dipalertinib Form 1 according to any of clauses 1F to 10F, containing 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 no more than about 0% of any other crystalline form of dipalertinib. 12F. Crystalline dipalertinib Form 1 according to any of clauses 1F to 11F, containing 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 no more than about 0% of any other crystalline form of dipalertinib. 13F. The crystalline product according to any of clauses 1F to 12F, containing 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 no more than about 0% of any other crystalline form of dipalertinib. 14F. A pharmaceutical composition comprising a crystalline product according to any of clauses 1F-13F and at least one pharmaceutically acceptable excipient. 15F. Use of a crystalline product according to any of clauses 1F to 13F for the preparation of a pharmaceutical composition and / or pharmaceutical formulation, preferably wherein the pharmaceutical formulation is a tablet, capsule, or the like. 16F. A method for preparing a 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. 17F. A crystalline product according to any of clauses 1F to 13F or a pharmaceutical composition according to clause 14F for use as a medicament. 18F. A crystalline product according to any of clauses 1F to 13F or a pharmaceutical composition according to clause 14F for use in the treatment of cancer, in particular non-small cell lung cancer. 19F. A method for treating cancer, such as non-small cell lung cancer, comprising administering to a subject in need of treatment a therapeutically effective amount of a crystalline product according to any of clauses 1F to 13F or a pharmaceutical composition according to clause 14F. 20F. Use of a crystalline product according to any of clauses 1F to 13F in the preparation of another solid-state form of dipareltinib, dipareltinib succinic acid or dipareltinib succinate, dipareltinib adipic acid or dipareltinib adipic acid, dipareltinib fumaric acid or dipareltinib fumarate, in particular dipareltinib succinic acid or dipareltinib succinate. 21F. A process for preparing a solid-state form of dipareltinib, dipareltinib succinic acid or dipareltinib succinate, dipareltinib adipic acid or dipareltinib adipic acid salt, dipareltinib fumaric acid or dipareltinib fumarate, particularly dipareltinib succinic acid or dipareltinib succinate, comprising preparing any one or combination of crystalline products according to any one of clauses 1F to 13F and converting it to another solid-state form thereof.

[0165] Further aspects and embodiments of the present disclosure are described below in numbered clauses 1G to 15G. 1G. or less: (a) an XRPD pattern having characteristic peaks at 5.3, 15.8, 16.6, 19.7, and 22.0 degrees two-theta ± 0.2 degrees two-theta; or (b) XRPD pattern as illustrated in Figure 12 1. A crystalline form of dipalertinib designated as Form 4, characterized by data selected from one or more of: 2G. A crystalline form of dipalertinib according to clause 1G 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 dipalertinib according to Article 1G or Article 2G described by an XRPD pattern having characteristic peaks at 5.3, 9, 10.5, 13.8, 15.8, 16.6, 19.7, 22.0, 26.7 and 27.8 degrees two-theta ± 0.2 degrees two-theta. 4G. Crystalline Form 4 of dipalertinib according to clause 1G, 2G or 3G, further characterized by an XRPD pattern absent a peak at 3.0 to 4.2 degrees two-theta ± 0.2 degrees two-theta. 5G. An isolated crystalline form 4 of dipalertinib according to any of clauses 1G, 2G, 3G, or 4G. 6G. Crystalline dipalertinib Form 4 according to any of clauses 1G to 5G containing 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 no more than about 0% of any other crystalline form of dipalertinib. 7G. A crystalline product according to any of clauses 1G to 6G containing 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 no more than about 0% of any other crystalline form of dipalertinib. 8G. A pharmaceutical composition comprising a crystalline product according to any of clauses 1G to 7G and at least one pharmaceutically acceptable excipient. 9G. Use of a crystalline product according to any of clauses 1G to 7G for the preparation of a pharmaceutical composition and / or pharmaceutical formulation, preferably wherein the pharmaceutical formulation is a tablet or capsule. 10G. A method for preparing a 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. 11G. A crystalline product according to any of clauses 1G to 7G or a pharmaceutical composition according to clause 8G for use as a medicament. 12G. A crystalline product according to any of clauses 1G to 7G or a pharmaceutical composition according to clause 8G for use in the treatment of cancer, in particular non-small cell lung cancer. 13G. A method of treating cancer, such as non-small cell lung cancer, comprising administering to a subject in need of treatment a therapeutically effective amount of a crystalline product according to any of clauses 1G to 7G or a pharmaceutical composition according to clause 8G. 14G. Use of a crystalline product according to any of clauses 1G to 7G in the preparation of another solid-state form of dipareltinib, dipareltinib succinate or dipareltinib succinate, dipareltinib adipic acid or dipareltinib adipic acid, dipareltinib fumarate or dipareltinib fumarate, in particular dipareltinib succinate or dipareltinib succinate. 15G. A process for preparing a solid-state form of dipareltinib, dipareltinib succinate or dipareltinib succinate, dipareltinib adipic acid or dipareltinib adipic acid salt, dipareltinib fumarate or dipareltinib fumarate, particularly dipareltinib succinate or dipareltinib succinate, comprising preparing any one or combination of crystalline products according to any one of clauses 1G to 7G and converting it to another solid-state form thereof.

