Crystalline forms of HER2 inhibitors

Abstract

Crystalline forms of HER2 inhibitors are provided. [Solution] The present invention relates to crystalline forms of HER2 inhibitors, processes for preparing them, pharmaceutical compositions containing them, and their uses, particularly in the treatment and / or prevention of cancer, and for the preparation of solid dispersions of HER2 inhibitors.

Description

[Technical Field]

[0001] The present invention relates to a crystalline form of N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide. [Background technology]

[0002] N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]-diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide, also referred to herein as compound (1) or zongertinib, is a HER2 (ErbB2) inhibitor described in WO 2021 / 213800. Zongertinib is a potent and selective tyrosine kinase inhibitor of wild-type and mutant HER2 that retains wild-type epidermal growth factor receptor (EGFR). As such, zongertinib is useful for the treatment and / or prevention of diseases and / or conditions in which inhibition of wild-type and / or mutant HER2 is therapeutically beneficial, particularly oncological and / or hyperproliferative diseases, such as cancer. Different solid-state forms of an active pharmaceutical ingredient (API) often have different properties. Differences in the physicochemical properties of the solid-state forms can play an important role in improving pharmaceutical compositions; for example, improved solid-state forms of an API may enable pharmaceutical formulations with improved dissolution profiles or improved stability or shelf life to be made available. Furthermore, the processing or handling of the API during the formulation process may be improved. Novel solid-state forms of an API may therefore have desirable processing properties. They may be easier to handle, more suitable for storage, and / or allow for better purification compared to other solid-state forms.

[0003] For example, the tendency of an API to absorb water from the environment can negatively affect the pharmaceutical behavior and quality of a formulation containing the API. For example, water absorption can lead to chemical degradation (e.g., via hydrolysis), trigger changes in physical form (e.g., via hydrate formation), lead to changes in dissolution behavior, and affect powder properties such as flowability, compressibility, tableting, and compaction behavior. Moreover, the sudden appearance or disappearance of metastable polymorphs can present problems in pharmaceutical development. Similarly, serious consequences can occur if phase inversion occurs in a pharmaceutical dosage form, for example, upon storage. Therefore, there remains a need to improve the physicochemical properties, such as thermal stability, of N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]-diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide over prior art solutions. A particular object of the present invention is to improve the physical and chemical stability of Compound (1), for example, against temperature and / or moisture stress. Another object of the present invention is to improve the powder properties, such as crystallinity, hygroscopicity, and morphology, of Compound (1). There is also a strong need to provide forms of Compound (1) that exhibit low hygroscopicity and / or are thermodynamically stable to avoid phase transformation during pharmaceutical processing or storage. [Brief explanation of the drawings]

[0004] [Figure 1] FIG. 1 shows an X-ray powder diffractogram (XRPD) of crystalline Form I of Compound (1); the x-axis shows the scattering angle in °2-theta and the y-axis shows the intensity of the scattered X-ray beam in counts per second (cps) of detected photons. [Figure 2] FIG. 1 shows an X-ray powder diffractogram (XRPD) of crystalline Form III of Compound (1); the x-axis shows the scattering angle in °2-theta and the y-axis shows the intensity of the scattered X-ray beam in counts per second (cps) of detected photons. [Figure 3]FIG. 1 shows an X-ray powder diffractogram (XRPD) of crystalline Form IV of Compound (1); the x-axis shows the scattering angle in °2-theta and the y-axis shows the intensity of the scattered X-ray beam in counts per second (cps) of detected photons. [Figure 4] FIG. 1 shows an overlay of X-ray powder diffractograms (XRPD) of Form I (bottom), Form III (middle), and Form IV (top) of Compound (1). [Figure 5a] FIG. 1 shows a background Raman spectrum. [Figure 5b] FIG. 1 shows the Raman spectrum of crystalline Form I of Compound (1). [Figure 5c] FIG. 1 shows the Raman spectrum of crystalline Form III of Compound (1). [Figure 5d] FIG. 1 shows the Raman spectrum of crystalline Form IV of Compound (1). [Figure 6] FIG. 1 shows a DSC plot of crystalline Form I of Compound (1). [Figure 7] FIG. 1 shows a DSC plot of crystalline Form III of Compound (1). [Figure 8] FIG. 1 shows a DSC plot of crystalline Form IV of Compound (1). [Figure 9] FIG. 1 shows a TGA plot of crystalline Form I of Compound (1). [Figure 10] FIG. 1 shows a TGA plot of crystalline Form III of Compound (1). [Figure 11] FIG. 1 shows a TGA plot of crystalline Form IV of Compound (1). [Figure 12] FIG. 1 shows DVS sorption and desorption isotherms for crystalline Form I of Compound (1). [Figure 13] FIG. 3 shows an overlay of the X-ray powder diffractogram (XRPD) of crystalline Form I measured before (bottom) and after (top) the DVS experiment described in Example 3.5. [Figure 14] FIG. 1 shows DVS sorption and desorption isotherms for crystalline Form III of Compound (1). [Figure 15] FIG. 1 shows DVS sorption and desorption isotherms for crystalline Form IV of Compound (1). [Figure 16] FIG. 1 shows an SEM image of crystalline Form I of Compound (1) (magnification: ×2000; scale bar: 30 μm). [Figure 17] FIG. 1 shows an SEM image of crystalline Form III of Compound (1) (magnification: ×1000; scale bar: 80 μm). [Figure 18] FIG. 1 shows an SEM image of crystalline Form IV of Compound (1) (magnification: ×440; scale bar: 100 μm). [Figure 19] FIG. 1 shows an overlay of the Form IV diffractogram calculated from SXRD data (bottom) along with two experimental diffractograms of a reference Form IV sample (middle and top). [Figure 20] FIG. 1 shows an overlay of powder X-ray diffractograms of Form III of compound (1) under different stress conditions: from bottom to top, reference Form III sample, Form III stressed at 90° C. / 78% RH for 21 days, Form III stressed at 90° C. / 3% RH for 21 days, and reference Form III sample. [Figure 21] FIG. 1 shows an overlay of powder X-ray diffractograms of Form IV of Compound (1) under different stress conditions: from bottom to top, a reference Form IV sample, Form IV stressed at 90° C. / 78% RH for 21 days, Form IV stressed at 90° C. / 3% RH for 21 days, and a reference Form IV sample. [Figure 22] FIG. 1 shows an overlay of powder X-ray diffractograms of Form I of Compound (1) before (lower curve) and after (upper curve) stress at 150° C. for 6 hours. [Figure 23] FIG. 1 shows an overlay of powder X-ray diffractograms of Form II of Compound (1) before (lower curve) and after (upper curve) vacuum drying at 40° C., which causes a phase change from Form II to Form V. [Figure 24]FIG. 1 shows an overlay of powder X-ray diffractograms of Form VI of Compound (1) before (lower curve) and after (upper curve) stress at 120° C. for 1 hour, which caused a phase change from Form VI to amorphous Compound (1). [Figure 25] FIG. 1 shows an overlay of powder X-ray diffractograms of various crystalline forms of Compound (1): from bottom to top, Form III, Form I, Form II, Form V, Form IV, Form VI, and Form VII. [Figure 26] FIG. 1 shows X-ray powder diffractograms (XRPDs) of spray-dried amorphous solid dispersions of Compound (1) using 75% by weight HPMCAS-M (top curve) and 50% by weight HPMCAS-M (bottom curve) from Example 6 herein compared to the XRPD of crystalline Compound (1). [Figure 27] FIG. 1 shows the X-ray powder diffractograms (XRPDs) of spray-dried amorphous solid dispersions of Compound (1) using 75% by weight PVP-VA (top curve) and 50% by weight PVP-VA (bottom curve) from Example 6 herein compared to the XRPD of crystalline Compound (1). [Figure 28] FIG. 1 shows the X-ray powder diffractograms (XRPDs) of spray-dried amorphous solid dispersions of Compound (1) using 75% by weight Eudragit® L100 (top curve) and 50% by weight Eudragit® L100 (bottom curve) from Example 6 herein compared to the XRPD of crystalline Compound (1). [Figure 29] FIG. 1 shows X-ray powder diffractograms (XRPDs) of spray-dried amorphous solid dispersions of Compound (1) using 75% by weight HPMC HME 15LV (top curve) and 50% by weight HPMC HME 15LV (bottom curve) from Example 6 herein compared to the XRPD of crystalline Compound (1). Summary of the Invention

[0005] According to a first aspect, there are provided different crystalline forms of compound (1) as shown below: [ka]

[0006] In a further aspect, there is provided a method for producing the crystalline form of Compound (1) shown above. The crystalline forms of Compound (1) obtained or obtainable by such a method represent a further aspect of the present invention.

[0007] In yet a further aspect, provided are uses and methods for treating and / or preventing oncological and / or hyperproliferative diseases, particularly cancer, using crystalline forms of Compound (1). In yet another embodiment, a pharmaceutical composition comprising a crystalline form of Compound (1) is provided.

[0008] Also provided herein is the use of the crystalline form of Compound (1) to prepare a solid dispersion of Compound (1). Also provided is a process for preparing a solid dispersion of Compound (1) having a crystalline form of Compound (1). DETAILED DESCRIPTION OF THE INVENTION

[0009] It is an object of the present invention to improve the physicochemical properties, such as thermal stability, of compound (1), wherein compound (1) has the following structure: [ka]

[0010] Crystalline Forms I, III, and IV, as defined herein, have one or more improved properties in terms of chemical stability, physical stability, melting point, hygroscopicity, morphology, solubility, crystallinity, flowability, bulk density, compactness, and wettability compared to other solid-state forms. In particular, crystalline Forms I, III, and IV have been found to improve the physical and chemical stability of Compound (1) against temperature and / or moisture stress, thus enabling its stable storage. For example, no irreversible phase changes occurred during DVS experiments with Forms I, III, and IV (see Example 3.5). In addition, Form I was polymorphically stable when subjected to temperature stress as well (see Example 4.2). Accelerated stress stability studies performed on Forms III and IV showed that neither form underwent a phase change even under extreme storage conditions of 90°C / 3% RH and 90°C / 78% RH (see Example 4.1).

[0011] Form I contains higher levels of residual solvents, including water, and has a lower melting point than Forms III and IV. Form I can be converted to Form III and / or Form IV, for example, under competitive slurry conditions. Forms III and IV may allow for greater stability during storage of Compound (1) than Form I, which is important for maintaining the quality of the compound over time. Forms III and IV have very similar melting points. Solid-state stability data indicates that they are both stable crystalline forms. Forms III and IV do not readily interconvert under competitive slurry conditions. Any of the crystalline Forms I, III, and IV described herein, or mixtures thereof, can be advantageously used to prepare solid dispersions comprising Compound (1) and a pharmaceutically acceptable dispersion carrier. Therefore, the identity of the crystalline form—whether it is Form I, III, or IV—is not critical to the formulation process of Compound (1) into a solid dispersion. For example, Forms III and IV exhibit comparable solubility properties in the solvent systems used to prepare such solid dispersions.

[0012] Crystalline Forms I, III, and IV, as defined herein, have been found to exhibit improved thermal stability over the amorphous form of Compound (1), which directly impacts the quality of the material and its preservation during storage. Furthermore, isolation of crystalline Forms I, III, and / or IV is generally not only more convenient at the production scale than solid / liquid separations, but also allows for superior control of the chemical purity of the material by relying on a well-defined crystalline lattice. This, in turn, opens opportunities for particle engineering via the development / optimization of crystallization procedures and / or milling protocols.

[0013] As such, the polymorphic forms according to the present invention surprisingly exhibit significant advantageous physicochemical properties that allow for stable production and storage of Compound (1) and the reliable manufacture of safe and efficacious pharmaceutical drug products containing Compound (1). The terms "crystalline form", "polymorphic form" and "polymorph" are used interchangeably herein and refer to a single chemical entity, e.g., compound X, or a multi-component composition, e.g., a salt or solvate, e.g., X a Y b Z c Each has a unique crystal lattice (periodic arrangement of molecules) and exhibits a unique X-ray diffraction pattern. When discussing the crystalline forms of Compound (1) shown below, all of crystalline Forms I, III, and IV are meant, including each broader aspect or definition and each embodiment thereof.

[0014] The term "solid state form," as used herein, refers to any crystalline and / or amorphous phase of a compound, for example, Compound (1). The crystalline form of Compound (1) of the present invention can be characterized by analytical methods well known in the pharmaceutical industry for characterizing solids. Such methods include, but are not limited to, XRPD, ssNMR, FTIR spectroscopy, Raman spectroscopy, DSC, TGA, and GMS. The crystalline form of Compound (1) of the present invention can be characterized by one of the analytical methods described above or by combining two or more of them. In particular, the crystalline form of Compound (1) of the present invention can be characterized by any one of the following embodiments or by combining two or more of the following embodiments. As used in the present invention, "Cu-Kα radiation" includes Cu-Kα1 radiation and Cu-Kα1,2 radiation, where Cu-Kα1 radiation has a wavelength of 1.54056 Å and Cu-Kα1,2 radiation has a mean wavelength of 1.54184 Å. As used herein, the term “Compound (1)” refers to the compound defined below:

[0015] [ka]

[0016] The IUPAC name for compound (1) is N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide. In the event of a conflict between the IUPAC name and the depicted formula, the formula takes precedence. Compound (1) is disclosed in WO 2021 / 213800 as example compound I-01. Compound (1) is also known as zongertinib. WO 2021 / 213800 describes [1,3]diazino[5,4-d]pyrimidines such as compound (1) as HER2 inhibitors and provides a synthetic procedure for compound (1). The properties of compound (1) and evidence of its inhibitory effect on HER2 wild-type and YVMA kinase activity while preserving EGFR are also disclosed in WO 2021 / 213800, which is incorporated herein by reference.

[0017] Form IV According to a first aspect, a crystalline form is provided, also referred to as Form IV in the sense of the present invention. According to Form IV of the present invention: (a) CuK with wavelengths of 1.54056 Å or 1.54184 Å α an X-ray powder diffraction pattern comprising peaks at the following 2θ values: (5.9±0.2)°, (11.7±0.2)°, and (16.7±0.2)° when measured using radiation at a temperature in the range of 20°C to 30°C; and / or (b) a Raman spectrum containing a peak at one of the following wavenumbers, expressed as inverse centimeters: 640±2 and / or 831±2, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm. A crystalline form of Compound (1) is provided, characterized by having:

[0018] [ka]

[0019] According to an embodiment of Form IV, the crystalline form has a CuK wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (5.9±0.2)°, (11.7±0.2)°, and (16.7±0.2)°. According to a further embodiment of Form IV, the crystalline form has a CuK 10 .OMEGA. wavelength of 1.54056 .ANG. or 1.54184 .ANG. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (5.9±0.1)°, (11.7±0.1)°, and (16.7±0.1)°. According to a further embodiment of Form IV, the crystalline form has a CuK 10 .OMEGA. wavelength of 1.54056 .ANG. or 1.54184 .ANG. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (5.9±0.2)°, (11.7±0.2)°, (14.7±0.2)°, and (16.7±0.2)°. According to a further embodiment of Form IV, the crystalline form has a CuK 10 .OMEGA. wavelength of 1.54056 .ANG. or 1.54184 .ANG. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (5.9±0.1)°, (11.7±0.1)°, (14.7±0.1)°, and (16.7±0.1)°.

[0020] According to a further embodiment of Form IV, the crystalline form has a CuK 10 .OMEGA. wavelength of 1.54056 .ANG. or 1.54184 .ANG. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (5.9±0.2)°, (11.7±0.2)°, (14.7±0.2)°, (16.7±0.2)°, (18.8±0.2)°, and (19.2±0.2)°.

[0021] According to a further embodiment of Form IV, the crystalline form has a CuK 10 .OMEGA. wavelength of 1.54056 .ANG. or 1.54184 .ANG. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (5.9±0.1)°, (11.7±0.1)°, (14.7±0.1)°, (16.7±0.1)°, (18.8±0.1)°, and (19.2±0.1)°. According to a further embodiment of Form IV, the crystalline form has a CuK 10 .OMEGA. wavelength of 1.54056 .ANG. or 1.54184 .ANG. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, comprising peaks at the following 2θ values: (5.9±0.2)°, (11.5±0.2)°, (11.7±0.2)°, (14.7±0.2)°, (16.7±0.2)°, (18.8±0.2)°, (19.2±0.2)°, (24.3±0.2)°, and (25.8±0.2)°.

[0022] According to a further embodiment of Form IV, the crystalline form has a CuK 10 .OMEGA. wavelength of 1.54056 .ANG. or 1.54184 .ANG. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, comprising peaks at the following 2θ values: (5.9±0.1)°, (11.5±0.1)°, (11.7±0.1)°, (14.7±0.1)°, (16.7±0.1)°, (18.8±0.1)°, (19.2±0.1)°, (24.3±0.1)°, and (25.8±0.1)°. According to a further embodiment of Form IV, the crystalline form has a CuK 10 .OMEGA. wavelength of 1.54056 .ANG. or 1.54184 .ANG. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, comprising peaks at the following 2θ values: (5.9±0.2)°, (11.5±0.2)°, (11.7±0.2)°, (14.7±0.2)°, (16.7±0.2)°, (18.8±0.2)°, (19.2±0.2)°, (21.3±0.2)°, (24.3±0.2)°, and (25.8±0.2)°.

[0023] According to a further embodiment of Form IV, the crystalline form has a CuK 10 .OMEGA. wavelength of 1.54056 .ANG. or 1.54184 .ANG. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, comprising peaks at the following 2θ values: (5.9±0.1)°, (11.5±0.1)°, (11.7±0.1)°, (14.7±0.1)°, (16.7±0.1)°, (18.8±0.1)°, (19.2±0.1)°, (21.3±0.1)°, (24.3±0.1)°, and (25.8±0.1)°. According to further embodiments of Form IV, the crystalline form has a Raman spectrum comprising a peak at any one of the following wavenumbers, expressed as inverse centimeters: 640±2 and / or 831±2, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm.

[0024] According to a further embodiment of Form IV, the crystalline form has a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, comprising peaks at the following wavenumbers, expressed as inverse centimeters: 640±2. According to a further embodiment of Form IV, the crystalline form has a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, comprising peaks at the following wavenumbers, expressed as inverse centimeters: 831±2. According to further embodiments of Form IV, the crystalline form has a Raman spectrum comprising peaks at the following wavenumbers, expressed as inverse centimeters: 640±2 and 831±2, when measured at a wavelength of 785 nm and at temperatures in the range of 20°C to 30°C.

[0025] According to a further embodiment of Form IV, the crystalline form has a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, comprising peaks at the following wavenumbers, expressed as inverse centimeters: 238±2, 640±2, and 831±2. According to a further embodiment of Form IV, the crystalline form has a CuK 10 .OMEGA. wavelength of 1.54056 .ANG. or 1.54184 .ANG. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (5.9±0.2)°, (11.7±0.2)°, and (16.7±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes a peak at any one of the following wavenumbers, expressed as inverse centimeters: 640±2 and / or 831±2.

[0026] According to a further embodiment of Form IV, the crystalline form has a CuK 10 .OMEGA. wavelength of 1.54056 .ANG. or 1.54184 .ANG. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (5.9±0.2)°, (11.7±0.2)°, and (16.7±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes a peak at any one of the following wavenumbers, expressed as inverse centimeters: 640±1 and / or 831±1. According to a further embodiment of Form IV, the crystalline form has a CuK 10 .OMEGA. wavelength of 1.54056 .ANG. or 1.54184 .ANG. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (5.9±0.1)°, (11.7±0.1)°, and (16.7±0.1)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes a peak at any one of the following wavenumbers, expressed as inverse centimeters: 640±2 and / or 831±2.