Claims

1. below: (a) an XRPD pattern with characteristic peaks at 7.9, 12.0, 15.8, 17.5, and 19.3 degrees 2-theta ± 0.2 degrees 2-theta; (b) XRPD pattern as illustrated in Figure 1; (c) A solid-state compound having characteristic peaks at 164.7, 158.4, 154.4, 121.0, and 109.0 ppm ± 0.2 ppm. 13 C NMR spectrum, (d) In solid state as illustrated in any of Figures 6a, 6b or 6c. 13 C NMR spectrum, and (e) any combination of these 1. Crystalline dipalertinib Form 1, characterized by data selected from one or more of:

2. 2. The crystalline dipalertinib Form 1 of claim 1, characterized 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 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. 3. The crystalline dipalertinib Form 1 of claim 1 or claim 2, 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 two-theta ± 0.2 degrees two-theta.

4. 4. The crystalline Form 1 of dipalertinib of any one of claims 1 to 3, further characterized by an XRPD pattern having an absence of peaks between 3.0 and 6.6 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks between 8.4 and 9.8 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks between 12.5 and 13.2 degrees 2-theta ± 0.2 degrees 2-theta.

5. below: (a) Solid-state chromatograms with the following absolute chemical shift differences from the reference peak at 103.7 ppm ± 1 ppm: 61.1, 54.7, 50.8, 17.3, and 5.3 ppm ± 0.1 ppm 13 C NMR spectrum, (b) A solid-state ion concentration of 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. 13 C NMR, and (c) any combination of these 5. The crystalline dipalertinib Form 1 according to any one of claims 1 to 4, characterized by data selected from one or more of:

6. 6. The crystalline dipalertinib Form 1 of any one of claims 1 to 5, which is isolated.

7. 7. The crystalline dipalertinib Form 1 of any one of claims 1 to 6, which is in an anhydrous form.

8. 8. The crystalline dipalertinib Form 1 of any one of claims 1 to 7, containing 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 no more than about 0% of any other crystalline form of dipalertinib.

9. 9. The crystalline dipalertinib Form 1 of any one of claims 1 to 8, containing 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 no more than about 0% of any other crystalline form of dipalertinib.

10. below: (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) XRPD pattern as illustrated in Figure 12, and (c) any combination of these 1. Crystalline dipalertinib Form 4, characterized by data selected from one or more of:

11. 11. The crystalline dipalertinib Form 4 of claim 10, characterized 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 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.

12. 12. The crystalline dipalertinib Form 4 of claim 10 or claim 11, 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 two-theta ± 0.2 degrees two-theta.

13. 13. The crystalline Form 4 of dipalertinib of any one of claims 10 to 12, further characterized by an XRPD pattern having no peaks at 3.0 to 4.2 degrees two-theta ± 0.2 degrees two-theta.

14. 14. The crystalline dipalertinib Form 4 of any one of claims 10 to 13, which is isolated.

15. 15. The crystalline dipalertinib Form 4 of any one of claims 10-14, containing 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 no more than about 0% of any other crystalline form of dipalertinib.

16. 16. The crystalline dipalertinib Form 4 of any one of claims 10-15, containing 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 no more than about 0% of any other crystalline form of dipalertinib.

17. Crystalline dipareltinib succinate.

18. Co-crystal, crystalline dipalertinib succinate.

19. below: (a) an XRPD pattern with peaks at 7.5, 8.5, 9.3, 11.7 and 14.5 degrees 2-theta ± 0.2 degrees 2-theta; (b) XRPD pattern as illustrated in Figure 3; (c) A solid-state compound having characteristic peaks at 179.9, 165.6, 156.2, 146.8, and 126.5 ppm ± 0.2 ppm. 13 C NMR spectrum, (d) In solid state as illustrated in any of Figures 8a, 8b or 8c. 13 C NMR spectrum, and (e) any combination of these data 19. The crystalline product of claim 17 or claim 18, designated as Form C1, characterized by data selected from one or more of:

20. 20. The crystalline product of any one of claims 17-19, designated as Form C1, characterized by an XRPD pattern having peaks at 7.5, 8.5, 9.3, 11.7, and 14.5 degrees two-theta ± 0.2 degrees two-theta, and 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.

21. 21. The crystalline product of any one of claims 17-20, designated Form C1, characterized by an 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.

22. 22. The crystalline product of any one of claims 17 to 21, further characterized by an XRPD pattern having no peaks between 3.0 and 4.3 degrees 2-theta ± 0.2 degrees 2-theta and / or no peaks between 4.9 and 7.0 degrees 2-theta ± 0.2 degrees 2-theta.

23. Solid-state ion exchangers with characteristic peaks at 179.9, 165.6, 156.2, 146.8 and 126.5 ppm ± 0.2 ppm 13 C NMR spectrum and the solid-state C NMR spectrum with the following absolute chemical shift differences from the reference peak at 102.82 ppm ± 1 ppm: 77.1, 62.7, 53.3, 44.0, and 23.7 ppm ± 0.1 ppm. 13 23. The crystalline product of any one of claims 17 to 22, designated as Form C1, characterized by a C NMR spectrum.

24. Solid state with 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 13 24. The crystalline product of any one of claims 17 to 23, designated as Form C1, characterized by a C NMR spectrum.

25. 25. The crystalline product of any one of claims 17 to 24, designated as Form C1, wherein the crystalline form is an anhydrous form.

26. 26. The crystalline product of any one of claims 17-25, designated as Form C1, containing about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% of dipareltinib succinic acid or any other crystalline form of crystalline dipareltinib succinate.

27. 27. The crystalline product of any one of claims 17-26, designated as Form C1, containing about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% amorphous dipareltinib succinic acid or crystalline dipareltinib succinate.

28. Crystalline dipalertinib adipic acid.

29. Co-crystal, crystalline dipalertinib adipic acid.

30. below: (a) an XRPD pattern with peaks at 5.3, 5.9, 11.9, 14.3 and 17.8 degrees 2-theta ± 0.2 degrees 2-theta; (b) XRPD pattern as illustrated in Figure 9, and (c) any combination of these data 30. The crystalline product of claim 28 or claim 29, designated as Form C6, characterized by data selected from one or more of:

31. 31. The crystalline product of any one of claims 28-30, designated Form C6, characterized by an XRPD pattern having peaks at 5.3, 5.9, 11.9, 14.3, and 17.8 degrees two-theta ± 0.2 degrees two-theta, and 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.

32. 32. The crystalline product of any one of claims 28-31, designated Form C6, characterized by an XRPD pattern having peaks at 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.

33. 33. The crystalline product of any one of claims 28 to 32, further characterized by an XRPD pattern having no peaks between 3.0 and 4.3 degrees 2-theta ± 0.2 degrees 2-theta, and / or no peaks between 6.5 and 6.8 degrees 2-theta ± 0.2 degrees 2-theta, and / or no peaks between 8.0 and 9.2 degrees 2-theta ± 0.2 degrees 2-theta.

34. below: (a) A solid-state ionomer having characteristic peaks at 178.8, 174.1, 166.5, 156.7, and 107.9 ppm ± 0.2 ppm. 13 C NMR spectrum, (b) In solid state as illustrated in either Figure 10a, Figure 10b or Figure 10c 13 C NMR spectrum, and (c) any combination of these data 34. The crystalline product of any one of claims 28-33, designated Form C6, characterized by data selected from one or more of:

35. Solid-state chromatograms with the following absolute chemical shift differences from the reference peak of 101.8 ppm ± 1 ppm: 77.0, 72.3, 64.7, 54.9, and 6.1 ppm ± 0.1 ppm. 13 35. The crystalline product of any one of claims 28-34, designated as Form C6, characterized by a C NMR spectrum.

36. Solid state ion concentration with 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 13 36. The crystalline product of any one of claims 28-35, designated as Form C6, characterized by C NMR.

37. 37. The crystalline product of any one of claims 28 to 36, designated Form C6, in an anhydrous form.

38. 38. The crystalline product of any one of Claims 28-37, designated as Form C6, containing 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 no more than about 0% of dipalertinib adipic acid or any other crystalline form of crystalline dipalertinib adipic acid salt.

39. 39. A pharmaceutical composition comprising the crystalline product of any one of claims 1 to 38 and at least one pharmaceutically acceptable excipient.

40. 39. Use of a crystalline product according to any one of claims 1 to 38 for the preparation of a pharmaceutical composition and / or pharmaceutical formulation, preferably wherein the pharmaceutical formulation is a tablet, capsule or the like.

41. 40. A process for preparing the pharmaceutical composition of claim 39, comprising combining the crystalline product of any one of claims 1 to 38 with at least one pharmaceutically acceptable excipient.

42. 40. A crystalline product according to any one of claims 1 to 38 or a pharmaceutical composition according to claim 39 for use as a medicament.

43. 40. A crystalline product according to any one of claims 1 to 38 or a pharmaceutical composition according to claim 39 for use in the treatment of cancer, in particular non-small cell lung cancer.

44. 40. A method for treating cancer, in particular non-small cell lung cancer, comprising administering a therapeutically effective amount of a crystalline product of any one of claims 1 to 38 or a pharmaceutical composition of claim 39 to a subject in need of treatment.

45. 40. Use of the crystalline product of any one of claims 1 to 38 in the preparation of another solid state form of dipareltinib, dipareltinib succinic acid or dipareltinib succinate, dipareltinib adipic acid or dipareltinib adipic acid salt, dipareltinib fumaric acid or dipareltinib fumarate, in particular dipareltinib succinic acid or dipareltinib succinate.

46. 39. A method for preparing a solid-state form of dipalertinib or a dipalertinib salt or a dipalertinib co-crystal, comprising preparing any one or combination of the crystalline products of any one of claims 1 to 38 and converting it to another solid-state form thereof.

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