[0027] According to a further embodiment of Form IV, the crystalline form has a CuK 10 .OMEGA. wavelength of 1.54056 .ANG. or 1.54184 .ANG. αIt has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (5.9±0.2)°, (11.7±0.2)°, and (16.7±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes peaks at the following wavenumbers, expressed as inverse centimeters: 640±2 and 831±2. According to a further embodiment of Form IV, the crystalline form has a CuK 10 .OMEGA. wavelength of 1.54056 .ANG. or 1.54184 .ANG. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (5.9±0.2)°, (11.7±0.2)°, and (16.7±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes peaks at the following wavenumbers, expressed as inverse centimeters: 640±2 or 831±2.

[0028] According to a further embodiment of Form IV, the crystalline form has a CuK 10 .OMEGA. wavelength of 1.54056 .ANG. or 1.54184 .ANG. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (5.9±0.2)°, (11.7±0.2)°, (14.7±0.2)°, (16.7±0.2)°, (18.8±0.2)°, and (19.2±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes peaks at the following wavenumbers, expressed as inverse centimeters: 238±2, 640±2, and 831±2.

[0029] According to a further embodiment of Form IV, the crystalline form has a CuK 10 .OMEGA. wavelength of 1.54056 .ANG. or 1.54184 .ANG. αIt has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (5.9±0.2)°, (11.7±0.2)°, (14.7±0.2)°, (16.7±0.2)°, (18.8±0.2)°, and (19.2±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes peaks at the following wavenumbers, expressed as inverse centimeters: 238±1, 640±1, and 831±1. According to a further embodiment of Form IV, the crystalline form is in a substantially pure form.

[0030] The term "substantially pure," when referring to a designated crystalline form of Compound (1), means that the designated crystalline form contains less than about 20% (by weight) of residual components, e.g., alternative polymorphs or isomorphic crystalline forms. Preferably, a substantially pure form of Compound (1) contains less than about 10% (by weight) of alternative polymorphs or isomorphic crystalline forms, more preferably less than about 5% (by weight), e.g., less than about 3% (by weight), and most preferably less than about 1% (by weight) of alternative polymorphs or isomorphic crystalline forms. The term "isomorphic form," as used herein, refers to a form that has the same overall crystal structure but slight differences in cell dimensions, i.e., exhibits a similar, but not identical, XRPD pattern. Some solvates may be isomorphic due to the relatively small size of certain solvent molecules compared to the active compound. In a preferred embodiment of Form IV, the crystalline form has a TGA thermogram characterized by a mass loss from approximately 243°C (±5°C) to approximately 580°C (±5°C). Preferably, the mass loss is measured at a heating rate of 20°C / min. Additionally or alternatively, preferably, the mass loss is about 50% by weight based on the weight of the crystalline form.

[0031] In a preferred embodiment of Form IV, the crystalline form has a TGA thermogram characterized by a mass loss between approximately 420°C (±5°C) and approximately 455°C (±5°C). Preferably, the mass loss is measured at a heating rate of 20°C / min. Additionally or alternatively, preferably, the mass loss is about 50% by weight based on the weight of the crystalline form. As used herein, the terms "approximately" and "about" mean within a statistically significant range of values. Such a range may be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1%, and most typically within 0.1% of the stated value or range. Sometimes, such a range may be within the experimental error typical of the standard methods used to measure and / or determine a given value or range. In another embodiment of Form IV, the crystalline form has a TGA thermogram that exhibits a mass loss of 2.0% or less, preferably 1.5% or less, and more preferably 1.3% or less, by weight based on the weight of the crystalline form when heated from 25°C to 244°C at a rate of 20°C / min.

[0032] According to further embodiments of Form IV, the crystalline form has a melting point between 220° C. and 240° C. According to further embodiments of Form IV, the crystalline form has a melting point between 225° C. and 235° C. According to further embodiments of Form IV, the crystalline form has a melting point of approximately 232° C. (±5° C.). In these embodiments, the melting point is preferably determined by differential scanning calorimetry (DSC), in particular at a heating rate of 10° C. / min.

[0033] In another embodiment of Form IV, the crystalline form is characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, at a temperature of (229±2)°C, preferably (229±1)°C, e.g., with a peak onset at about 229°C, when measured at a heating rate of 10°C / min. In a further embodiment of Form IV, the crystalline form is characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, with a peak maximum at a temperature of (232±2)°C, preferably (232±1)°C, for example at about 232°C, when measured at a heating rate of 10°C / min. In a further embodiment of Form IV, the crystalline form is characterized by exhibiting a mass change of 2.0% or less, preferably 1.0% or less, and most preferably 0.5% or less, by weight based on the weight of the crystalline form, when measured using DVS at a relative humidity in the range of 0% to 90% and a temperature of (25.0±1.0)°C. In a further embodiment of Form IV, the crystalline form is characterized by exhibiting a mass change of 2.0% or less, preferably 1.0% or less, and most preferably 0.5% or less, e.g., 0.4% or less, by weight based on the weight of the crystalline form, when measured using DVS at a relative humidity in the range of 0% to 80% and a temperature of (25.0±1.0)°C.

[0034] In one embodiment of Form IV, the crystalline form is anhydrous. The terms "anhydrous" or "anhydrate," as used herein, refer to a crystalline solid in which water is not incorporated or accommodated in the crystal structure. The anhydrous form may still contain residual water that is not part of the crystal structure but may be adsorbed on the surface or absorbed into disordered regions of the crystal. Typically, the anhydrous form contains no more than 2.0% by weight, preferably no more than 1.0% by weight, and most preferably no more than 0.5% by weight of water, based on the weight of the crystalline form. In a further embodiment of Form IV, the crystalline form is slightly hygroscopic. The term "slightly hygroscopic," as used herein, refers to a compound that exhibits a water uptake of at most 2% by weight in a sorption cycle, based on the weight of the compound, as measured using DVS at a relative humidity in the range of 0% to 90% RH and a temperature of (25.0±1.0)°C.

[0035] In yet another embodiment of Form IV, the crystalline form is characterized by exhibiting a triclinic unit cell having space group P-1. Preferably, the unit cell has a CuK α When measured using single-crystal X-ray diffraction at 283-303K using radiation, the following parameters are approximately a=9.4141(12)Å b=10.5120(13)Å c=15.6630(19)Å α=91.327(6)° β=102.462(7)° γ=114.987(8)° It has.

[0036] In a preferred embodiment, the present invention relates to a composition comprising crystalline Form IV, as defined herein, wherein the crystalline form of Compound (1) is present in an amount of at least about 50% (w / w), 60% (w / w), 65% (w / w), 67% (w / w), 70% (w / w), 75% (w / w), 80% (w / w), or 82% (w / w), preferably at least about 85% (w / w) or 88% (w / w), more preferably at least about 90% (w / w), such as at least about 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% (w / w), and even for example, in an amount equal to about 100% (w / w), based on the weight of the composition. The remaining material may include other solid forms of Compound (1), such as amorphous Compound (1), and / or reaction and / or processing impurities resulting from the preparation of the composition, but excluding any pharmaceutically acceptable excipients. Preferably, the remaining material is amorphous Compound (1). According to a further aspect, provided is a process for the preparation of a crystalline form of Compound (1), wherein Compound (1) is:

[0037] [ka] Here, the process includes the following steps: i) dissolving compound (1) in at least one organic solvent by heating; ii) cooling the solution obtained in step (i), whereby a crystalline form of compound (1) is formed; and iii) isolating at least a portion of the crystalline form of compound (1) obtained in step (ii).

[0038] Preferably, according to this process, crystalline Form IV as defined herein is at least partially formed, in particular selectively formed. According to this method and according to step i), compound (1) is dissolved in at least one organic solvent by heating. In this regard, any one or more solvents may be used. In particular, it may be preferred that the solvent is an alcohol or that the solvent mixture contains an alcohol. More preferably, the solvent is n-butanol or that the solvent mixture contains n-butanol. Dissolution may be achieved, for example, at a temperature of 75°C or higher, for example at about 90°C, for example, by stirring the mixture. According to step ii), the mixture is cooled using a suitable cooling rate. For example, an initial slow cooling at a cooling rate of less than 1°C / min, for example less than 0.5°C / min, for example about 0.2°C / min, optionally followed by a rapid cooling at a higher cooling rate than the slow cooling, such as to room temperature, for example to about 20°C, can be used. By means of cooling, crystalline Form IV is formed.

[0039] Finally, the resulting crystalline form can be isolated according to step iii), which can be achieved by a common process. According to an embodiment, it may be preferable to filter and wash the crystals. As a further example, crystalline Form IV may also be formed in the presence of seed crystals, for example, by using already formed seed crystals of crystalline Form III. In this regard, a mixture of alcohol and another organic solvent can be used to dissolve compound (1). As an example of the organic solvent, anisole can be used in an amount suitable for dissolving compound (1). For example, a mixture of anisole and n-butanol can be used in a volume ratio of approximately 1:1. The alcohol can then be at least partially removed by distillation. The resulting mixture can be seeded with crystalline Form III and held at a temperature of 100° C. or greater. The mixture can then be cooled to room temperature, and the resulting solid isolated as crystalline Form IV.

[0040] According to a further aspect, there is provided a method for manufacturing a cellular membrane comprising: i) dissolving compound (1) in at least one organic solvent by heating; and ii) cooling the solution obtained in step (i), whereby a crystalline form of compound (1) is formed. is a crystalline form obtainable or obtained by In this embodiment of the obtained or obtainable crystalline form, steps (i) and (ii) may be carried out as detailed above.

[0041] A crystalline form obtainable or obtained by a process according to the aspects described in this section for Form IV and preferred embodiments thereof is a further object of the present invention. Preferably, this crystalline form is characterized by having an X-ray powder diffraction pattern comprising peaks as defined above for Form IV and / or a Raman spectrum comprising peaks at wavenumbers as defined above for Form IV. Preferably, this crystalline form corresponds to Form IV as defined herein in its broadest form or in any embodiment.

[0042] Form III According to a further aspect, there is provided a crystalline form, also referred to as Form III in the sense of the present invention. According to Form III of the present invention: (a) CuK with wavelengths of 1.54056 Å or 1.54184 Å α an X-ray powder diffraction pattern comprising peaks at the following 2θ values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, and (16.2±0.2)° when measured using radiation at a temperature in the range of 20°C to 30°C; or (b) CuK with wavelengths of 1.54056 Å or 1.54184 Å α an X-ray powder diffraction pattern comprising peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, and (12.4±0.1)° when measured using radiation at a temperature in the range of 20°C to 30°C; or (c) a Raman spectrum containing a peak at one of the following wavenumbers, expressed as inverse centimeters, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm: 1310±2 and / or 1400±2; or (d) CuK with wavelengths of 1.54056 Å or 1.54184 Å α an X-ray powder diffraction pattern comprising peaks at the following 2-theta values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, and (16.2±0.2)°, when measured using radiation at a temperature in the range of 20°C to 30°C, and a Raman spectrum comprising a peak at any one of the following wavenumbers, expressed as inverse centimeters: 1310±2 and / or 1400±2, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm; or (e) CuK with wavelengths of 1.54056 Å or 1.54184 Å αA powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, containing peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, and (12.4±0.1)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, containing a peak at one of the following wavenumbers, expressed as inverse centimeters: 1310±2 and / or 1400±2. A crystalline form of Compound (1) is provided, characterized by having:

[0043] [ka]

[0044] According to an embodiment of Form III, the crystalline form is CuK having a wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, and (16.2±0.2)°. According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, and (12.4±0.1)°. According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, (12.4±0.1)°, and (16.2±0.1)°.

[0045] According to an embodiment of Form III, the crystalline form is CuK having a wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, (15.4±0.2)°, and (16.2±0.2)°. According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, (12.4±0.1)°, (15.4±0.1)°, and (16.2±0.1)°. According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, (16.2±0.2)°, and (18.3±0.2)°.

[0046] According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, (12.4±0.1)°, (16.2±0.1)°, and (18.3±0.1)°. According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. αIt has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, comprising peaks at the following 2θ values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, (13.5±0.2)°, (13.8±0.2)°, (16.2±0.2)°, and (18.3±0.2)°.

[0047] According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, comprising peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, (12.4±0.1)°, (13.5±0.1)°, (13.8±0.1)°, (16.2±0.1)°, and (18.3±0.1)°.

[0048] According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, (15.4±0.2)°, (16.2±0.2)°, and (18.3±0.2)°. According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, (12.4±0.1)°, (15.4±0.1)°, (16.2±0.1)°, and (18.3±0.1)°.

[0049] According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. αIt has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, comprising peaks at the following 2θ values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, (13.5±0.2)°, (13.8±0.2)°, (14.0±0.2)°, (15.4±0.2)°, (16.2±0.2)°, and (18.3±0.2)°. According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, comprising peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, (12.4±0.1)°, (13.5±0.1)°, (13.8±0.1)°, (14.0±0.1)°, (15.4±0.1)°, (16.2±0.1)°, and (18.3±0.1)°.

[0050] According to further embodiments of Form III, the crystalline form has a Raman spectrum comprising a peak at any one of the following wavenumbers, expressed as inverse centimeters: 1310±2 and / or 1400±2, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm. According to a further embodiment of Form III, the crystalline form has a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, comprising peaks at the following wavenumbers, expressed as inverse centimeters: 1310±2. According to a further embodiment of Form III, the crystalline form has a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, comprising peaks at the following wavenumbers, expressed as inverse centimeters: 1400±2.

[0051] According to further embodiments of Form III, the crystalline form has a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, comprising peaks at the following wavenumbers, expressed as inverse centimeters: 1310±2 and 1400±2. According to further embodiments of Form III, the crystalline form has a Raman spectrum comprising a peak at any one of the following wavenumbers, expressed as inverse centimeters: 1310±2 and / or 1400±2, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, and a peak at any one of the following wavenumbers, expressed as inverse centimeters: 485±2, 610±2 and / or 1029±2, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm. According to a further embodiment of Form III, the crystalline form has a Raman spectrum comprising peaks at the following wavenumbers, expressed as inverse centimeters, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm: 485±2, 610±2, 1029±2, 1310±2, and 1400±2.

[0052] According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, and (16.2±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes a peak at any one of the following wavenumbers, expressed as inverse centimeters: 1310±2 and / or 1400±2. According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. αIt has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, that includes peaks at the following 2θ values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, (15.4±0.2)°, and (16.2±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, that includes a peak at any one of the following wavenumbers, expressed as inverse centimeters: 1310±2 and / or 1400±2.

[0053] According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, and (16.2±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes peaks at the following wavenumbers, expressed as inverse centimeters: 1310±2 and 1400±2. According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, (15.4±0.2)°, and (16.2±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes peaks at the following wavenumbers, expressed as inverse centimeters: 1310±2 and 1400±2.

[0054] According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. αIt has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, and (16.2±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes peaks at the following wavenumbers, expressed as inverse centimeters: 485±2, 610±2, 1029±2, 1310±2, and 1400±2.

[0055] According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, (15.4±0.2)°, and (16.2±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes peaks at the following wavenumbers, expressed as inverse centimeters: 485±2, 610±2, 1029±2, 1310±2, and 1400±2. According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, and (12.4±0.1)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes a peak at any one of the following wavenumbers, expressed as inverse centimeters: 1310±2 and / or 1400±2.

[0056] According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. αIt has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, and (12.4±0.1)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes peaks at the following wavenumbers, expressed as inverse centimeters: 1310±2 and 1400±2. According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, (12.4±0.1)°, and (16.2±0.1)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes a peak at any one of the following wavenumbers, expressed as inverse centimeters: 1310±2 and / or 1400±2.

[0057] According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, that includes peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, (12.4±0.1)°, (15.4±0.1)°, and (16.2±0.1)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, that includes a peak at any one of the following wavenumbers, expressed as inverse centimeters: 1310±2 and / or 1400±2.

[0058] According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. αIt has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, (12.4±0.1)°, and (16.2±0.1)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes peaks at the following wavenumbers, expressed as inverse centimeters: 1310±2 and 1400±2.

[0059] According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, that includes peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, (12.4±0.1)°, (15.4±0.1)°, and (16.2±0.1)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, that includes a peak at any one of the following wavenumbers, expressed as inverse centimeters: 1310±2 and 1400±2. According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, and (12.4±0.1)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes peaks at the following wavenumbers, expressed as inverse centimeters: 485±2, 610±2, 1029±2, 1310±2, and 1400±2.

[0060] According to a further embodiment of Form III, the crystalline form has a CuK 10 saturation wavelength of 1.54056 Å or 1.54184 Å. αIt has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, (15.4±0.2)°, (16.2±0.2)°, and (18.3±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes peaks at the following wavenumbers, expressed as inverse centimeters: 485±2, 610±2, 1029±2, 1310±2, and 1400±2. According to a further embodiment of Form III, the crystalline form is in a substantially pure form. In a preferred embodiment of Form III, the crystalline form has a TGA thermogram characterized by a mass loss from approximately 240°C (±5°C) to approximately 580°C (±5°C). Preferably, said mass loss is measured at a heating rate of 20°C / min. Additionally or alternatively, preferably, said mass loss is approximately 61% by weight, based on the weight of the crystalline form.

[0061] In a preferred embodiment of Form III, the crystalline form has a TGA thermogram characterized by a mass loss between approximately 420°C (±5°C) and approximately 454°C (±5°C). Preferably, the mass loss is measured at a heating rate of 20°C / min. Additionally or alternatively, preferably, the mass loss is approximately 61% by weight, based on the weight of the crystalline form. In another embodiment of Form III, the crystalline form has a TGA thermogram that, when heated from 25°C to 240°C at a rate of 20°C / min, exhibits a mass loss of 2.0% or less, preferably 1.5% or less, and more preferably 1.1% or less, by weight based on the weight of the crystalline form. According to further embodiments of Form III, the crystalline form has a melting point between 220° C. and 240° C. According to further embodiments of Form III, the crystalline form has a melting point between 225° C. and 230° C. According to further embodiments of Form III, the crystalline form has a melting point of approximately 231° C. (±5° C.). In these embodiments, the melting point is preferably determined by differential scanning calorimetry (DSC), in particular at a heating rate of 10° C. / min.

[0062] In another embodiment of Form III, the crystalline form is characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, at a temperature of (228±2)°C, preferably (228±1)°C, e.g., with a peak onset at about 228°C, when measured at a heating rate of 10°C / min.

[0063] In a further embodiment of Form III, the crystalline form is characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, with a peak maximum at a temperature of (231±2)°C, preferably (231±1)°C, for example at about 231°C, when measured at a heating rate of 10°C / min. In a further embodiment of Form III, the crystalline form is characterized by exhibiting a mass change of 2.0% by weight or less, preferably 1.7% by weight or less, based on the mass of the crystalline form, when measured using DVS at a relative humidity in the range of 0% to 90% and a temperature of (25.0±1.0)°C.

[0064] In a further embodiment of Form III, the crystalline form is characterized by exhibiting a mass change of 2.0% or less, preferably 1.5% or less, and most preferably 1.2% or less, by weight based on the weight of the crystalline form, when measured using DVS at a relative humidity in the range of 0% to 80% and a temperature of (25.0±1.0)°C. In one embodiment of Form III, the crystalline form is anhydrous. In a further embodiment of Form III, the crystalline form is slightly hygroscopic. In a preferred embodiment, the present invention relates to a composition comprising crystalline Form III, as defined herein, wherein the crystalline form of Compound (1) is present in an amount of at least about 50% (w / w), 60% (w / w), 65% (w / w), 67% (w / w), 70% (w / w), 75% (w / w), 80% (w / w), or 82% (w / w), preferably at least about 85% (w / w) or 88% (w / w), more preferably at least about 90% (w / w), such as at least about 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% (w / w), and even for example, in an amount equal to about 100% (w / w), based on the weight of the composition. The remaining material may include other solid forms of Compound (1), such as amorphous Compound (1), and / or reaction and / or processing impurities resulting from the preparation of the composition, but excluding any pharmaceutically acceptable excipients. Preferably, the remaining material is amorphous Compound (1). According to a further aspect, provided is a process for the preparation of a crystalline form of Compound (1), wherein Compound (1) is:

[0065] [ka] Here, the process includes the following steps: i) providing a suspension of compound (1) in at least one organic solvent; ii) stirring the suspension obtained in step (i) until a crystalline form of compound (1) is formed; and iii) isolating at least a portion of the crystalline form of compound (1) obtained in step (ii).

[0066] Preferably, according to this process, crystalline Form III as defined herein is at least partially formed, in particular selectively formed. According to this method and according to step i), compound (1) is preferably suspended or slurried in at least one organic solvent by heating. In this regard, any one or more organic solvents may be used. In a preferred embodiment of this aspect, the at least one organic solvent is an alcohol or an ester. In a preferred embodiment of this aspect, the at least one organic solvent is an ester. In a preferred embodiment of this aspect, the at least one organic solvent is isopropanol or isopropyl acetate (IPAc). In a preferred embodiment of this aspect, the at least one organic solvent is isopropyl acetate (IPAc). Suspension is achieved, for example, at a temperature of 50°C or higher, for example at approximately 70°C (±5°C), for example by stirring the mixture.

[0067] The stirring is carried out according to step (ii). In some embodiments of this aspect, the stirring in step (ii) is at a temperature of 18°C ​​to 75°C and / or for a period of 1 to 18 hours. In some embodiments of this aspect, the stirring in step (ii) is at a temperature of at least 50°C and / or for a period of at least 8 hours. In alternative or additional preferred embodiments of this aspect, the stirring in step (ii) is at a temperature of 55°C to 75°C and / or for a period of 10 to 18 hours. In alternative embodiments of this aspect, the stirring in step (ii) is at a temperature of 18°C ​​to 30°C and / or for a period of 1 to 3 hours, e.g., approximately 2 hours. During stirring, the slurry or suspension can be cooled at an appropriate cooling rate. The preferred cooling rate can be decreased in subsequent cooling phases. Generally, cooling can be performed from the stirring temperature described above to room temperature. During cooling, crystalline Form III can form as a solid.

[0068] The solid thus formed can then be isolated. This can be achieved by a common process. According to an embodiment, isolation can be carried out by means of filtering the mixture. According to an embodiment, the process described above may comprise an additional step of seeding, in which case seed crystals of crystalline Form III may be added to the suspension, preferably at the start of the stirring step ii). According to a further aspect, there is provided a method for manufacturing a cellular membrane comprising: i) providing a suspension of compound (1) in at least one organic solvent; and ii) stirring the suspension obtained in step (i) until a crystalline form of compound (1) is formed. is a crystalline form obtained or obtainable by In this embodiment of the obtained or obtainable crystalline form, steps (i) and (ii) may be carried out as detailed above. A crystalline form obtainable or obtained by a process according to the aspects described in this section for Form III and preferred embodiments thereof is a further object of the present invention. Preferably, this crystalline form is characterized by having an X-ray powder diffraction pattern comprising peaks as defined above for Form III and / or a Raman spectrum comprising peaks at wavenumbers as defined above for Form III. Preferably, this crystalline form corresponds to Form III as defined herein in its broadest form or in any embodiment.

[0069] Form I According to a further aspect, there is provided a crystalline form, also referred to as Form I in the sense of the present invention. According to Form I of the present invention: (a) CuK with wavelengths of 1.54056 Å or 1.54184 Å α a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (7.9±0.2)° and (12.1±0.2)° when measured using radiation at a temperature in the range of 20°C to 30°C; and / or (b) a Raman spectrum containing a peak at one of the following wavenumbers, expressed as inverse centimeters, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm: 1411±2 and / or 1602±2. A crystalline form of Compound (1) is provided, characterized by having:

[0070] [ka]

[0071] Alternatively, according to form I of the present invention, (a) CuK with wavelengths of 1.54056 Å or 1.54184 Å α and / or a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (7.9±0.2)° and (12.0±0.2)° when measured using radiation at a temperature in the range of 20°C to 30°C. (b) a Raman spectrum containing a peak at one of the following wavenumbers, expressed as inverse centimeters, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm: 1411±2 and / or 1602±2. A crystalline form of Compound (1) is provided, characterized by having:

[0072] [ka]

[0073] According to an embodiment of Form I, the crystalline form has a CuK wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (7.9±0.2)° and (12.1±0.2)°. According to an embodiment of Form I, the crystalline form has a CuK wavelength of 1.54056 Å or 1.54184 Å. αIt has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (7.9±0.2)° and (12.0±0.2)°.

[0074] According to a further embodiment of Form I, the crystalline form has a CuK NMR spectrum having a wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (7.9±0.1)° and (12.1±0.1)°. According to a further embodiment of Form I, the crystalline form has a CuK NMR spectrum having a wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern including peaks at the following 2θ values: (7.9±0.1)° and (12.0±0.1)° when measured using radiation at a temperature in the range of 20°C to 30°C. According to a further embodiment of Form I, the crystalline form has a CuK NMR spectrum having a wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.1±0.2)°, (7.9±0.2)°, (11.1±0.2)°, (12.0±0.2)°, (17.2±0.2)°, and (17.9±0.2)°.

[0075] According to a further embodiment of Form I, the crystalline form has a CuK NMR spectrum having a wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.1±0.1)°, (7.9±0.1)°, (11.1±0.1)°, (12.0±0.1)°, (17.2±0.1)°, and (17.9±0.1)°. According to a further embodiment of Form I, the crystalline form has a CuK NMR spectrum having a wavelength of 1.54056 Å or 1.54184 Å. αIt has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, comprising peaks at the following 2θ values: (6.1±0.2)°, (7.9±0.2)°, (11.1±0.2)°, (12.0±0.2)°, (13.9±0.2)°, (15.6±0.2)°, (17.2±0.2)°, (17.9±0.2)°, and (18.8±0.2)°. According to a further embodiment of Form I, the crystalline form has a CuK NMR spectrum having a wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, comprising peaks at the following 2θ values: (6.1±0.1)°, (7.9±0.1)°, (11.1±0.1)°, (12.0±0.1)°, (13.9±0.1)°, (15.6±0.1)°, (17.2±0.1)°, (17.9±0.1)°, and (18.8±0.1)°.

[0076] According to a further embodiment of Form I, the crystalline form has a CuK NMR spectrum having a wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, comprising peaks at the following 2θ values: (6.1±0.2)°, (7.9±0.2)°, (11.1±0.2)°, (12.0±0.2)°, (12.9±0.2)°, (13.9±0.2)°, (15.6±0.2)°, (17.2±0.2)°, (17.9±0.2)°, and (18.8±0.2)°. According to a further embodiment of Form I, the crystalline form has a CuK NMR spectrum having a wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, comprising peaks at the following 2θ values: (6.1±0.1)°, (7.9±0.1)°, (11.1±0.1)°, (12.0±0.1)°, (12.9±0.1)°, (13.9±0.1)°, (15.6±0.1)°, (17.2±0.1)°, (17.9±0.1)°, and (18.8±0.1)°.

[0077] According to further embodiments of Form I, the crystalline form has a Raman spectrum comprising a peak at any one of the following wavenumbers, expressed as inverse centimeters: 1411±2 and / or 1602±2, when measured at a temperature in the range of 20° C. to 30° C. and a wavelength of 785 nm.

[0078] According to further embodiments of Form I, the crystalline form has a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, comprising peaks at the following wavenumbers, expressed as inverse centimeters: 1411±2. According to further embodiments of Form I, the crystalline form has a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, comprising peaks at the following wavenumbers, expressed as inverse centimeters: 1602±2. According to further embodiments of Form I, the crystalline form has a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, comprising peaks at the following wavenumbers, expressed as inverse centimeters: 1411±2 and 1602±2. According to further embodiments of Form I, the crystalline form has a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, comprising peaks at the following wavenumbers, expressed as inverse centimeters: 824±2, 1411±2, and 1602±2.

[0079] According to a further embodiment of Form I, the crystalline form has a CuK NMR spectrum having a wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (7.9±0.2)° and (12.1±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes peaks at the following wavenumbers, expressed as inverse centimeters: 1411±2 and / or 1602±2. According to a further embodiment of Form I, the crystalline form has a CuK NMR spectrum having a wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (7.9±0.2)° and (12.0±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes a peak at one of the following wavenumbers, expressed as inverse centimeters: 1411±2 and / or 1602±2. According to a further embodiment of Form I, the crystalline form has a CuK NMR spectrum having a wavelength of 1.54056 Å or 1.54184 Å. α The powder X-ray diffraction pattern includes peaks at the following 2θ values: (7.9±0.1)° and (12.1±0.1)° when measured using radiation at a temperature in the range of 20°C to 30°C, and a Raman spectrum including a peak at any one of the following wavenumbers, expressed as inverse centimeters: 1411±2 and / or 1602±2 when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm.

[0080] According to a further embodiment of Form I, the crystalline form has a CuK NMR spectrum having a wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (7.9±0.1)° and (12.0±0.1)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes a peak at one of the following wavenumbers, expressed as inverse centimeters: 1411±2 and / or 1602±2. According to a further embodiment of Form I, the crystalline form has a CuK NMR spectrum having a wavelength of 1.54056 Å or 1.54184 Å. αIt has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (7.9±0.2)° and (12.1±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes peaks at the following wavenumbers, expressed as inverse centimeters: 1411±2 and 1602±2.

[0081] According to a further embodiment of Form I, the crystalline form has a CuK NMR spectrum having a wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (7.9±0.2)° and (12.0±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes peaks at the following wavenumbers, expressed as inverse centimeters: 1411±2 and 1602±2.

[0082] According to a further embodiment of Form I, the crystalline form has a CuK NMR spectrum having a wavelength of 1.54056 Å or 1.54184 Å. α It has a powder X-ray diffraction pattern, when measured using radiation at a temperature in the range of 20°C to 30°C, which includes peaks at the following 2θ values: (6.1±0.2)°, (7.9±0.2)°, (11.1±0.2)°, (12.0±0.2)°, (17.2±0.2)°, and (17.9±0.2)°, and a Raman spectrum, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm, which includes peaks at the following wavenumbers, expressed as inverse centimeters: 824±2, 1411±2, and 1602±2. According to a further embodiment of Form I, the crystalline form is in a substantially pure form. In a preferred embodiment of Form I, the crystalline form has a TGA thermogram characterized by a mass loss from approximately 100°C (±5°C) to approximately 580°C (±5°C). Preferably, the mass loss is measured at a heating rate of 20°C / min. Additionally or alternatively, preferably, the mass loss is approximately 48% by weight based on the weight of the crystalline form.

[0083] In a preferred embodiment of Form I, the crystalline form has a TGA thermogram characterized by a mass loss between approximately 419°C (±5°C) and approximately 463°C (±5°C). Preferably, the mass loss is measured at a heating rate of 20°C / min. Additionally or alternatively, preferably, the mass loss is approximately 48% by weight based on the weight of the crystalline form. According to further embodiments of Form I, the crystalline form has a melting point between 160° C. and 180° C. According to further embodiments of Form I, the crystalline form has a melting point between 165° C. and 175° C. According to further embodiments of Form I, the crystalline form has a melting point of approximately 171° C. (±5° C.). In these embodiments, the melting point is preferably determined by differential scanning calorimetry (DSC), in particular at a heating rate of 10° C. / min. In another embodiment of Form I, the crystalline form is characterized by having a DSC curve comprising an endothermic peak at a temperature of (165±2)°C, preferably (165±1)°C, e.g., having a peak onset at about 165°C, when measured at a heating rate of 10°C / min. In a further embodiment of Form I, the crystalline form is characterized by having a DSC curve comprising an endothermic peak having a peak maximum at a temperature of (171±2)°C, preferably (171±1)°C, for example at about 171°C, when measured at a heating rate of 10°C / min.

[0084] In a preferred embodiment, the present invention relates to a composition comprising crystalline Form I, as defined herein, wherein the crystalline form of Compound (1) is present in an amount of at least about 50% (w / w), 60% (w / w), 65% (w / w), 67% (w / w), 70% (w / w), 75% (w / w), 80% (w / w), or 82% (w / w), preferably at least about 85% (w / w) or 88% (w / w), more preferably at least about 90% (w / w), for example, at least about 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% (w / w), and even for example, in an amount equal to about 100% (w / w), based on the weight of the composition. The remaining material may include other solid forms of Compound (1), such as amorphous Compound (1), and / or reaction and / or processing impurities resulting from the preparation of the composition, but excluding any pharmaceutically acceptable excipients. Preferably, the remaining material is amorphous Compound (1).

[0085] According to a further aspect, provided is a process for the preparation of a crystalline form of Compound (1), wherein Compound (1) is: [ka] Here, the process includes the following steps: i) dissolving compound (1) in a mixture of water and a solvent comprising at least one water-miscible organic solvent by heating; ii) cooling the solution obtained in step (i), whereby a crystalline form of compound (1) is formed; and iii) isolating at least a portion of the crystalline form of compound (1) obtained in step (ii).

[0086] Preferably, according to this process, crystalline Form I as defined herein is at least partially formed, in particular selectively formed. According to this method and step i), compound (1) is dissolved in at least one water-miscible organic solvent and water by heating. In particular, it may be preferable for the water-miscible organic solvent to comprise an alcohol. More preferably, the water-miscible organic solvent comprises isopropyl alcohol. The amount of water-miscible organic solvent may be in the range of 10% w / w HO or less. Dissolution can be achieved, for example, at a temperature of 75°C or higher, for example, at about 90°C, by, for example, stirring the mixture.

[0087] According to step ii), the mixture is cooled to a suitable temperature, for example below 85°C, for example around 75°C, and the solution is stirred. Optional seeding with crystalline Form I can be performed. Crystalline Form I can be formed by means of cooling, preferably to room temperature, for example around 20°C. Finally, the resulting crystalline form can be isolated according to step iii), which can be achieved by a common process. According to an embodiment, it may be preferable to filter and wash the crystals. As a further example, crystalline Form I can also be formed by dissolving Compound (1) in a mixture of an organic solvent containing an alcohol and one or more additional organic solvents. For example, a mixture of dichloromethane, tetrahydrofuran, and methanol can be used. The mixture can be washed with brine or the like. The mixture can then be distilled and diluted with an organic solvent such as tetrahydrofuran. The distillation and dilution can be repeated until the amount of water and alcohol is each 1.0% w / w or less. The mixture is cooled and kept at room temperature, for example, 20°C, to form crystalline Form I, which can be isolated by filtration or the like.

[0088] According to another embodiment, crystalline Form I is obtained as described in steps 1-6 of Example 1.1 (presented below). According to another embodiment, crystalline Form I is obtained as described in steps 1-5 of Example 1.2 (presented below).

[0089] According to a further aspect, there is provided a method for manufacturing a cellular membrane comprising: i) dissolving compound (1) by heating in a mixture of water and a solvent comprising at least one water-miscible organic solvent; and ii) cooling the solution obtained in step (i), whereby a crystalline form of compound (1) is formed. is a crystalline form obtained or obtainable by In this embodiment of the obtained or obtainable crystalline form, steps (i) and (ii) may be carried out as detailed above. A crystalline form obtainable or obtained by a process according to the aspects and preferred embodiments thereof described in this section for Form I is a further object of the present invention. Preferably, this crystalline form is characterized by having an X-ray powder diffraction pattern comprising peaks as defined above for Form I and / or a Raman spectrum comprising peaks at wavenumbers as defined above for Form I. Preferably, this crystalline form corresponds to Form I as defined herein in its broadest form or in any embodiment.

[0090] solid dispersion All solid-state forms described herein, individually or as mixtures, may be useful for generating solid dispersions. Therefore, further provided herein is the use of any one of crystalline Forms I, III, and IV described above, in their broadest form or in any embodiment, to produce a solid dispersion comprising Compound (1) and a pharmaceutically acceptable dispersion carrier. Also provided herein is the use of any one of crystalline Forms I, III, and IV (as described above, in their broadest form or in any embodiment), or a mixture thereof, to produce a solid dispersion comprising Compound (1) and a pharmaceutically acceptable dispersion carrier. In such solid dispersions, Compound (1) is preferably amorphous. In other words, the solid dispersion preferably comprises Compound (1) in amorphous form. Also provided herein is the use of any one of crystalline Forms I, III, IV (as described above in their broadest form or in any embodiment) or a mixture thereof to produce a solid dispersion consisting essentially of Compound (1) and a pharmaceutically acceptable dispersion carrier. As used herein, the terms "consisting essentially of" and "consisting essentially of" have the meanings ascribed to them in the art. In particular, they indicate that additional components may be present, especially those that do not have a significant effect on the characteristics of the respective dispersion, composition, or formulation. Such additional components may be, for example, residual solvent.

[0091] Also provided herein is the use of any one of crystalline Forms I, III, IV (as described above in their broadest form or in any embodiment), or a mixture thereof, to produce a solid dispersion consisting of Compound (1) and a pharmaceutically acceptable dispersion carrier. As used herein, the term "solid dispersion" refers to a system in the solid state comprising at least two components, wherein one component, e.g., Compound (1) or generally an active pharmaceutical ingredient (API), preferably in an amorphous state, is dispersed throughout another component, e.g., a pharmaceutically acceptable solid dispersion carrier, particularly a dispersion polymer.

[0092] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human tissue without undue toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0093] As used herein, the term "dispersion carrier" refers to a carrier component that allows an API, such as Compound (1), to be dispersed throughout, thereby forming a solid dispersion. In embodiments, Compound (1) is dispersed at a molecular level in a pharmaceutically acceptable dispersion carrier. In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer. Therefore, in the uses and processes described herein, the solid dispersion preferably comprises Compound (1) or a pharmaceutically acceptable salt thereof as defined herein and a polymer. Polymeric dispersion carriers are also referred to as "dispersion polymers." Polymers are widely used in solid dispersion formulations. Different polymeric carriers lead to solid dispersions with various properties in terms of physical stability, phase behavior, and drug release rate and extent. Due to their complex nature, the most suitable solid dispersion formulation carrier for a given API needs to be tested. The pharmaceutically acceptable dispersion polymer is preferably a neutral or acidic polymer.

[0094] In other embodiments, the pharmaceutically acceptable dispersion carrier is a polymer that is enteric (acidic polymer) or non-enteric (neutral polymer), preferably enteric. In other embodiments, the polymer is enteric or non-enteric, preferably enteric. The term "enteric polymer" refers to a pH-dependent acidic polymer that is insoluble or only slightly soluble at low pH (e.g., about pH 1 or higher but less than pH 3) but becomes soluble at higher pH (e.g., pH 5 or higher). In certain embodiments, the pH-dependent polymer can become soluble at a pH range of about pH 5 or higher, which is generally less acidic than the stomach environment and roughly corresponds to the pH value in the small intestine, e.g., about pH 6 to about pH 9, about pH 6 to about pH 8, about pH 5 to about pH 7, or about pH 5 to about pH 6. Examples of enteric polymers include, but are not limited to, methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate, HPMCAS), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer (Eudragit® L100), shellac, cellulose acetate trimellitate, sodium alginate, and zein. The term "non-enteric polymer" refers to a neutral polymer that does not exhibit pH-dependent solubility characteristics. Examples of non-enteric polymers include, but are not limited to, cellulose derivatives such as methylcellulose (MC), ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), poly-vinyl-pyrrolidone (PVP), copovidone, starch derivatives such as polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), poly(ethylene glycol) PEG, cyclodextrins, and Soluplus®, an amphiphilic copolymer of polyethylene glycol, polyvinylcaprolactam, and polyvinyl acetate.

[0095] In embodiments, the pharmaceutically acceptable dispersion carrier is a polymer, or more simply, the polymer is selected from the group consisting of hydroxypropylmethylcellulose and its esters, polyvinylpyrrolidone and its copolymers, and polymethacrylate and its copolymers. The pharmaceutically acceptable dispersion carrier can contain a mixture of two or more polymers.

[0096] In certain embodiments, the hydroxypropyl methylcellulose and its esters are selected from the group consisting of hydroxypropyl methylcellulose acetate (HPMCA), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), carboxymethyl ethyl cellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), hydroxypropyl methylcellulose acetate phthalate (HPMCAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose acetate trimellitate (HPMCAT), and carboxymethyl cellulose acetate butyrate (CMCAB). In certain embodiments, the hydroxypropyl methylcellulose and its esters are selected from the group consisting of hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose, especially hot melt extrusion grade hydroxypropyl methylcellulose.

[0097] In some embodiments, polyvinylpyrrolidone and its copolymers are selected from the group consisting of polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), polyvinyl alcohol, polyvinyl alcohol-polyvinyl acetate copolymer, and polyvinylpyrrolidone (PVP). Polyvinylpyrrolidone (PVP) is also commonly referred to as polyvidone or povidone. In some embodiments, polyvinylpyrrolidone and its copolymers are polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA).

[0098] In some embodiments, the polymethacrylates and copolymers thereof are selected from the group consisting of methacrylic acid-ethyl acrylate copolymers, methacrylic acid-methyl methacrylate copolymers, methyl methacrylate and methacrylic acid copolymers. Polymethacrylates and copolymers thereof are available, for example, from Evonik Industries AG under the trade name Eudragit®. Methacrylic acid-methyl methacrylate copolymers are available, for example, under the trade name Eudragit® L100. In certain embodiments, the polymethacrylates and copolymers thereof are methyl acrylate-methyl methacrylate copolymers. In embodiments, the pharmaceutically acceptable dispersion carrier is a polymer, or more simply, the polymer is selected from the group of hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone vinyl acetate copolymer (PVP-VA), methyl acrylate methyl methacrylate copolymer (such as Eudragit® L100), and hot melt extrusion grade hydroxypropyl methylcellulose (HPMC HME).

[0099] In certain embodiments, the pharmaceutically acceptable dispersion carrier is hydroxypropyl methylcellulose acetate succinate (HPMCAS). HPMCAS is also known as hypromellose acetate succinate. Hypromellose acetate succinate (HPMCAS) can be obtained by introducing acetyl and succinoyl groups into the hydroxyl groups of the backbone of hydroxypropyl methylcellulose (HPMC), also known as hypromellose. This procedure can be carried out by known methods, for example, by treating HPMC with acetic anhydride and / or succinic anhydride. Acetic anhydride and succinic anhydride can be reacted with hydroxypropyl methylcellulose (HPMC) under specific controlled conditions to produce HPMCAS with varying degrees of acetyl and succinoyl substitution.

[0100] HPMCAS is available in several grades (L, M, and H) that vary in the degree of acetyl and succinoyl group substitution based on the content (wt%) of acetyl and succinoyl groups in the HPMCAS molecule. Any grade of HPMCAS can be used in the solid dispersion of the present invention. Preferably, HPMCAS grades L, M, or H are used. In certain embodiments, the pharmaceutically acceptable dispersing carrier is HPMCAS grade L. In certain embodiments, the pharmaceutically acceptable dispersing carrier is HPMCAS grade M. HPMCAS grade M can contain an acetyl content of 7-11 wt%; a succinoyl content of 10-14 wt%; a methoxyl content of 21-25 wt%; and a hydroxypropoxy content of 5-9 wt%. Preferably, HPMCAS grade M (HPMCAS-M) is soluble at a pH of 6 or higher. In certain embodiments, the pharmaceutically acceptable dispersing carrier is HPMCAS grade H. Preferably, granular HPMCAS (HPMCAS-G) is used. HPMCAS-G can be used for any grade of HPMCAS, especially grade G, so HPMCAS-MG is used.

[0101] In certain embodiments, the pharmaceutically acceptable dispersion carrier is polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), a linear random polymer obtainable by free radical polymerization of monomers in ratios ranging from 70 / 30 to 30 / 70 vinyl acetate to vinylpyrrolidone. In certain embodiments, the pharmaceutically acceptable dispersion carrier is a methyl acrylate methyl methacrylate copolymer, such as Eudragit® L100. As used herein, "methyl acrylate methyl methacrylate copolymer" is used interchangeably with "methacrylic acid methyl methacrylate copolymer."

[0102] In certain embodiments, the pharmaceutically acceptable dispersion carrier is hot-melt extrusion grade hydroxypropyl methylcellulose (HPMC HME). HPMC HME refers to a modified grade of hydroxypropyl methylcellulose with a low glass transition temperature and melt viscosity, which can be used to create solid dispersions via hot-melt extrusion. HPMC HME is a water-soluble amorphous polymer, typically provided as a white to off-white powder, and is available in three grades that differ in terms of their molecular weight: HPMC HME 15LV, HPMC HME 100LV, and HPMC HME 4M. Preferably, the molecular weight (M) is less than 100 kDa. W ) is used. More preferably, HPMC HME 15 LV having a molecular weight (M) of less than 200 kDa is used. W ) is used. By dispersing the crystalline form of Compound (1), preferably at the molecular level, in a pharmaceutically acceptable dispersion carrier, e.g., a polymeric one, the amorphous state of Compound (1) can be obtained and maintained even when exposed to elevated temperature and / or humidity conditions, and the solid dispersion can reliably provide Compound (1) in amorphous form in solid dispersion embodiments, where Compound (1) is amorphous.

[0103] The term "amorphous," as used herein, refers to a condensed phase characterized by randomly oriented molecules and the absence of any microscopic order, resulting in the absence of diffraction peaks by XRPD; amorphous solid systems can be composed of a single chemical entity or can be multicomponent systems containing, for example, APIs, polymers, and other excipients, and lacking stoichiometric composition. Amorphous solids generally possess crystalline-like short-range molecular arrangements, but lack the long-range ordered molecular packing found in crystalline solids. The solid-state form of a solid can be determined, for example, by X-ray powder diffraction ("XRPD") or modulated differential scanning calorimetry ("mDSC").

[0104] In embodiments, the solid dispersion comprises, consists of, or consists essentially of amorphous Compound (1) and a pharmaceutically acceptable dispersion carrier, wherein Compound (1) is in a substantially amorphous solid-state form. In certain embodiments, the substantially amorphous solid-state form refers to a solid dispersion comprising at least 80% amorphous Compound (1) by weight, based on 100% total weight of Compound (1). In certain embodiments, the substantially amorphous solid-state form refers to a solid dispersion comprising at least 85% amorphous Compound (1) by weight, based on 100% total weight of Compound (1). In certain embodiments, the substantially amorphous solid-state form refers to a solid dispersion comprising at least 90% amorphous Compound (1) by weight, based on 100% total weight of Compound (1). In certain embodiments, the substantially amorphous solid-state form refers to a solid dispersion comprising at least 95% amorphous Compound (1) by weight, based on 100% total weight of Compound (1). In certain embodiments, a substantially amorphous solid-state form refers to a solid dispersion comprising at least 96, 97, 98, or 99% by weight of amorphous Compound (1), based on 100% by weight of the total weight of Compound (1). Thus, a solid dispersion can provide Compound (1) in an amorphous or essentially amorphous state. Such a solid dispersion can therefore be referred to as an amorphous solid dispersion. In embodiments, the solid dispersion is therefore an amorphous solid dispersion.

[0105] In one embodiment, the solid dispersion comprises a predetermined amount of Compound (1) or a pharmaceutically acceptable salt thereof. In this context, the predetermined amount refers to the initial amount of Compound (1) or a pharmaceutically acceptable salt thereof used to prepare the solid dispersion. In another embodiment, the solid dispersion comprises a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof. The solid dispersions of the invention can be prepared starting from Form I, III, or IV (in its broadest form or in any embodiment or aspect thereof) or mixtures thereof as described herein using any process known in the art for this purpose, for example, as disclosed in SV Bhujbal et al., Acta Pharmaceutica Sinica B 2021;11(8):2505e2536, which is incorporated herein by reference. According to the invention, the solid dispersions are generally prepared by dissolving the active substance and a pharmaceutically acceptable dispersion carrier in a solvent or mixture of solvents to form a feed solution, which is then removed from the feed solution, such as by spray drying, to form the solid dispersion.

[0106] A further aspect of the present invention is therefore a process for preparing the solid dispersion described herein, said process comprising: a) providing a mixture of compound (1) and a pharmaceutically acceptable dispersion carrier, and adding a solvent to obtain a solution or suspension; and b) removing the solvent from the solution or suspension to form a solid dispersion as described herein. Including, In step a), compound (1) is provided in its broadest form or in any embodiment as any one of crystalline forms I, III, or IV, as described above. Preferably, in step b), the solid dispersion comprises compound (1) in amorphous form.

[0107] A further aspect of the present invention is therefore a process for preparing the solid dispersion described herein, said process comprising: a) providing a mixture of compound (1) and a pharmaceutically acceptable dispersion carrier, and adding a solvent to obtain a solution or suspension; and b) removing the solvent from the solution or suspension to form a solid dispersion as described herein. Including, In step a), Compound (1) is provided in any one of crystalline Forms I, III, IV (in their broadest form or in any embodiment described above), or a mixture thereof. Preferably, in step b), the solid dispersion comprises Compound (1) in amorphous form.

[0108] The process may further comprise the step of drying the solid dispersion obtained in step b).

[0109] Solid dispersions obtained or obtainable by such processes are a further aspect of the present invention. In certain embodiments, there is provided a process for preparing the solid dispersion described herein, the process comprising: a) providing a solution or suspension comprising Compound (1) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable dispersion carrier, and at least one solvent; and b) removing the solvent from the solution or suspension to form a solid dispersion as described herein; and c) optionally drying the solid dispersion obtained in b). Including, In step a), Compound (1) is provided as any one of crystalline Forms I, III, IV (in its broadest form or in any embodiment, as described above) or as a mixture thereof.

[0110] The solution or suspension of step a) according to any of the processes described above may be referred to as a feed solution. In an embodiment, the removal of the solvent in step b) of the above-defined process is carried out by spray drying, freeze drying, rotary evaporation, distillation, drum drying and / or vacuum drying. In a preferred embodiment, the removal of the solvent in step b) is carried out by spray drying. Preferably, in step b), the solid dispersion comprises compound (1) in amorphous form. The term "spray drying," as used herein, is conventional and broadly used and generally refers to any process involving atomizing, by spraying, a solution, suspension, slurry, or emulsion containing one or more components of a desired product into droplets, followed by rapid evaporation of the sprayed droplets into a solid powder by hot air at a certain temperature and pressure. Spray drying is a process known to those skilled in the art.

[0111] Spray drying is generally carried out by preparing a feed solution by dissolving a crystalline form of Compound (1) and a pharmaceutically acceptable dispersion polymer in a solvent. The feed solution can be pumped into a drying chamber via an atomizer. The feed solution can be atomized by conventional means known in the art, such as a two-fluid sonicating nozzle, a pressure nozzle, a rotary nozzle, and a two-fluid non-sonicating nozzle. The solvent is then removed in the drying chamber to form a solid dispersion. A typical drying chamber uses a hot gas, such as forced air, nitrogen, nitrogen-enriched air, or argon, to dry the particles. The size of the drying chamber can be adjusted to achieve particle characteristics or throughput. The solid dispersions are preferably prepared by conventional spray drying techniques, although other techniques known in the art may be used, such as melt extrusion, freeze drying, rotary evaporation, co-precipitation, KinetiSol® Dispersing Technology (KSD), fluidized bed technology, drum drying, vacuum drying, or other solvent removal processes. The above process for preparing the solid dispersions described herein may comprise, between steps a) and b), an additional step of spraying the solution or suspension obtained in step a) onto an inert excipient core, which process belongs to the fluidized bed technique, in particular the fluidized bed granulation technique.

[0112] In certain embodiments, there is provided a process for preparing the solid dispersion described herein, the process comprising: (a) providing a solution or suspension comprising Compound (1) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable dispersion carrier, and at least one solvent; and (a') spraying the solution or suspension provided in (a) onto an inert excipient core; and (b') removing the solvent from the inert excipient core; and (c') optionally drying the excipient core containing the solid dispersion obtained in (c'); In step a), compound (1) is provided as any one of crystalline forms I, III, IV (described above in their broadest form or in any embodiment), or as a mixture thereof.

[0113] The spraying in step (a') can be carried out in a fluidized bed coater, for example as a top spray, bottom spray, Wurster, tangential or side rotor spray.

[0114] Any solvent or mixture of solvents in which crystalline compound (1) at least partially dissolves can be used. Examples of suitable solvents that can be used individually or as a mixture include water, alcohols such as methanol ("MeOH"), ethanol ("EtOH"), n-propanol, isopropanol, and butanol, such as n-butanol, 2-butanol, isobutanol, and tert-butanol; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; esters such as methyl acetate, ethyl acetate, and propyl acetate, isopropyl acetate, n-butyl acetate, and isobutyl acetate; and various other solvents such as dichloromethane (DCM), chloroform, tetrahydrofuran, acetonitrile, toluene, and 1,1,1-trichloroethane. In some embodiments, the solvent referred to in any of the above-described processes and embodiments thereof is selected from the group consisting of water, alcohols, ketones, esters, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, toluene, 1,1,1-trichloroethane, and mixtures thereof. In some embodiments, the solvent referred to in any of the above-described processes and embodiments thereof is selected from the group consisting of alcohols (especially methanol, ethanol, n-propanol, isopropanol, and butanol, such as n-butanol, 2-butanol, isobutanol, and tert-butanol), ketones (especially acetone, methyl ethyl ketone, and methyl isobutyl ketone), esters (especially methyl acetate, ethyl acetate, and propyl acetate, isopropyl acetate, n-butyl acetate, and isobutyl acetate), dichloromethane (DCM), tetrahydrofuran, acetonitrile, toluene, and 1,1,1-trichloroethane. Mixtures of solvents with water can also be used.

[0115] In embodiments, the solvent is a mixture of dichloromethane (DCM) and methanol (MeOH). The relative amounts of DCM and MeOH in the mixture can vary. Preferably, the mixture contains at least 25% MeOH by weight, based on 100% total weight of the mixture. In embodiments, the mixture contains excess DCM. More preferably, the weight:weight ratio of DCM:MeOH ranges from 25:75 to 95:5 (w / w). Preferably, DCM and MeOH are in a weight:weight ratio of approximately 25:75, 50:50, 70:30, 75:25, 80:20, 85:15, or 90:10. A solvent mixture of DCM:MeOH in a ratio of approximately 90:10 (w / w) has been found to advantageously allow for higher throughput for spray drying.

[0116] In embodiments, the concentration of solids in the feed solution (particularly the suspension or solution defined in step a) above) is in the range of about 1% to 20% by weight, based on 100% total weight of the feed solution. Preferably, the concentration of solids in the feed solution is in the range of about 5% to 15% by weight, more preferably about 8% to 12% by weight, based on 100% total weight of the feed solution. For example, the concentration of solids in the feed solution is about 8% or 10% by weight, based on 100% total weight of the feed solution.

[0117] After removal of the solvent by spray drying, the resulting solid dispersion is optionally subjected to a drying process to reduce the residual solvent content. In embodiments, drying is carried out at a temperature ranging from about room temperature to 100°C, preferably from about 30°C to 60°C, and more preferably from about 35°C to 45°C. For example, drying is carried out at a temperature of about 40°C. In other embodiments, drying is carried out at ambient pressure and / or under reduced pressure. For example, drying is carried out at ambient pressure or at a pressure of about 900 mbar or less, more preferably about 100 mbar or less, and most preferably about 50 mbar or less, e.g., about 20 mbar or less. In yet other embodiments, drying is carried out for a period ranging from about 6 hours to 72 hours, preferably from about 12 hours to 48 hours.

[0118] Pharmaceutical compositions, such as tablets, preferably film-coated tablets, can be manufactured according to conventional methods known to those skilled in the art. In embodiments, the manufacturing process can include the steps of 1) preparing a solid dispersion, such as by spray drying as described herein, 2) dry-granulating the solid dispersion with one or more suitable excipients, 3) blending the granules with suitable disintegrants and / or lubricants, and / or glidants, 4) compressing the blend into tablet cores, and 5) optionally film-coating the tablet cores. In an embodiment of the process for preparing a solid dispersion, Compound (1) in crystalline form may be provided in an amount ranging from 5% to 95% by weight, based on 100% total weight of the solid dispersion. In an embodiment of the process for preparing a solid dispersion, Compound (1) in crystalline form may be provided in an amount ranging from 25% to 75% by weight, based on 100% total weight of the solid dispersion. In an embodiment, the pharmaceutically acceptable dispersing carrier may be provided in an amount ranging from 5% to 95% by weight, based on 100% total weight of the solid dispersion. In an embodiment, the pharmaceutically acceptable dispersing carrier may be provided in an amount ranging from 25% to 75% by weight, based on 100% total weight of the solid dispersion.

[0119] In an embodiment of the process for preparing a solid dispersion, Compound (1) in crystalline form may be provided in an amount ranging from 20% to 50% by weight, based on 100% total weight of the solid dispersion. In an embodiment, Compound (1) in crystalline form may be provided in an amount ranging from 25% to 50% by weight, based on 100% total weight of the solid dispersion. In an embodiment, the pharmaceutically acceptable dispersing carrier may be provided in an amount ranging from 50% to 80% by weight, based on 100% total weight of the solid dispersion. In an embodiment, the pharmaceutically acceptable dispersing carrier may be provided in an amount ranging from 50% to 80% by weight, based on 100% total weight of the solid dispersion. In an embodiment, the pharmaceutically acceptable dispersing carrier may be provided in an amount ranging from 50% to 75% by weight, based on 100% total weight of the solid dispersion.

[0120] In embodiments, Compound (1) and the pharmaceutically acceptable dispersion carrier may be provided in approximately equal amounts by weight, such as approximately 50% by weight of Compound (1) and approximately 50% by weight of the pharmaceutically acceptable dispersion carrier. In embodiments, approximately 25% or 50% by weight of Compound (1) and approximately 75% or 50% by weight of a pharmaceutically acceptable dispersion carrier are provided. In an embodiment, in the process of preparing a solid dispersion, particularly in the solution or suspension of step a), the mass ratio of compound (1) to the pharmaceutically acceptable dispersing carrier is approximately 1:4 to 4:1, preferably 1:3 to 3:1, for example, 1:1 to 1:3. In an embodiment, in the process of preparing a solid dispersion, particularly in the solution or suspension of step a), the mass ratio of compound (1) to the pharmaceutically acceptable dispersing carrier is approximately 1:1.

[0121] Use for the treatment and / or prevention of oncological and / or hyperproliferative disorders In its broadest form or in any embodiment, the crystalline Forms I, III, IV described above can be used as pharmaceuticals. In particular, in its broadest form or in any embodiment, the crystalline Forms I, III, IV described above can be used for the treatment and / or prevention of oncological and / or hyperproliferative disorders, in particular in anti-cancer therapy. According to one aspect, there is provided crystalline Form I, as described above, in its broadest form or in any embodiment, for pharmaceutical use. According to one aspect, there is provided crystalline Form III, as described above, in its broadest form or in any embodiment, for pharmaceutical use. According to one aspect, there is provided crystalline Form IV, as described above, in its broadest form or in any embodiment, for pharmaceutical use. According to one aspect, there is provided a mixture of crystalline Forms I, III and / or IV, as described above, in its broadest form or in any embodiment, for pharmaceutical use.

[0122] According to one aspect, there is provided crystalline Form I, as described above, in its broadest form or in any embodiment, for use as an anti-cancer medicament. According to one aspect, there is provided crystalline Form III, as described above, in its broadest form or in any embodiment, for use as an anti-cancer medicament. According to one aspect, there is provided crystalline Form IV, as described above, in its broadest form or in any embodiment, for use as an anti-cancer medicament. In one embodiment, there is provided crystalline Form I, III, or IV, or mixtures thereof, as described above (in its broadest form or in any embodiment), for use in the treatment and / or prevention of diseases or disorders modulated by HER2, particularly oncological and / or hyperproliferative diseases. Another aspect refers to crystalline Form I, III, or IV, or mixtures thereof, as described above (in its broadest form or in any embodiment), for use in a method of treating and / or preventing diseases or disorders modulated by HER2, particularly oncological or hyperproliferative diseases.

[0123] A further aspect relates to methods of treating and / or preventing diseases or disorders modulated by HER2, in particular oncological and / or hyperproliferative diseases, comprising administering to a patient crystalline Form I, III, or IV, or a mixture thereof, as described above (in its broadest form or in any embodiment). In certain embodiments, such methods comprise administering to a human in need of such treatment a therapeutically effective amount of crystalline Form I, III, or IV, or a mixture thereof, as described above (in its broadest form or in any embodiment). A related aspect relates to the use of crystalline Form I, III or IV as described above (in its broadest form or in any embodiment), or mixtures thereof, in the manufacture of a medicament. Certain embodiments relate to the use of crystalline Form I, III or IV as described above (in its broadest form or in any embodiment), or mixtures thereof, in the manufacture of a medicament for the treatment and / or prevention of diseases or disorders modulated by HER2, in particular oncological and / or hyperproliferative diseases. In one aspect, there is provided crystalline Form I, III, or IV, or mixtures thereof, as described above (in its broadest form or in any embodiment), for use in the treatment and / or prevention of diseases and / or conditions, wherein inhibition of wild-type and / or mutant HER2 is of therapeutic benefit, particularly for the treatment and / or prevention of diseases and / or conditions, wherein inhibition of HER2 exon 20 mutant protein is of therapeutic benefit. Examples of such diseases and / or conditions include, but are not limited to, oncological and / or hyperproliferative diseases, e.g., cancer.

[0124] One aspect relates to crystalline Form I, III or IV, or mixtures thereof, as described above (in its broadest form or in any embodiment), for use in the treatment and / or prevention of oncological and / or hyperproliferative diseases. As used herein, the term "hyperproliferative disease" refers to a condition in which cell growth is increased above normal levels. Hyperproliferative diseases include malignant diseases, such as cancer, and non-malignant diseases. In a preferred embodiment, the hyperproliferative disorder is cancer. As used herein, the term "oncological disease" refers to a disease or condition associated with cancer or a cancer indication. Cancers can be classified by the type of tissue from which they originate (histological type) and by the primary site, or location in the body where the cancer first develops.

[0125] In certain embodiments, the oncological and / or hyperproliferative disease is cancer. In certain embodiments, crystalline Form I, as described above, in its broadest form or in any embodiment, is provided for use in the treatment and / or prevention of cancer. In certain embodiments, crystalline Form III, as described above, in its broadest form or in any embodiment, is provided for use in the treatment and / or prevention of cancer. In certain embodiments, crystalline Form IV, as described above, in its broadest form or in any embodiment, is provided for use in the treatment and / or prevention of cancer. In certain embodiments, a mixture of crystalline Forms I, III, and / or IV, as described above, in its broadest form or in any embodiment, is provided for use in the treatment and / or prevention of cancer. Another aspect refers to crystalline Form I, III, or IV, or mixtures thereof, as described above (in its broadest form or in any embodiment), for use in a method of treating and / or preventing cancer.

[0126] A further aspect relates to methods of treating and / or preventing cancer, wherein the method comprises administering to a patient crystalline Form I, III, or IV, or a mixture thereof, as described above (in its broadest form or in any embodiment). In certain embodiments, such methods comprise administering to a human in need of such treatment a therapeutically effective amount of crystalline Form I, III, or IV, or a mixture thereof, as described above (in its broadest form or in any embodiment). Certain embodiments relate to the use of crystalline Form I, III, or IV, or mixtures thereof, as described above (in its broadest form or in any embodiment), in the manufacture of a medicament for the treatment and / or prevention of cancer. In embodiments, the cancer is HER2-overexpressing, HER2-amplified, and / or HER2-mutated. In embodiments, the cancer is a HER2 exon 20-mutated cancer.

[0127] In an embodiment, the oncological and / or hyperproliferative disease is a HER2-overexpressing, HER2-amplified and / or HER2-mutated cancer. "HER2-overexpressing," as used herein, refers to a cancer in which the cells of the cancer or tumor express HER2 at levels detectable by immunohistochemistry (e.g., IHC 2+ or IHC 3+) and / or methods that assay for ERBB2 messenger RNA. "HER2 amplified", as used herein, refers to a cancer in which the cancer or tumor cells present more than two, particularly more than three, four, five, six, seven, eight, nine or ten, preferably more than six copies of the HER2 gene ERBB2.

[0128] HER2 expression, gene copy number and amplification can be measured, for example, by determining nucleic acid sequencing (e.g., sequencing of genomic DNA or cDNA), measuring mRNA expression, measuring protein abundance, or a combination thereof. HER2 testing methods include immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), chromogenic in situ hybridization (CISH), ELISA, and RNA quantification using techniques such as RT-PCR, microarray analysis and next-generation sequencing (NGS). HER2 expression in or on cancer sample cells can be compared with reference cells. The reference cells can be non-cancerous cells obtained from the same subject as the sample cells. The reference cells can be non-cancerous cells obtained from a different subject or a group of subjects.

[0129] If the cancer has HER2 overexpression and / or HER2 amplification in or on the cells, the cancer can be said to be "HER2 positive." "HER2 mutant," as used herein, refers to a cancer that has at least one mutation, i.e., an alteration in the nucleic acid sequence of the HER2 gene and / or an alteration in the amino acid sequence of the HER2 protein, including, but not limited to, those listed below. Mutations can be found by any method known to those skilled in the art, such as molecular diagnostic methods, including, but not limited to, polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP), denaturing gradient gel electrophoresis (DGGE), heteroduplex analysis, restriction fragment length polymorphism (RFLP), next-generation sequencing (NGS), and whole exome sequencing. "Cancer with a HER2 exon 20 mutation" or "HER2 exon 20 mutant cancer," as used herein, refers to a cancer in which the cancer or tumor cells have at least one HER2 exon 20 mutation, including but not limited to, the mutations listed below.

[0130] ERBB2 (HER2) exon 20 encodes part of the kinase domain and spans amino acids 769 to 835. Any mutation, insertion, duplication, or deletion within this region is defined as an exon 20 mutation, including the following mutations: p.A772_G773insMMAY; p.Y772_A775_dup(YVMA); p.A775_G776insYVMA; p.Y772insYVMA; p.M774delinsWLV; p.A775_G776insSVMA; p.A775_G776insVVMA; p.A775_G776insVVMA insYVMS;p.A775_G776insC;p.A776_delinsVC;p.A776_delinsLC;p.A776_delinsVV;p.A776_delinsAVGC;p.A776_delinsIC;p.A776_V777delinsCVC;p.V777_insE;p.G778_P780dup(GSP);p.G776_delinsVC ("p." refers to the HER2 protein).

[0131] Additionally, oncogenic HER2 mutations exist outside of exon 20, including the following mutations: p.S310F; p.R678Q; p.L755S; p.L755A; p.L755P; p.S310Y; p.S310A; p.V842I; p.D769Y; p.D769H; p.R103Q; p.G1056S; p.I767M; p.L869R; p.L869R; p.T733I; p.T862A; p.V697L; p.V777L; p.V777M; p.R929W; p.D277H; p.D277Y; p.G660D ("p" refers to the HER2 protein).

[0132] In embodiments, the oncological and / or hyperproliferative disease or cancer is one of the following cancers, tumors or other proliferative diseases, but is not limited to: Cancers / tumors / carcinomas of the head and neck: for example, tumors / carcinomas / cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lips, gums, alveolar ridge, retromolar trigone, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including base of tongue, tonsils, tonsillar pillars, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands); Cancers / tumors / carcinomas of the lung: e.g., non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, renal clear cell carcinoma, bronchoalveolar epithelial), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, mixed oat cell carcinoma); Mediastinal neoplasms: for example, neurogenic tumors (including neurofibroma, schwannoma, malignant schwannoma, neurosarcoma, ganglioneuroblastoma, ganglioneuromatosis, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, non-seminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangioleiomyoma); Cancers / tumors / carcinomas of the gastrointestinal (GI) tract: e.g., esophagus, stomach (gastric cancer), pancreas, liver and biliary tree (including hepatocellular carcinoma (HCC), e.g., childhood HCC, fibrolamellar HCC, mixed HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; bile duct adenocarcinoma; cholangiocellular carcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatzkin tumor), gallbladder, extrahepatic bile duct, small intestine (including duodenum, jejunum, ileum) ), large intestine (cecum, colon, rectum, anus; including colorectal cancer and gastrointestinal stromal tumors (GIST)), genitourinary system (kidney, e.g., renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), adrenal gland tumor, Grawitz tumor; ureter; bladder, e.g., urachal carcinoma, urothelial carcinoma; urethra, e.g., distal, bulbomembranous, prostatic; prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-refractory), including penis); tumors / carcinomas / cancers of the appendix; Cancer / tumor / carcinoma of the testis: e.g., seminoma, non-seminoma; Gynecological cancers / tumors / carcinomas: for example, tumors / carcinomas / cancers of the ovaries, fallopian tubes, peritoneum, cervix, vulva, vagina, and uterine corpus (including endometrium and fundus); Cancers / tumors / carcinomas of the breast: e.g., breast carcinoma (invasive ductal, colloid, lobular invasive, tubular, adenoid cystic, papillary, medullary, mucinous), hormone receptor positive breast cancer (estrogen receptor positive breast cancer, progesterone receptor positive breast cancer), HER2 positive breast cancer, triple negative breast cancer, Paget's disease of the breast; Cancers / tumors / carcinomas of the endocrine system: for example, tumors / carcinomas of the endocrine glands, thyroid gland (thyroid carcinoma / tumor; papillary, follicular, anaplastic, medullary), parathyroid gland (parathyroid carcinoma / tumor), adrenal cortex (adrenocortical carcinoma / tumor), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal gland, pineal gland, carotid body, islet cell tumor, paraganglia, pancreatic endocrine tumors (PET; non-functioning PET, PPoma, gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumor; Sarcomas of soft tissues: e.g., fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of tendon sheath, solitary fibrous tumor of the pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexus sarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small cell tumor; Sarcomas of bone: e.g., myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, and mesenchymal chondrosarcoma), osteosarcoma (including parosteal, periosteal, high-grade superficial, small cell, radiation-induced osteosarcoma, and Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantinoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, and chondroblastoma; Mesothelioma: e.g., pleural mesothelioma, peritoneal mesothelioma; Cancers of the skin: for example, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentigo, nodular, and intraocular melanoma), actinic keratosis, and eyelid cancer; Neoplasms of the central nervous system and brain: for example, astrocytoma (cerebral, cerebellar, diffuse, fibrillary, anaplastic, pilocytic, protoplasmic, round cell), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, medulloblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, ganglioneuroma, neuroblastoma, retinoblastoma, schwannoma (e.g., auditory), spinal axis tumor; peripheral nervous system cancer; Lymphomas and leukemias: for example, B-cell non-Hodgkin's lymphoma (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), and Burkitt's lymphoma (BL)), T-cell non-Hodgkin's lymphoma (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma) (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytoma, chronic B-cell lymphocytic leukemia (BchlorineL); Cutaneous T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte-predominant HD (NLPHD), nodular sclerosing HD (NSHD), mixed cellularity HD (MCHD), lymphocyte-rich typical HD, and lymphocyte-depleted HD (LDHD)), large granular lymphocyte leukemia (LGL), chronic myeloid leukemia (CML), acute myeloid / myeloid leukemia myeloid leukemia (AML), acute lymphocytic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myelogenous / myelocytic leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML); Carcinoma of unknown primary site (CUP).

[0133] All cancers / tumors / carcinomas described above are characterized by their specific location / origin within the body and are meant to include both primary tumors and metastatic tumors derived therefrom. Preferably, cancers as defined herein (e.g., included in any embodiment referring to a cancer type) are metastatic, advanced, and / or unresectable.

[0134] All cancers / tumors / carcinomas described above can be further differentiated by their histopathological classification: Epithelial cancers, such as squamous cell carcinoma (SCC) (carcinoma in situ, superficial invasive, verrucous carcinoma, pseudosarcoma, undifferentiated, transitional cell, lymphoepithelial), adenocarcinoma (AC) (well-differentiated, mucinous, papillary, pleomorphic giant cell, ductal, small cell, signet ring cell, spindle cell, clear cell, oat cell, colloidal, adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinic cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid); oncocellular carcinoma; Non-epithelial cancers, such as sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological neoplasms, mixed and undifferentiated carcinomas.

[0135] In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, endocrine cancer, gastrointestinal cancer, gynecological cancer, head and neck tumors, lung cancer, nervous system cancer, and skin cancer.

[0136] Preferably, the brain cancer is glioblastoma or glioma. Preferably, the breast cancer is lobular breast cancer. Additionally or alternatively, the breast cancer is preferably metastatic. Preferably, the endocrine cancer is a nerve sheath tumor, more preferably a HER2-mutated nerve sheath tumor. Preferably, the gastrointestinal cancer is selected from the group consisting of anal cancer, appendix cancer, bile duct cancer, bladder cancer, colorectal cancer, esophagogastric cancer, stomach cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, and small intestine cancer. Additionally or alternatively, the gastrointestinal cancer may be a gastrointestinal neuroendocrine tumor, preferably a HER2 mutant type. More preferably, the gastrointestinal cancer is selected from the group consisting of gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, and esophageal adenocarcinoma, in particular metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, and metastatic esophageal adenocarcinoma.

[0137] Preferably, said gynecological cancer is selected from the group consisting of cervical cancer, uterine cancer, endometrial cancer and ovarian cancer. Preferably, the head and neck tumor is a salivary gland cancer or tumor. Preferably, the lung cancer is non-small cell lung cancer (NSCLC). Preferably, the nervous system cancer is a peripheral nervous system cancer, more preferably a HER2-amplified peripheral nervous system cancer. Preferably, the skin cancer is not melanoma, i.e., a non-melanoma skin cancer. In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, nerve sheath tumor, anal cancer, appendix cancer, bile duct cancer, bladder cancer, colorectal cancer, esophagogastric cancer, stomach cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, small intestine cancer, neuroendocrine gastrointestinal cancer, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, metastatic esophageal adenocarcinoma, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, salivary gland cancer, non-small cell lung cancer (NSCLC), peripheral nervous system cancer, and non-melanoma skin cancer.

[0138] In some embodiments, the cancer is a HER2-overexpressing, HER2-amplified and / or HER2-mutated (particularly HER2 exon 20 mutated) cancer selected from the group consisting of glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, nerve sheath tumor, anal cancer, appendix cancer, bile duct cancer, bladder cancer, colorectal cancer, esophagogastric cancer, stomach cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, small intestine cancer, neuroendocrine gastrointestinal cancer, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, metastatic esophageal adenocarcinoma, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, salivary gland cancer, non-small cell lung cancer (NSCLC), peripheral nervous system cancer, and non-melanoma skin cancer. In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, bile duct cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, stomach cancer, esophageal tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0139] In some embodiments, the cancer is a HER2-overexpressing, HER2-amplified and / or HER2-mutated (particularly HER2 exon 20 mutated) cancer selected from the group consisting of brain cancer, breast cancer, bile duct cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, gastric cancer, esophageal tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer. In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, skin cancer, stomach cancer, esophageal tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0140] In embodiments, the cancer is a HER2-overexpressing, HER2-amplified and / or HER2-mutated (particularly HER2 exon 20 mutated) cancer selected from brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, skin cancer, gastric cancer, esophageal tumors, head and neck tumors, gastrointestinal cancer, gallbladder tumors, kidney cancer, liver cancer, lung cancer and prostate cancer. In other embodiments, the cancer is selected from the group consisting of breast cancer, bladder cancer, colorectal cancer, gastrointestinal cancer, esophageal cancer, or lung cancer. In further embodiments, the cancer is selected from lung cancers / tumors / carcinomas, such as non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, renal clear cell carcinoma, bronchoalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, mixed oat cell carcinoma). In yet further embodiments, the cancer is NSCLC. In yet further embodiments, the cancer is HER2 exon 20 mutant NSCLC.

[0141] In one embodiment, the cancer is advanced, unresectable, or metastatic NSCLC with a HER2 mutation, wherein the HER2 mutation is in the tyrosine kinase domain. Preferably, in this embodiment, the solid dispersion or pharmaceutical composition described herein is administered as a first-line treatment. More preferably, in this embodiment, the solid dispersion or pharmaceutical composition described herein is administered as a second-line or further-line treatment. In an embodiment, the cancer is HER2-positive metastatic breast cancer. Preferably, in this embodiment, the solid dispersion or pharmaceutical composition described herein is administered as a first-line treatment. More preferably, in this embodiment, the solid dispersion or pharmaceutical composition described herein is administered as a second-line or further-line treatment.

[0142] In an embodiment, the cancer is HER2-positive metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, or metastatic esophageal adenocarcinoma. Preferably, in this embodiment, the solid dispersion or pharmaceutical composition described herein is administered as a first-line treatment. More preferably, in this embodiment, the solid dispersion or pharmaceutical composition described herein is administered as a second-line or further-line treatment. In another aspect, the present invention relates to crystalline Form I, III or IV or mixtures thereof as described above (in its broadest form or in any embodiment) for use in the treatment and / or prevention of oncological and / or hyperproliferative diseases as defined herein, wherein crystalline Form I, III or IV or mixtures thereof are administered in combination with a cytostatic and / or cytotoxic active substance and / or in combination with radiotherapy and / or immunotherapy. In another aspect, the present invention relates to the combination of crystalline Form I, III or IV as described above (in its broadest form or in any embodiment) or mixtures thereof with cytostatic and / or cytotoxic active substances and / or with radiotherapy and / or immunotherapy for use in the treatment and / or prevention of cancer.

[0143] The crystalline Forms I, III or IV described above (in their broadest form or in any embodiment) can be used by themselves or in combination with one or more other pharmacologically active substances, such as state-of-the-art or standard of care compounds, such as cell growth inhibitors, anti-angiogenic agents, steroids or immune modulators / checkpoint inhibitors.

[0144] Pharmacologically active agents that may be administered in combination with the crystalline forms described herein include hormones, hormone analogs and antihormones (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g., anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g., goserelin acetate, leuprolide), inhibitors of growth factors and / or their corresponding receptors (growth factors, e.g., platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin, insulin-like growth factor (IGF), ... Insulin-like growth factors (IGFs), human epidermal growth factors (HERs, e.g., HER2, HER3, HER4), and hepatocyte growth factor (HGF), and / or their corresponding receptors), and inhibitors include, but are not limited to, for example, (anti) growth factor antibodies, (anti) growth factor receptor antibodies, and tyrosine kinase inhibitors (e.g., cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib , bevacizumab, pertuzumab, and trastuzumab; antimetabolites (e.g., antifolates, e.g., methotrexate, raltitrexed, pyrimidine analogs, e.g., 5-fluorouracil (5fluorineU), ribonucleoside and deoxyribonucleoside analogs, capecitabine and gemcitabine, purine and adenosine analogs, e.g., mercaptopurine, thioguanine, cladribine, and pentostatin, cytarabine (arabinose),C), fludarabine); antitumor antibiotics (e.g., anthracyclines such as doxorubicin, Doxil (PEGylated liposomal doxorubicin hydrochloride, Myocet (non-PEGylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); alkylating agents (e.g., estramustine, mechlorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nifedipine, trosoureas, such as carmustine and lomustine, thiotepa; mitotic inhibitors (e.g., vinca alkaloids, such as vinblastine, vindesine, vinorelbine, and vincristine; and taxanes, such as paclitaxel and docetaxel); angiogenesis inhibitors (e.g., tasquinimod), tubulin inhibitors; DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxins, such as etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone), serine / threonine kinase inhibitors (e.g., PDK 1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors, dual mTOR / PI3K inhibitors, STK33 inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors), protein-protein interaction inhibitors (e.g., IAP activators, Mcl-1, MDM2 / MDMX), MEK inhibitors, ERK inhibitors, KRAS inhibitors (e.g., KRASG12C inhibitors), signal transduction pathway inhibitors (e.g., SOS1 inhibitors), FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors, Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogs (e.g., everolimus, temsirolimus, ridaforolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors agents, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors, immunotherapy agents, for example, immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, PD-L2, LAG3, and TIM3 binding molecules / immunoglobulins, e.g., ipilimumab, nivolumab, pembrolizumab, etc.), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (e.g., anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), T cell engagers (e.g., CD3 These include bispecific engagers (BiTEs®) such as CD3 x BCMA, CD3 x CD33, CD3 x CD19, PSMA x CD3), tumor vaccines, and various chemotherapeutic agents such as amifostine, anagrelide, clodronate, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer.

[0145] Pharmaceutical Composition According to a further aspect, the present invention relates to a pharmaceutical composition comprising crystalline Form I, III or IV as described above (in its broadest form or in any embodiment) and one or more pharmaceutically acceptable excipients. According to a further aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form I, III, or IV, or a mixture thereof, as described above (in its broadest form or in any embodiment), and one or more pharmaceutically acceptable excipients. Another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of the solid dispersion described herein and one or more pharmaceutically acceptable excipients. The term "therapeutically effective amount," as used herein, refers to a quantity of a substance that is capable of eliminating symptoms of disease or preventing or alleviating these symptoms or prolonging the survival of a treated patient.

[0146] The term "pharmaceutically acceptable excipient" refers to a non-toxic component that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable excipients that can be used in the compositions of this invention include fillers, disintegrants, glidants, lubricants, and coating agents. The compositions can contain additional pharmaceutically acceptable excipients selected from buffers, dispersants, surfactants, wetting agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, processing aids, colorants, sweeteners, flavors, flavoring agents, diluents, and other known additives that can be used in the manufacture of pharmaceutical products. The pharmaceutical composition may contain conventional non-toxic pharmaceutically acceptable excipients. In an embodiment of the pharmaceutical composition, one or more pharmaceutically acceptable excipients are selected from the group consisting of fillers, disintegrants, glidants, lubricants, and coating agents. In an embodiment, the pharmaceutical composition comprises a filler, a disintegrant, a glidant, and a lubricant. In an embodiment, the pharmaceutical composition comprises a filler, a disintegrant, a glidant, a lubricant, and a coating agent. It should be understood that the pharmaceutical composition may comprise one or more excipients for each function, for example, one or more fillers, one or more disintegrants, one or more glidants, one or more lubricants, and one or more coating agents.

[0147] In embodiments, the filler is selected from the group consisting of microcrystalline cellulose, mannitol, and mixtures thereof. In embodiments, the disintegrant is selected from the group consisting of cross-linked sodium carboxymethylcellulose, also referred to as croscarmellose, or sodium bicarbonate, crospovidone, sodium starch glycolate, and mixtures thereof. In certain embodiments, the disintegrant is croscarmellose sodium. In embodiments, the glidant is colloidal silicon dioxide. In embodiments, the lubricant is selected from the group consisting of stearyl fumarate, magnesium stearate, and mixtures thereof. In certain embodiments, the lubricant is sodium stearyl fumarate.

[0148] In embodiments of the pharmaceutical composition, the one or more pharmaceutically acceptable excipients include mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate.

[0149] In certain embodiments, the pharmaceutical composition may include a coating, such as when formulated as a film-coated tablet. In embodiments, the coating may include a film-forming agent, such as partially hydrolyzed polyvinyl alcohol, an anti-adherent agent, such as talc, a pigment, such as titanium dioxide, glyceryl mono- and dicaprylocaprate (GMDCC), and iron oxide, such as iron oxide yellow, and a lubricant, such as sodium lauryl sulfate. Coatings are commercially available under the trademark Opadry® AMB II Yellow, for example. In a preferred embodiment, the coating does not contain titanium dioxide, for example, is titanium dioxide-free. The crystalline form present in the solid dispersion may be as defined in any of the above aspects, objects and / or embodiments, and therefore in particular by at least one of crystalline forms I, III, and IV.

[0150] The crystalline form present in the pharmaceutical composition may be as defined in any of the above aspects, objects and / or embodiments, and therefore in particular by at least one of crystalline forms I, III, and IV. In particular, the present invention provides pharmaceutical compositions comprising crystalline Form I as defined herein and one or more pharmaceutically acceptable excipients. In particular, the present invention provides pharmaceutical compositions comprising crystalline Form III as defined herein and one or more pharmaceutically acceptable excipients. In particular, the present invention provides a pharmaceutical composition comprising crystalline Form IV as defined herein and one or more pharmaceutically acceptable excipients. In certain embodiments, a pharmaceutical composition comprising a crystalline form defined herein comprises one or more pharmaceutically acceptable excipients and an additional therapeutic agent.

[0151] According to a further embodiment, the pharmaceutical composition comprises at least one other cytostatic and / or cytotoxic active substance. Suitable formulations for administering the compounds of the invention will be apparent to those of ordinary skill in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions—particularly solutions for injection (sc, iv, im) and infusion (injectable)—elixirs, syrups, sachets, emulsions, inhalable or dispersible powders. Suitable tablets can be obtained, for example, by mixing one or more compounds in crystalline form with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants. The applicable daily dosage range of the described crystalline forms is usually 1 mg to 2000 mg, preferably 10 mg to 1000 mg. The dosage for intravenous use is between 1 mg and 1000 mg at different infusion rates, preferably between 5 mg and 500 mg at different infusion rates. However, it may sometimes be necessary to deviate from the amounts specified, depending on the body weight, age, route of administration, severity of the disease, individual response to the drug, the nature of its formulation, and the time or interval over which the drug is administered (continuous or intermittent treatment with one or more doses per day). Thus, in some cases, it may be sufficient to use less than the minimum dose indicated above, while in other cases the upper limit may have to be exceeded. When administering large amounts, it may be advisable to divide them into a number of smaller doses distributed over the day. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0152] It should be understood that any of the above exemplified aspects or embodiments can be combined with any other of the above exemplified aspects or embodiments to provide additional aspects or embodiments. In particular, for Form IV, each embodiment that characterizes a crystalline form by its X-ray diffraction pattern can be combined with any other embodiment that characterizes a crystalline form by its Raman spectrum to provide further embodiments, where a crystalline form is characterized by its X-ray diffraction pattern and its Raman spectrum. The same applies to Forms III and I.

[0153] In many of the embodiments described above, peaks in the X-ray diffraction pattern (i.e., X-ray diffraction peaks) are listed as absolute values ​​followed by an error range, e.g., (6.2±0.2)°, where 6.2 is the absolute value and ±0.2 is the error range, so that the peaks are between 6.0° and 6.4°. The error range is typically ±0.1 or ±0.2. For all aspects or embodiments having an error range of ±0.2 referenced in the XRPD, a corresponding embodiment having an error range of ±0.1 is disclosed herein. This means that in any aspect or embodiment referencing an error range of ±0.2, 0.2 can be replaced by 0.1 to provide additional embodiments of the present invention.

[0154] Similarly, in many of the embodiments described above, peaks included in the Raman spectra (i.e., Raman peaks) are listed as absolute values ​​followed by an error range, e.g., 831±2, where 831 is the absolute value and ±2 is the error range, such that the peaks are between 829 and 833. The error range is typically ±2. For every aspect or embodiment having a ±2 error range referred to in the Raman, a corresponding embodiment having a ±1 error range is disclosed herein. This means that in any aspect or embodiment referring to a ±2 error range, the 2 can be replaced by 1 to provide additional embodiments of the invention. In all embodiments referring to X-ray diffraction peaks, the peaks preferably have a relative intensity of more than 5%, especially where the X-ray diffraction pattern is obtained with the experimental parameters reported in Table 1. The features and advantages of the present invention will become apparent from the following detailed examples, which illustrate, by way of example, the principles of the invention without limiting the scope of the invention: [Example]

[0155] Abbreviation The following abbreviations are used herein:

[0156] [Table 1] The solid crystalline forms of Compound (1) can be produced as polymorphic Forms I, III, and IV. Examples of methods for producing each of the defined polymorphic forms are provided below in Examples 1 and 2.

[0157] Example 1 Preparation of crystalline forms of compound (1) general Unless otherwise specified, all reactions are carried out in commercially available equipment using methods commonly used in chemical laboratories. Starting materials that are air and / or moisture sensitive are stored under protective gas, and the corresponding reactions and manipulations using them are carried out under protective gas (nitrogen or argon). If a compound is to be represented both by a structural formula and by its name, in case of conflict the structural formula will control.

[0158] Analysis method 1 1 H NMR spectra are recorded in dimethylsulfoxide-d6 (DMSO-d6) on a Bruker (400 MHz) spectrometer.

[0159] MS measurements were performed using a Waters ACQuITY QDa Detector coupled to an LC system. The ionization parameters were as follows: mass range 100-800; cone voltage 15 V; sampling rate 15 pts / sec; capillary voltage 0.8 V + / -; probe temperature 600 °C. HPLC method for determining the ratio of compound (5a) and compound (5b): HPLC equipped with gradient pump (600 bar), column thermostat, UV-detector and autosampler thermostat.

[0160] [Table 2]

[0161] Example 1.1 Route 1 to obtain crystalline Forms I and III Scheme 1. Synthesis of Compound 1 from Compounds 9, 10, and 6b Based on a Halogen Leaving Group

[0162] [ka]

[0163] Starting materials 9 and 10 are commercially available or can be prepared according to procedures known in the art. For example, compound 9 can be prepared as described in WO 97 / 32880, WO 2010 / 026262, or WO 2020 / 239999, and compound 10 can be prepared as described in WO 2019 / 214634, WO 2021 / 156178, WO 2021 / 213800, or WO 2022 / 003575.

[0164] Step 1. Preparation of compound (8') from compound (9) and compound (10). General Procedure. All calculations are made with respect to compound (9).

[0165] A clean, N2-sparged vessel is charged with compound 9 (1.0 equiv.), compound 10 (1.0 equiv.), and toluene (2.0 V). Stirring is initiated, and IPA (10.0 V) is added. Upon completion of the addition, the mixture is heated to 43°C and held until the reaction is complete. The reaction mixture is then cooled to 22°C, stirred for 30 minutes, and filtered. The solid is washed twice with IPA (1.5 V) and dried in vacuo at 50°C to give compound 8' as a solid in 93% yield.

[0166] Analysis information Compound (8'): 1H NMR (400 MHz, DMSO-d6) δ ppm 2.21 (s, 3 H) 2.77 (s, 3 H) 4.05 (s, 3 H) 7.09 (d, J=8.76 Hz, 1 H) 7.15 (d, J=2.50 Hz, 1 H) 7.34 (dd, J=9.01, 2.25 Hz, 1 H) 7.85 (dd, J=8.63, 2.63 Hz, 1 H) 7.89 (d, J=2.50 Hz, 1 H) 7.97 (d, J=9.01 Hz, 1 H) 8.66 (s, 1 H) 9.27 (s, 1 H) 9.48 (s, 1 H) 10.04 (br s, 1 H); LR EI MS m / z: 430.14

[0167] Step 2. Preparation of compounds (5a) / (5b) from compound (8'). General Procedure. All calculations are made with respect to compound (8'). A clean, N2-sparged vessel is charged with compound (8') (1.0 equiv., HCl salt) and ethanol (5.5 V). Stirring is initiated, the contents are sparged with N2, and the internal temperature of the vessel is adjusted to 25 °C. To this mixture is charged a solution of Na2MoO4 (1.1 mol%) in water (2.2 V), followed by 30% aqueous HO2 (1.20 equiv.), while maintaining the internal temperature of the vessel at 25 °C. Upon completion of the addition, the mixture is stirred at 25 °C for 3 hours or more. The excess HO2 is then quenched with a solution of Na-L-ascorbate (0.10 equiv.) in water (0.3 V). The mixture is stirred for 15 minutes at 25 °C, followed by the addition of DMSO (6.1 V) and water (0.2 V). The pH of the mixture was adjusted to 5.0-6.0 using triethylamine, and the mixture was heated to 40°C, followed by the addition of water (6 V) while maintaining the internal vessel temperature at 40°C. The mixture was then brought to 25°C, and the solid was filtered. The solid was washed with a solution of water (2.0 V) and ethanol (0.5 V) and dried in vacuo at ambient temperature to afford compounds 5a / 5b as solids in 94% yield and respective ratios of 95:5 to 70:30, as determined by the analytical methods reported above.

[0168] Analysis information Compound (5a): 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.27 (s, 3 H) 3.10 (s, 3 H) 3.84 (s, 4 H) 6.88 (d, J=8.76 Hz, 1 H) 7.02 (dd, J=8.69, 2.19 Hz, 1 H) 7.13 (d, J=2.25 Hz, 1 H) 7.59 (d, J=8.75 Hz, 1 H) 7.73 (dd, J=8.69, 2.56 Hz, 1 H) 0.00 (d, J=6.50 Hz, 1 H) 8.21 (s, 1 H) 8.78 (s, 1 H) 9.60 (s, 1 H) 10.46 (s, 1H); LR EI MS m / z: 446.15 Step 3. Preparation of compound (4') from compounds (5a) / (5b) and compound (6b). General Procedure.

[0169] The stoichiometry calculation for compound 6b is based on the calculated content of compound 5a and compound 5b. The calculated content is obtained by subtracting residual solvent, KF, ROI, and total impurities from a theoretical value of 100%, rather than comparing it to a reference standard of known potency. The calculation of the amount of THF is based on the mass input of a mixture of compound 5a and compound 5b. A clean N2-sparged vessel is charged with Compounds 5a / 5b (1.0 equivalent), Compound 6b (1.3 equivalents), and THF (9.0 V) and stirring is initiated. The mixture is heated to 60°C and stirred for 6 hours or more. Upon completion of the reaction, the mixture is cooled to -10°C, stirred for 1 hour, and filtered. The wet cake is recharged to the vessel and triturated with THF (2 V) at 5°C for 1 hour, then filtered and washed with THF (1 V). The product is dried in vacuo at ambient temperature. Yield: 87%.

[0170] Analysis information Compound (4'): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (m, 11 H) 1.86 (br d, J=10.01 Hz, 2 H) 2.26 (s, 3 H) 3.17 (br t, J=11.38 Hz, 2 H)-3.50 - 3.70 (m, 2 H) 3.84 (s, 3 H)-4.69 - 5.06 (br. S., 2 H)-6.86 - 6.95 (m, 2 H) 7.00 (dd, J=8.63, 2.38 Hz, 1 H) 7.10 (d, J=2.25 Hz, 1 H) 7.57 (d, J=8.76 Hz, 1 H) 7.78 (dd, J=8.76, 2.50 Hz, 1 H) 7.84 (d, J=2.25 Hz, 1 H) 8.18 (s, 1 H) 8.38 (s, 1 H) 9.06 (s, 1 H) 9.57 (s, 1 H); LR EI MS m / z: 582.25

[0171] Step 4. Preparation of compound (3') from compound (4'). General Procedure. All calculations are made with respect to compound (4'). To a clean, N2-sparged vessel #1, IPA (6.0 V) is charged and stirring is initiated. Acetyl chloride (7.50 equiv.) is then charged while maintaining the internal vessel temperature below 45° C. The mixture is heated to 65° C. and stirred for approximately 1 hour. Compound 4' (1 equivalent) and DMSO (4.0 V) are charged to a clean, N2-sparged vessel #2, and the mixture is stirred to obtain a homogeneous slurry. The contents of vessel #2 are charged to vessel #1 while the internal vessel temperature is maintained at 65 °C. The reaction is stirred for 5 hours or more, then cooled to ambient temperature and filtered. The solid is washed with IPA (2.0 V) and dried in vacuo at 50 °C to give compound 3' in quantitative yield.

[0172] Analysis information Compound (3'): 1H NMR (400 MHz, DMSO-d6) δ ppm-1.51 - 1.72 (m, 2 H) 2.10 (br d, J=9.76 Hz, 2 H) 2.24 (s, 3 H) 3.17 (m, 2 H)-3.29 - 3.51 (m, 1 H) 4.07 (s, 3 H)-4.82 - 5.32 (wide signal) 7.13 (d, J=8.50 Hz, 1 H) 7.17 (d, J=2.25 Hz, 1 H) 7.39 (dd, J=9.01, 2.25 Hz, 1 H)-7.76 - 7.86 (m, 2 H) 8.01 (d, J=9.01Hz, 1H) 8.41 (br d, J=3.50 Hz, 3 H) 8.62 (s, 1 H) 9.21 (s, 1 H) 9.57 (s, 1 H) 10.53 (br s, 1 H); LR EI MS m / z: 482.29

[0173] Step 5. Preparation of compound (2a') from compound (3'). General Procedure. All calculations are made with respect to compound (3'). A clean, N2-sparged vessel is charged with compound (3') (1.0 equiv.) and THF (8.0 V) and stirring is initiated. The mixture is charged with a solution of K3PO4-5H2O (4.0 equiv.) in water (6.0 V) while maintaining an internal vessel temperature of 22 °C. The mixture is stirred until complete dissolution (e.g., between 15 minutes and 1 hour, depending on scale), then stirring is stopped, the layers are allowed to settle, and the mixture is cooled to 6 °C. A solution of K3PO4-5H2O (1.02 equiv.) in water (1.5 V) is charged, stirring is initiated, and the mixture is cooled to 6 °C. The mixture is charged with a solution of 3-chloropropionyl chloride (1.02 equiv.) in anhydrous THF (0.92 V) while maintaining an internal temperature of 6 °C. The reaction is stirred for 3 hours or more, then the mixture is allowed to reach ambient temperature, stirring is stopped, and the layers are allowed to settle and separate. To the organic layer, DCM (4.0 V) and brine (2.0 V) are added. The layers are separated and the organics are filtered through an activated carbon filter. The resulting solution is subjected to azeotropic distillation at atmospheric pressure to remove water, targeting a final volume of 8 V. The resulting slurry is brought to ambient temperature and filtered. The solid is washed with IPA (2.0 V) and dried in vacuo to give compound (2a') in 69% yield.

[0174] Analysis information Compound (2a'): 1H NMR (400 MHz, DMSO-d6) δ ppm-1.33 - 1.51 (m, 2 H) 1.89 (br dd, J=12.76, 3.00 Hz, 2 H) 2.26 (s, 3 H) 2.58 (t, J=6.38 Hz, 2 H)-3.20 - 3.32 (m, 2 H)-3.76 - 3.87 (m, 5 H)-3.88 - 4.02 (m, 1 H) 4.83 (br signal, 2 H) 6.89 (d, J=8.76 Hz, 1 H) 7.00 (dd, J=8.76, 2.25 Hz, 1 H) 7.10 (d, J=2.25 Hz, 1 H) 7.57 (d, J=8.76 Hz, 1 H) 7.77 (dd, J=8.76, 2.50 Hz, 1 H) 7.84 (d, J=2.50 Hz, 1 H) 8.04 (d, J=7.50 Hz, 1 H) 8.17 (s, 1 H) 8.39 (s, 1 H) 9.07 (s, 1 H) 9.58 (s, 1 H); LR EI MS m / z: 572.17

[0175] Step 6. Preparation of Compound (1) Form I from Compound (2a'). General Procedure. All calculations are made with respect to compound (2a'). A clean, N2-sparged vessel is charged with compound 2a' (1.0 equiv.) and THF (8.0 V) and stirring is initiated. A solution of KOH (2.0 equiv.) in water (3.5 V) is charged to the mixture while maintaining an internal vessel temperature of 23 °C. The reaction is heated to 38 °C and stirred for 18 hours or more. Upon completion of the reaction, the mixture is brought to ambient temperature, stirring is stopped, and the aqueous layer is removed. The organics are concentrated under vacuum to a target volume of 4.0 V and diluted with DCM (6.0 V) and MeOH (3.0 V). The resulting solution is washed with brine (2.0 V) and the organics are separated. The DCM and MeOH are exchanged for THF via atmospheric distillation to a target volume of 8.0 V. The mixture is brought to ambient temperature and the slurry is filtered. The solid is washed with THF (2.0 V) and dried in vacuo to afford crystalline Form I of compound 1 in 91% yield.

[0176] Step 7. Conversion of Compound (1) Form I to Compound (1) Form III. General Procedure. All calculations are made with respect to Form I of Compound (1). A clean, N2-sparged vessel is charged with crude Compound (1) Form I (1.0 equivalent), isopropanol or isopropyl acetate (8.0 V) and stirring is initiated. Seed crystals of Compound (1) Form III can be added, if available. The slurry is stirred at ambient temperature for 2 hours and filtered. The solid is washed with isopropanol or isopropyl acetate (2.0 V) and dried in vacuo to give Compound (1) Form III in 97% yield.

[0177] Example 1.2 Route 2 to obtain crystalline Forms I and IV Scheme 2. Synthesis of Compound (1) from Compound (9), Compound (10), and Compound (7′) Based on a Sulfur-Containing Leaving Group

[0178] [ka] Steps 1 and 2 are carried out as described in Example 1.1.

[0179] Step 3. Preparation of compound (2b') from compound (5a) / (5b) and compound (7'). General Procedure. All calculations are made with respect to compound (5a). A clean, N2-sparged vessel #1 is charged with compound 7' (1.4 equiv.), water (1.0 V), brine (0.75 V), and 2-Me-THF (9.0 V) and stirring is initiated. The mixture is cooled to 10 °C and 50% aqueous NaOH (0.47 V) is added while maintaining the internal vessel temperature below 20 °C. The biphasic mixture is vigorously stirred. After layers form, or after approximately 30-60 minutes, stirring is stopped and the layers are allowed to settle and separate. The aqueous layer is back-extracted with 2-Me-THF (4 V). The organics are then combined, and the 2-Me-THF is exchanged with DMAc to target a volume of approximately 7 V. The resulting solution of the free base of compound 7' in DMAc is stored until used in the next step. A clean, N2-sparged vessel #2 is charged with Compound 5a / Compound 5b (1.0 equiv.), followed by the solution of Compound 7' in DMAc. Stirring is initiated, and the mixture is heated to 68°C and held for approximately 6 hours. The mixture is then brought to ambient temperature and filtered. The solid is washed with MeOH (4V) and dried in vacuo to give Compound 2b' as a solid in 76% yield.

[0180] Analysis information Compound (2b'): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 - 1.49 (m, 1 H) 1.83 - 1.95 (m, 1 H) 2.06 (s, 1 H) 2.26 (s, 1 H) 2.37 (t, J=7.25 Hz, 1 H) 2.67 (t, J=7.25 Hz, 1 H) 3.26 (br t, J=11.51 Hz, 1 H) 3.84 (s, 1 H) 3.88 - 3.98 (m, 1 H) 4.75 - 4.90 (m, 1 H) 6.89 (d, J=8.75 Hz, 1 H) 7.00 (dd, J=8.50, 2.00Hz, 1H) 7.10 (d, J=2.00 Hz, 1 H) 7.57 (d, J=8.76 Hz, 1 H) 7.77 (dd, J=8.76, 2.25 Hz, 1 H) 7.84 (d, J=2.00 Hz, 1 H) 7.91 (br d, J=7.50 Hz, 1 H) 8.17 (s, 1 H) 8.39 (s, 1 H) 9.07 (s, 1 H) 9.57 (s, 1 H); LR EI MS m / z: 292.74.

[0181] Step 4. Preparation of compound (2d') from compound (2b'). General Procedure. All calculations are made with respect to compound (2b'). A clean, N2-sparged vessel #1 is charged with compound (2b') (1.0 equiv.), DMAc (8.0 V), and a solution of Na2WO4 (2 mol%) in water (0.45 V). Stirring is initiated, and the mixture is heated to 70 °C. A 30% aqueous solution of HO2 (2.6 equiv.) is slowly charged while maintaining the internal vessel temperature at 70 °C. Upon completion of the addition, the mixture is stirred at 70 °C for approximately 16 hours, then cooled to 50 °C, and DMSO (0.22 equiv.) is added. The mixture is further cooled to 4 °C, followed by the addition of IPAc (4.0 V). The resulting slurry is stirred for an additional 4 hours at 4 °C and filtered. The solid is washed with a mixture of DMAc (0.76 V) and IPAc (2.25 V) and dried in vacuo. The resulting compound (2d') is recharged to the vessel and triturated in water (16V) for 18 hours at 72° C. The slurry is then cooled and the product is filtered and dried in vacuo.

[0182] If necessary, compound 2c' can be enriched in the reaction mixture using a substoichiometric amount of oxidant and then isolated by standard purification methods. Compound 2c' is characterized by 300 MHz NMR spectroscopy and infusion MS as described below.

[0183] Analysis information Compound (2d'): 1H NMR (400 MHz, DMSO-d6) δ ppm-1.34 - 1.48 (m, 2 H)-1.85 - 1.95 (m, 2 H)-2.54 - 2.62 (m, 2 H) 2.99 (s, 3 H)-3.22 - 3.38 (m, 4 H) 3.84 (s, 3 H)-3.87 - 4.00 (m, 1 H) 4.82 (br d, 2 H) 6.89 (d, J=8.75 Hz, 1 H) 7.00 (dd, J=8.76, 2.25 Hz, 1 H) 7.10 (d, J=2.25 Hz, 1 H) 7.57 (d, J=8.50 Hz, 1 H) 7.77 LR EI MS m / z: 616.22. Compound (2c'): 1 H NMR (300 MHz, DMSO-d6) δ ppm-1.34 - 1.58 (m, 2 H)-1.83 - 2.02 (m, 2 H) 2.27 (s, 3 H)-2.50 - 2.66 (m, 4 H)-2.77 - 3.41 (m, 6 H) 3.84 (s, 3 H)-3.88 - 4.05 (m, 1 H) 4.77 (br d, J=13.33 Hz, 1 H) 6.90 (d, J=8.65 Hz, 1 H) 6.99 (dd, J=8.72, 2.27 Hz, 1 H) 7.13 (d, J=2.20 Hz, 1 H) 7.53 (d, J=8.79 Hz, 1 H)-7.73 - 7.85 (m, 2 H) 7.94 (d, J=7.47 Hz, 1 H) 8.13 (s, 1 H) 8.38 (s, 1 H) 9.02 (s, 1 H) 9.37 (s, 1 H); LR MS: 600.25.

[0184] ステップ5. Compound (2d') and compound (1) are prepared in form I. Generally smooth. All calculations are made with respect to compound (2d'). A clean, N2-sparged vessel #1 is charged with compound (2d') (1.0 equiv.), 45% aqueous KOH (1.5 equiv.), THF (8.9 V), and MeCN (1.6 V) and stirring is initiated. The mixture is heated to 42 °C and stirred for approximately 14 hours, then cooled to 30 °C and stirred for an additional 10 hours. Upon completion of the reaction, the mixture is reheated to 45 °C, stirring is stopped, and the layers are separated. The organic layer is washed successively with 2.5 M phosphate buffer and brine. The organics are subjected to azeotropic distillation using THF to remove water, targeting a final volume of 6 V. Upon completion of the distillation, the slurry is brought to ambient temperature, filtered, and washed with THF. The solid is dried in vacuo at 50 °C to give crystalline Form I of compound (1) in 81% yield. Step 6. Conversion of Compound (1) Form I to Compound (1) Form IV. General Procedure. All calculations are made with respect to compound (1). A clean, N2-sparged vessel is charged with Compound (1) (1.0 equivalent), seed crystals of Compound (1) Form IV (2% by weight), and IPAc (20V) and stirring is initiated. The mixture is heated to 70°C and stirred for approximately 20 hours, then cooled to 20°C. The slurry is filtered, and the solid is washed successively with IPAc and water. The solid is dried in vacuo at 50°C to give Compound (1) Form IV in 95% yield.

[0185] Example 2 Preparation of solid state forms of compound (1) It should be noted that the input form of compound (1) is not strictly necessary for the crystallization procedure, provided that complete dissolution is achieved prior to crystallization. In the case of complete dissolution, the compound (1) starting material can be produced, for example, according to the synthesis described in WO 2021 / 213800 or according to the procedure disclosed under Example 1 herein.

[0186] Example 2.1 Preparation of Form I First Example Procedure for Preparation of Form I (Crystallization) 19 kg of Compound (1) (any solid-state form) is dissolved in a mixture of about 54 kg of THF, about 160 kg of DCM, and about 48 kg of MeOH. Residual inorganic salts are removed by washing with brine (48 kg). Undissolved particulate matter is removed by polish filtration of the organic layer. The organic layer is then distilled to about 160 L, and the mixture is diluted with 78 kg of THF. The distillation, THF dilution, distillation sequence is repeated to levels of water and MeOH, each ≦1.0% w / w. Upon completion of the distillation, the resulting slurry is held at ambient temperature for no more than 12 hours and filtered to obtain Form I. Second Example Procedure for Preparation (Crystallization) of Form I 6 g of Form IV or any other solid form of Compound (1) (e.g., prepared according to one of the Examples described herein) is dissolved in 75 g of 5% w / w HO in IPA solution at 90° C. The solution is slowly cooled to 75° C. and seeded with 60 mg of Form I. The mixture is stirred at 75° C. for 2 hours and then cooled to 20° C. at a rate of 0.3° C. / min. Upon completion of cooling, the solid is filtered and dried to obtain Form I.

[0187] Example 2.2 Preparation of Form III Example Procedure for Preparation of Form III (Slurry) 17 kg of Form I of Compound (1) is mixed with 271 kg of IPAc. The slurry is heated to 70°C. 0.2 kg of seed crystals of Form III of Compound (1) (e.g., prepared according to one of the Examples described herein) are added to the slurry, and the mixture is stirred for about 16 hours. At the end of the holding period, the mixture is gradually cooled to 53°C in about 40 minutes, then to 33°C in about 40 minutes, and then to 25°C. The resulting slurry is stirred for about 1 hour and filtered. The solid is washed with 27 kg of IPAc and dried to obtain Form III. The procedure can be carried out without the addition of seed crystals.

[0188] Example 2.3 Preparation of Form IV First Example of Procedure for Preparation (Crystallization) of Form IV300 mg of Form I of Compound (1) is dispersed in 3 ml of 1-BuOH. The mixture is heated to 90°C with overhead stirring. Dissolution can be observed. The solution is cooled to 75°C at a rate of 0.2°C / min, followed by rapid cooling to 20°C. The resulting slurry is held at 20°C for approximately 12 hours while stirring and filtering to yield Form IV. Second Example Procedure for Preparation (Crystallization) of Form IV Form III of Compound (1) or any other solid form is dissolved in 10 volumes of a 1:1 mixture of 1-BuOH and anisole at 110°C. The solution is distilled under slight vacuum, during which most of the 1-BuOH is removed. The solution is seeded with Form III seed crystals and held at 110°C to obtain a slurry. The mixture is stirred while cooling to ambient temperature and filtered to obtain isolated Compound (1) as Form IV, even though it is not seeded with Form III. Third Example Procedure for Preparation of Form IV (Slurry) Forms I and IV of Compound (1) are slurried in IPAc at a temperature ranging from 25 to 75°C for 72 to 168 hours. The mixture is allowed to reach ambient temperature, if applicable, and filtered to obtain Compound (1) as Form IV. When Compound (1) is obtained as described in Example 1.2 above, this third exemplary procedure for the preparation of Form IV can also be carried out starting from Form I alone, with or without seeding.

[0189] Example 2.4 Preparation of Reference Form II Example Procedure for Preparation of Form II (Slurry) Form I of Compound (1) (30 mg) is slurried in methanol (1.5 mL) at a temperature of 55° C. for 2 hours. The mixture is cooled to room temperature and filtered to obtain Form II of Compound (1). The XRPD diffractogram of Form II, in particular, is shown in FIG.

[0190] Example 2.5 Preparation of Reference Form VI Example Procedure for Preparation of Form VI (Slurry)Compound (1) Form III is slurried in water at 50° C. for 2 hours, cooled to room temperature, and slurried for an additional 168 hours. The mixture is filtered to provide Compound (1) as Form VI. The XRPD diffractogram of Form VI, among others, is shown in FIG.

[0191] Example 2.6 Preparation of Reference Form VII Example Procedure for Preparation (Crystallization) of Form VII A mixture of Compound (1) (30 mg) in methyl ethyl ketone (1.5 mL) is heated to 55° C. for 30-60 minutes. The resulting clear solution is filtered into a clean vial and allowed to stand at room temperature without stirring to afford Form VII. The XRPD diffractogram of Form VII, among others, is shown in FIG. 25.

[0192] Example 3 Characterization of the solid-state form of compound (1) Solid crystalline Forms I, III, and IV of Compound (1) can be characterized by powder X-ray diffraction (XRPD or PXRD), Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), scanning electron microscopy (EMS), and, where applicable, single crystal X-ray diffraction (SXRD), as described, for example, below.

[0193] Example 3.1 Characterization by powder X-ray diffraction (XRPD or PXRD) The solid state forms of compound (1) can be analyzed and identified by XRPD. Generally, XRPD is performed using CuK with a wavelength of 1.54184 Å. α Measurements are made at temperatures in the range of 20°C to 30°C using CuKα radiation (CuKα1,2 radiation). The Kα2 is filtered out by the software, resulting in CuKα radiation (CuKα1 radiation) with a wavelength of 1.54060 Å. For XRPD analysis, the methodology may be as follows.

[0194] Each solid compound (approximately 0.2 g) is typically subsampled onto a stainless steel sample holder fitted with a zero diffraction plate (ZDP). The sample holder is then leveled with a glass slide to create a flat sample surface level with the sample holder. The instrument used for the analysis is a Bruker D2 Phaser (system EQ-SSRD-XRD-01). A corundum reference standard is run each day to evaluate system performance. For the system to be suitable for acceptance, two peaks must be within ±0.02° 2θ. The instrument settings for the measurement of solid compound samples can be seen in Table 1. Processing (removal of Kα2 contribution, peak labeling) is completed using DIFFRAC.EVA software (version 5.0). The experimental parameters for XRPD measurements are shown below:

[0195] [Table 3]

[0196] Processed XRPD diffractograms for each of the polymorphic forms are shown in Figure 1 (Form I), Figure 2 (Form III), and Figure 3 (Form IV). An XRPD overlay of all three forms is presented in Figure 4. It can be seen that each of the three polymorphic forms has its own unique XRPD fingerprint, and each form is identifiable by XRPD. Table 2 lists the peaks (with relative intensity greater than 5%) for each form. Table 3 lists the most characteristic peaks to use when attempting to identify a given polymorphic form where alternative forms are present. Diagnostic peaks indicate peak positions where impurities have relatively high intensity peaks, and the sample dominant form has a flat baseline.

[0197] [Table 4]

[0198] With respect to Table 2, the bold peaks were determined to be characteristic peaks and are marked "* Peaks marked with " " have a relative intensity greater than 10% and are ** Peaks marked with " have a relative intensity greater than 50%. Furthermore, the peaks are listed in order of peak position (°2θ), with similar peak positions in the same row.

[0199] [Table 5]

[0200] Example 3.2 Raman spectroscopic characterization The resulting crystalline Forms I, III, and IV of Compound (1) can be further analyzed and identified by means of Raman spectroscopy. The methodology for this can be as follows: The solid compound is typically subsampled to a thickness of approximately 0.5 mm or greater in a vial cap. The instrument used for the analysis is a BWTek i-Raman Plus probe. The instrument settings for the measurement of the solid compound sample can be found in Table 4. BWSpec 4 software is used to complete processing (dark subtraction, background removal, peak labeling, diffractogram generation). The experimental parameters are further detailed in Table 4 below:

[0201] [Table 6]

[0202] The processed Raman spectra can be seen individually in Figures 5a-5d, where Figure 5a shows the background Raman spectrum; Figure 5b shows the Raman spectrum of crystalline Form I; Figure 5c shows the Raman spectrum of crystalline Form III; and Figure 5d shows the Raman spectrum of crystalline Form IV. A summary of the peaks is listed in Table 5. In Table 5, only peaks not present in the background are listed, bolded peaks were determined to be characteristic peaks, and peaks are listed by Raman shift (cm -1 ) and similar shifts are listed in the same column. Additionally, Table 6 lists the characteristic Raman peaks (cm) for the identification of polymorphic impurities. -1 ) are shown.

[0203] [Table 7]

[0204] [Table 8]

[0205] Example 3.3 Characterization by Differential Scanning Calorimetry (DSC) The resulting crystalline Forms I, III, and IV of Compound (1) can be further analyzed and identified by means of differential scanning calorimetry (DSC). The methodology for this can be as follows: The solid form (approximately 5 mg) is placed in an aluminum pan and sealed. The instrument used for the analysis is a TA Instruments DSC 25. The experimental settings are listed in Table 7. The processing is completed using TRIOS software.

[0206] [Table 9] The DSC plots for each polymorphic form of Compound (1) can be seen in Figure 6 (Form I), Figure 7 (Form III) and Figure 8 (Form IV). A summary of the DSC events is listed in Table 8. From a comparison of the melting points of each form, Form IV is expected to be the most thermodynamically stable, followed very closely by Form III. Form I is expected to be the least thermodynamically stable. An exothermic event around 240°C was observed for all three polymorphic Forms I, III, and IV.

[0207] [Table 10]

[0208] Example 3.4 Characterization by thermogravimetric analysis (TGA) The resulting crystalline Forms I, III, and IV of Compound (1) can be further analyzed and identified by means of thermogravimetric analysis (TGA). The methodology for this can be as follows: The solid compound (approximately 5 mg) is placed in an aluminum pan and sealed. The instrument used for the analysis is a TA Instruments TGA 550. The experimental settings are listed in Table 9. The same sample lot from the DSC test is used for the TGA test. The processing is completed using TRIOS software.

[0209] [Table 11]

[0210] TGA plots for each polymorphic form of Compound (1) can be seen in Figure 9 (Form I), Figure 10 (Form III), and Figure 11 (Form IV). A summary of the TGA events is listed in Table 10. All three forms decomposed around 440°C. A mass loss event of around 1% correlates with the melting temperatures for Form III and Form IV, around 235°C. This small mass loss may be due to solvent released from the crystal lattice of the Form III and Form IV solids upon melting.

[0211] [Table 12]

[0212] Example 3.5 Dynamic Vapor Sorption (DVS) Characterization To study the hygroscopic behavior of crystalline Forms I, III, and IV of Compound (1), sorption isotherms obtained by DVS were recorded on a DVS-1 or DVS intrinsic from Surface Measurement Systems. The methodology for this can be as follows: Monitor the mass of the solid while systematically changing the relative humidity (RH). Repeat the RH from 0% to 90% to 0% in 10% steps twice. Keep the temperature constant at (25.0 ± 1.0) °C during the measurements. Hold each step until mass stability is achieved. A camera inside the instrument captures images at the end of each step, allowing for observation of any visual changes in the solid form during analysis. Figure 12 shows the isotherm plot of Form I. A maximum water uptake (=change in mass, Δm) of 7.3 wt% was observed up to 90% RH, which is fully reversible. The sample absorbs 5.4 wt% water at 80% RH. Therefore, Form I is classified as a hygroscopic material. Despite significant hysteresis observed between the sorption and desorption curves, especially in the RH range above about 40%, no irreversible phase changes occurred during the DVS experiment, as confirmed by PXRD performed on samples before and after DVS was performed (Figure 13).

[0213] Figure 14 shows the isotherm plot for Form III. A maximum water uptake of 1.7 wt% was observed up to 90% RH, which is fully reversible. The sample absorbed 1.2 wt% water at 80% RH. Therefore, Form III is classified as a slightly hygroscopic material. There is no indication of irreversible phase transformation or hydrate formation as a result of water vapor sorption, as indicated by the lack of hysteresis between the sorption and desorption curves. No change in visual appearance was observed for Form III during humidity cycling. Figure 15 shows the isotherm plot for Form IV. A maximum water uptake of 0.5 wt% was observed up to 90% RH, which is fully reversible. The sample absorbed 0.4 wt% water at 80% RH. Therefore, Form IV is classified as a slightly hygroscopic material. There is no indication of irreversible phase transformation or hydrate formation as a result of water vapor sorption, as indicated by the lack of hysteresis between the sorption and desorption curves. No changes in visual appearance were observed for Form IV during humidity cycling. Table 11 summarizes the events observed for different crystalline forms of Compound (1) during DVS experiments.

[0214] [Table 13]

[0215] Example 3.6 Characterization by scanning electron microscopy (SEM) SEM images for each of the polymorphic forms are shown in Figure 16 (Form I), Figure 17 (Form III), and Figure 18 (Form IV). Form I exhibits a needle-like morphology, while Form III and Form IV consist primarily of plate-like crystals.

[0216] Example 3.7 Characterization by single crystal X-ray diffraction (SXRD) Single crystals of crystalline Form IV of compound (1) were grown by slow evaporation at room temperature from a solution in anisole:1-butanol (8:1). A clear, colorless block with approximate dimensions of 0.170 x 0.07 x 0.05 mm was selected and mounted on a MiTeGen MicroMount™ with Paraton-N oil. Three frames separated in reciprocal space were recorded to provide the orientation matrix and initial cell parameters. Final cell parameters were obtained and refined based on the complete data set. A diffraction minimum was observed during typical collection times (≦60 seconds), so a collection time of 360 seconds / degree of data exposure was used for the complete data set. Diffraction data were acquired at room temperature on a Rigaku R-AXIS RAPID diffractometer equipped with a sealed-tube copper source (λ = 1.54184 Å) and a Spider curved image plate detector at 50 kV / 40 mA. Reciprocal space diffraction datasets were acquired to a resolution of 0.81 Å using a 5° oscillation step and 300 seconds of exposure per frame. Diffraction images were processed and scaled using Rigaku Oxford Diffraction software (RapidAuto; Rigaku OD: The Woodlands, TX, 2015). Observation of the crystals after data collection showed no signs of decomposition.

[0217] The structure was solved using Olex216 with an embedded SHELXT17 structure analysis program using direct methods. The structure was refined with the SHELXL18 refinement package using least-squares minimization. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were included in the model at geometrically calculated positions and refined using a riding model. Initial structure analysis provided a calculated powder diffraction pattern consistent with Form IV (see the bottom diffractogram in Figure 19).

[0218] [Table 14]

[0219] Example 4 Polymorphic stability of solid-state forms of compound (1) Example 4.1 Polymorphic stability of Form III and Form IV Form III and Form IV were stored open under stress conditions of 90°C / 3% RH and 90°C / 78% RH for a period of 21 days and analyzed for polymorphic stability by powder X-ray diffraction.

[0220] A Bruker D2 Phaser X-Ray Diffractometer (XRD, EQ-SSRD-XRD-01) can be used to characterize the samples. The settings used during the sample measurements are listed in Table 13. The raw results are evaluated using DIFFRAC.EVA (Bruker, V5.0) software. The Kα2 contribution was removed, and a peak search was performed using peak search parameters (width 0.302 and threshold 1.0).

[0221] [Table 15]

[0222] A test sample (approximately 0.3 g) is typically subsampled into an agate mortar and pestle. The sample is ground for approximately 1 minute to achieve a fine, uniform powder. The sample is then transferred into a stainless-steel sample holder fitted with a zero diffraction plate (ZDP). The sample holder is then flattened with a glass slide to create a flat sample surface level with the sample holder. Overlays of processed powder X-ray diffractograms for Form III and Form IV under different stress conditions are shown in Figures 20 and 21, respectively. Form III control and test samples stored at 90°C / 3% relative humidity (RH) and 90°C / 78% RH for a period of 21 days were stable and matched the Form III reference standard, with no missing or extraneous reflections observed. Similarly, Form IV control and test samples stored at 90°C / 3% RH and 90°C / 78% RH for a period of 21 days were stable and matched the Form IV reference standard.

[0223] Example 4.2 Polymorphic Stability of Form I, Form II and Form VI Crystalline Forms I, II, and VI of Compound (1) were exposed to temperature stress under the conditions outlined in Table 14, and the samples were analyzed for polymorphic stability by powder X-ray diffraction method as described in Example 4.1.

[0224] [Table 16] As can be seen from Table 14, Form I was exposed to the most severe temperature stress, yet it was the only form that remained unchanged (see also Figure 22), while Form II underwent a phase change to Form V (see also Figure 23), and Form VI became amorphous Compound (1) (see also Figure 24). Reference XRPD diffractograms for Forms I and V, among others, are shown in Figure 25.

[0225] Example 5 Chemical stability of the solid-state form of compound (1) To study Form III and Form IV under severe stress conditions, both crystalline forms were exposed to a range of elevated temperatures (between 60°C and 90°C) and humidity (between 3% RH and 79% RH) for durations of up to 21 days. To do so, control samples were stored refrigerated in the presence of desiccant for the duration of the study and measured simultaneously with the stressed samples by HPLC at a wavelength of 252 nm. The related substance results for Form III and Form IV are summarized in Tables 15 and 16, respectively. No color change was observed after stress for either Form III or Form IV.

[0226] [Table 17]

[0227] For Form III, there was no significant increase in any related substances under any of the accelerated stress conditions. The lack of degradant formation under extreme stress (up to 21 days at 90°C / 78% RH) confirms that Form III is chemically very stable in the solid state.

[0228] [Table 18]

[0229] Like Form III, Form IV does not show a significant increase in any related substances under any of the accelerated stress conditions. The lack of degradant formation under extreme stress (up to 21 days at 90°C / 78% RH) confirms that Form IV is also chemically very stable in the solid state.

[0230] Example 6 Preparation of solid dispersions containing compound (1) and different dispersion polymers In this example, solid dispersions were prepared containing 25% by weight or 50% by weight of compound (1) and 75% by weight or 50% by weight of the dispersion carrier HPMCAS-M (Shin-Etsu AQOAT), PVP-VA, Eudragit® L100, or HPMC HME 15LV, respectively.

[0231] The solid dispersion of this example can be prepared according to the following protocol: the solid dispersion is spray dried from a spray solution composition comprising Compound (1) as crystalline Form I, III, IV (as described herein in its broadest form or in any embodiment thereof) or a mixture thereof, a dispersion carrier, and a DCM:MeOH (1:1 (w / w)) solvent system, having a solids content of 8% by weight of total solids, using a two-fluid nozzle type and 1.0 mm / 1.0 mm nozzle cap / tip dimensions, an inlet temperature of 85-90°C, an outlet temperature of 45-50°C, atomization at 3.0 bar, and a pressure of 0.50 m. 3 The solid dispersion is produced using a Procept 4M8TRX spray dryer with a drying gas air flow rate of 1 / min and a solution feed rate of approximately 15 g / min. Secondary drying of the dispersion is carried out in a tray dryer type vacuum dryer in a collection vessel at 40°C for 22.5 hours. The spray drying yield results obtained following the protocol from the previous paragraph are summarized in Table 17, where gA represents grams API (active pharmaceutical ingredient, i.e., Compound (1)).

[0232] [Table 19]

[0233] Example 7 Characterization of solid dispersions by X-ray powder diffraction (XRPD) XRPD can be obtained according to the following protocol: XRPD analysis is performed on a Rigaku Miniflex 600 diffractometer. A sample of approximately 10 mg of a solid dispersion of Compound (1) with a dispersing carrier, for example, HPMCAS-M, PVP-VA, Eudragit® L100, or HPMC HME 15LV as in Example 6, is placed on a zero-background sample disk and placed in the autosampler of the Rigaku Miniflex 600. The sample is analyzed using the instrument parameters listed in Table 18 below.

[0234] [Table 20]

[0235] XRPDs obtained according to the protocol from the previous paragraph using various solid dispersions prepared under Example 6 are presented in Figures 26-29. Their comparison to the XRPDs of crystalline Compound (1) in the same figures demonstrates the absence of crystalline material in the samples. Specifically, the XRPDs of solid dispersions of 25% or 50% by weight of Compound (1) and the dispersing carriers HPMCAS-M, PVP-VA, Eudragit® L100, or HPMC HME 15LV exhibit a lack of sharp peaks and the presence of an amorphous halo. The lack of sharp diffraction peaks indicates that the solid dispersions are consistent with an amorphous form of Compound (1).

Claims

1. (a) CuK with wavelengths of 1.54056 Å or 1.54184 Å α a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (5.9±0.2)°, (11.7±0.2)°, and (16.7±0.2)° when measured using radiation at a temperature in the range of 20°C to 30°C; and / or (b) a Raman spectrum containing a peak at any one of the following wavenumbers, expressed as inverse centimeters: 640±2 and / or 831±2, when measured at a temperature in the range of 20° C. to 30° C. and a wavelength of 785 nm. A crystalline form of compound (1), characterized by having: 【Chemistry 1】

2. CuK with wavelength of 1.54056 Å or 1.54184 Å α 10. The crystalline form of claim 1, characterized by having a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (5.9±0.2)°, (11.7±0.2)°, and (16.7±0.2)°, when measured using radiation at a temperature in the range of 20°C to 30°C.

3. CuK with wavelength of 1.54056 Å or 1.54184 Å α 3. The crystalline form of claim 1 or 2, characterized by having a powder X-ray diffraction pattern comprising peaks at the following 2-theta values: (5.9±0.2)°, (11.7±0.2)°, (14.7±0.2)°, (16.7±0.2)°, (18.8±0.2)°, and (19.2±0.2)°, when measured using radioactive radiation at a temperature in the range of 20°C to 30°C.

4. 4. The crystalline form of any one of claims 1 to 3, characterized by having a Raman spectrum comprising a peak at any one of the following wavenumbers, expressed as inverse centimeters, when measured at a temperature in the range of 20°C to 30°C and at a wavelength of 785 nm: 640±2 and / or 831±2.

5. 5. The crystalline form of any one of claims 1 to 4, characterized by having a Raman spectrum comprising peaks at the following wavenumbers, expressed as inverse centimeters, when measured at a temperature in the range of 20°C to 30°C and at a wavelength of 785 nm: 238±2, 640±2, and 831±2.

6. (a) CuK with wavelengths of 1.54056 Å or 1.54184 Å α an X-ray powder diffraction pattern comprising peaks at the following 2-theta values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, and (16.2±0.2)°, when measured using radiation at a temperature in the range of 20°C to 30°C; or (b) CuK with wavelengths of 1.54056 Å or 1.54184 Å α an X-ray powder diffraction pattern comprising peaks at the following 2-theta values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, and (12.4±0.1)° when measured using radiation at a temperature in the range of 20°C to 30°C; or (c) a Raman spectrum comprising a peak at any one of the following wavenumbers, expressed as inverse centimeters, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm: 1310±2 and / or 1400±2; or (d) CuK with wavelengths of 1.54056 Å or 1.54184 Å α a powder X-ray diffraction pattern comprising peaks at the following 2-theta values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, and (16.2±0.2)°, when measured using radiation at a temperature in the range of 20°C to 30°C, and a Raman spectrum comprising a peak at any one of the following wavenumbers, expressed as inverse centimeters: 1310±2 and / or 1400±2, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm; or (e) CuK with wavelengths of 1.54056 Å or 1.54184 Å α a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, and (12.4±0.1)°, when measured using radiation at a temperature in the range of 20°C to 30°C, and a Raman spectrum comprising a peak at any one of the following wavenumbers, expressed as inverse centimeters: 1310±2 and / or 1400±2, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm. A crystalline form of compound (1), characterized by having: 【Chemistry 2】

7. CuK with wavelength of 1.54056 Å or 1.54184 Å α 7. The crystalline form of claim 6, characterized by having a powder X-ray diffraction pattern comprising peaks at the following 2-theta values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, and (16.2±0.2)°, when measured using radioactive radiation at a temperature in the range of 20°C to 30°C.

8. CuK with wavelength of 1.54056 Å or 1.54184 Å α 8. The crystalline form of claim 6 or 7, characterized by having a powder X-ray diffraction pattern comprising peaks at the following 2-theta values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, (16.2±0.2)°, and (18.3±0.2)°, when measured using radioactive radiation at a temperature in the range of 20°C to 30°C.

9. CuK with wavelength of 1.54056 Å or 1.54184 Å α 9. The crystalline form of any one of claims 6 to 8, characterized by having a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, and (12.4±0.1)°, when measured using radioactive radiation at a temperature in the range of 20°C to 30°C.

10. 10. The crystalline form of any one of claims 6 to 9, characterized by having a Raman spectrum comprising a peak at any one of the following wavenumbers, expressed as inverse centimeters, when measured at a temperature in the range of 20°C to 30°C and at a wavelength of 785 nm: 1310±2 and / or 1400±2.

11. 11. The crystalline form of any one of claims 6 to 10, characterized by having a Raman spectrum comprising peaks at the following wavenumbers, expressed as inverse centimeters, when measured at a temperature in the range of 20°C to 30°C and at a wavelength of 785 nm: 485±2, 610±2, 1029±2, 1310±2, and 1400±2.

12. CuK with wavelength of 1.54056 Å or 1.54184 Å α 12. The crystalline form of any one of claims 6 to 11, characterized by having a powder X-ray diffraction pattern comprising peaks at the following 2-theta values: (6.2±0.2)°, (9.5±0.2)°, (11.4±0.2)°, (12.4±0.2)°, and (16.2±0.2)°, when measured using radiation at a temperature in the range of 20°C to 30°C, and a Raman spectrum comprising a peak at any one of the following wavenumbers, expressed as inverse centimeters: 1310±2 and / or 1400±2, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm.

13. CuK with wavelength of 1.54056 Å or 1.54184 Å α 13. The crystalline form of any one of claims 6 to 12, characterized by having a powder X-ray diffraction pattern comprising peaks at the following 2-theta values: (6.2±0.1)°, (9.5±0.1)°, (11.4±0.1)°, and (12.4±0.1)°, when measured using radiation at a temperature in the range of 20°C to 30°C, and a Raman spectrum comprising a peak at any one of the following wavenumbers, expressed as inverse centimeters: 1310±2 and / or 1400±2, when measured at a temperature in the range of 20°C to 30°C and a wavelength of 785 nm.

14. (a) CuK with wavelengths of 1.54056 Å or 1.54184 Å α a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (7.9±0.2)° and (12.0±0.2)° when measured using radiation at a temperature in the range of 20°C to 30°C; and / or (b) a Raman spectrum that includes a peak at any one of the following wavenumbers, expressed as inverse centimeters: 1411±2 and / or 1602±2, when measured at a temperature in the range of 20° C. to 30° C. and a wavelength of 785 nm. A crystalline form of compound (1), characterized by having: 【Transformation 3】

15. CuK with wavelength of 1.54056 Å or 1.54184 Å α 15. The crystalline form of claim 14, characterized by having a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (7.9±0.2)° and (12.0±0.2)° when measured using radioactive radiation at a temperature in the range of 20°C to 30°C.

16. CuK with wavelength of 1.54056 Å or 1.54184 Å α 16. The crystalline form of claim 14 or 15, characterized by having a powder X-ray diffraction pattern comprising peaks at the following 2-theta values: (6.1±0.2)°, (7.9±0.2)°, (11.1±0.2)°, (12.0±0.2)°, (17.2±0.2)°, and (17.9±0.2)°, when measured using radioactive radiation at a temperature in the range of 20°C to 30°C.

17. 17. The crystalline form of any one of claims 14 to 16, characterized by having a Raman spectrum comprising a peak at any one of the following wavenumbers, expressed as inverse centimeters, when measured at a temperature in the range of 20°C to 30°C and at a wavelength of 785 nm: 1411±2 and / or 1602±2.

18. 18. The crystalline form of any one of claims 14 to 17, characterized by having a Raman spectrum comprising peaks at the following wavenumbers, expressed as inverse centimeters, when measured at a temperature in the range of 20°C to 30°C and at a wavelength of 785 nm: 824±2, 1411±2, and 1602±2.

19. A process for the preparation of a crystalline form of compound (1), comprising: 【Chemistry 4】 Steps below i) dissolving compound (1) in at least one organic solvent by heating; ii) cooling the solution obtained in step (i), whereby a crystalline form of compound (1) is formed; and iii) isolating at least a portion of the crystalline form of compound (1) obtained in step (ii). The process includes:

20. 20. The process of claim 19, wherein a crystalline form of compound (1) as defined in any one of claims 1 to 5 is at least partially formed.

21. 21. A crystalline form obtainable or obtained by the process of claim 19 or 20.

22. 22. The crystalline form of claim 21, characterized by having an X-ray powder diffraction pattern comprising peaks as defined in any one of claims 1 to 5, and / or a Raman spectrum comprising peaks at wavenumbers as defined in any one of claims 1 to 5.

23. A process for the preparation of a crystalline form of compound (1), comprising: 【Transformation 5】 Steps below i) providing a suspension of compound (1) in at least one organic solvent; ii) stirring the suspension obtained in step (i) until a crystalline form of compound (1) is formed; and iii) isolating at least a portion of the crystalline form of compound (1) obtained in step (ii). The process includes:

24. 24. The process of claim 23, wherein a crystalline form of compound (1) as defined in any one of claims 6 to 13 is at least partially formed.

25. 25. A crystalline form obtainable or obtained by the process of claim 23 or 24.

26. 26. The crystalline form of claim 25, characterized by having an X-ray powder diffraction pattern comprising peaks as defined in any one of claims 6 to 13, and / or a Raman spectrum comprising peaks at wavenumbers as defined in any one of claims 6 to 13.

27. A process for the preparation of a crystalline form of compound (1), comprising: 【Transformation 6】 Steps below i) dissolving compound (1) in a mixture of water and a solvent comprising at least one water-miscible organic solvent by heating; ii) cooling the solution obtained in step (i), whereby a crystalline form of compound (1) is formed; and iii) isolating at least a portion of the crystalline form of compound (1) obtained in step (ii). The process includes:

28. 28. The process of claim 27, wherein a crystalline form of compound (1) as defined in any one of claims 14 to 18 is at least partially formed.

29. 29. A crystalline form obtainable or obtained by the process of any one of claims 27 or 28.

30. 30. The crystalline form of claim 29, characterized by having an X-ray powder diffraction pattern comprising peaks as defined in any one of claims 14 to 18, and / or a Raman spectrum comprising peaks at wavenumbers as defined in any one of claims 14 to 18.

31. 31. A crystalline form as defined in any one of claims 1 to 18, 21, 22, 25, 26, 29 or 30 for use as a pharmaceutical.

32. 31. A crystalline form as defined in any one of claims 1 to 18, 21, 22, 25, 26, 29 or 30 for use in the treatment and / or prevention of oncological and / or hyperproliferative diseases, in particular cancer.

33. 33. The crystalline form for use according to claim 32, wherein the oncological and / or hyperproliferative disease is a cancer selected from the group consisting of brain cancer, breast cancer, bile duct cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, gastric cancer, esophageal tumors, head and neck tumors, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumors, kidney cancer, liver cancer, lung cancer and prostate cancer.

34. 34. The crystalline form for use according to claim 32 or 33, wherein the oncological and / or hyperproliferative disease is a HER2-overexpressing, HER2-amplified and / or HER2-mutated cancer.

35. A pharmaceutical composition comprising a crystalline form as defined in any one of claims 1 to 18, 21, 22, 25, 26, 29 or 30, and one or more pharmaceutically acceptable excipients.

36. Use of a crystalline form as defined in any one of claims 1 to 18, 21, 22, 25, 26, 29 or 30, or a mixture thereof, for preparing a solid dispersion comprising compound (1) and a pharmaceutically acceptable dispersion carrier.

37. 37. The use according to claim 36, wherein the solid dispersion comprises compound (1) in amorphous form.

38. 1. A process for preparing a solid dispersion comprising: a) providing a mixture of compound (1) and a pharmaceutically acceptable dispersion carrier, and adding a solvent to obtain a solution or suspension; and b) Removing the solvent from the solution or suspension to form a solid dispersion Including, The process wherein in step a) compound (1) is provided as a crystalline form or a mixture thereof as defined in any one of claims 1 to 18, 21, 22, 25, 26, 29 or 30.

39. 39. The process of claim 38, wherein in step b), the solid dispersion comprises compound (1) in amorphous form.

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