Solid state forms of zipalertinib hydrochloride and process for preparation thereof

Abstract

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

Description

SOLID STATE FORMS OF ZIPALERTINIB HYDROCHLORIDE AND PROCESS FOR PREPARATION THEREOFFIELD OF THE DISCLOSURE

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

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

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

[0004] The compound is described in International Publication No. WO 2015025936. International Publication Nos. WO 2024121805 and WO 2024248083 disclose solid state forms of Zipalertinib.

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

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

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

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

[0009] The present disclosure also provides uses of the said solid state forms of Zipalertinib hydrochloride in the preparation of other solid state forms of Zipalertinib, Zipalertinib hydrochloride or other salts or co-crystals and their solid state forms thereof.

[0010] The present disclosure provides crystalline polymorphs of Zipalertinib hydrochloride for use in medicine, including for the treatment of cancer, particularly Non-Small Cell Lung Cancer (“NSCLC”).

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

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

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

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

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

[0016] The present disclosure also provides uses of crystalline polymorphs of Zipalertinib hydrochloride of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g., cancer, particularly NSCLC. The medicament may be administered as an intranasal dosage form, or may be administered as an oral dosage form.

[0017] According to any aspect or embodiment of the present disclosure, pharmaceutical compositions or formulations for the treatment of cancer, particularly NSCLC, are preferably in the form of oral dosage form.BRIEF DESCRIPTION OF THE DRAWINGS

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

[0019] Figure 2 shows a characteristic XRPD of crystalline Zipalertinib hydrochloride Form A.DETAILED DESCRIPTION OF THE DISCLOSURE

[0020] The present disclosure encompasses solid state forms of Zipalertinib salts, particularly of Zipalertinib hydrochloride, including crystalline polymorphs of Zipalertinib hydrochloride, processes for preparation thereof, and pharmaceutical compositions thereof.

[0021] Solid state properties of Zipalertinib and of Zipalertinib salts, such as Zipalertinib hydrochloride, and crystalline polymorphs thereof can be influenced by controlling the conditions under which Zipalertinib and crystalline polymorphs thereof are obtained in solid form.

[0022] The solid-state form may be referred to herein as “Zipalertinib hydrochloride Form Name” or “Crystalline Form Name of Zipalertinib hydrochloride” or “Crystalline Zipalertinib hydrochloride Form Name” or “Crystalline polymorph Name of Zipalertinib hydrochloride” or “Crystalline Zipalertinib hydrochloride polymorph Name” or “ Zipalertinib hydrochloride polymorph Name”. For example, crystalline Form A of Zipalertinib hydrochloride may be interchangeably referred to herein as Zipalertinib hydrochloride Form A or as Crystalline Zipalertinib hydrochloride Form A or as Crystalline polymorph A of Zipalertinib hydrochloride or as Crystalline Zipalertinib hydrochloride polymorph A or Zipalertinib hydrochloride polymorph A.

[0023] A solid-state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression “substantially free of any other forms” will be understood to mean that the solid state form contains about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of thesubject compound as measured, for example, by XRPD. Thus, a crystalline polymorph of Zipalertinib, Zipalertinib salt (preferably Zipalertinib hydrochloride) or of Zipalertinib complexes described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the subject crystalline polymorph of Zipalertinib or of Zipalertinib complexes. In some embodiments of the disclosure, the described crystalline polymorph of Zipalertinib or of Zipalertinib complexes may contain from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), or from about 5% to about 10% (w / w) of one or more other crystalline polymorph of the same Zipalertinib, Zipalertinib salt (preferably Zipalertinib hydrochloride) or of Zipalertinib complexes. Particularly, according to any aspect or embodiment, a crystalline polymorph of Zipalertinib, Zipalertinib salt (preferably Zipalertinib hydrochloride) or Zipalertinib complexes, which is substantially free of any other solid state forms, may contain no more than about 5%, no more than about 3%, no more than about 2%, or no more than about 1% of any other crystalline polymorph of the same Zipalertinib, Zipalertinib salt (preferably Zipalertinib hydrochloride) or Zipalertinib complex. For example, a crystalline form of Zipalertinib hydrochloride which is described as polymorphically pure (or substantially free of any other forms) preferably means that the crystalline form contains: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Zipalertinib hydrochloride, as measured, for example, by XRPD.

[0024] A compound may be referred to herein as chemically pure or purified compound or as substantially free of any other compounds. As used herein in this context, the expression “substantially free of any other compounds” will be understood to mean that the pure compound contains about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other compound as measured, for example, by HPLC. Thus, pure or purified Zipalertinib or of Zipalertinib salt, such as Zipalertinib hydrochloride described herein as substantially free of any compounds would be understood to contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the subject Zipalertinib or of Zipalertinib salt, such as Zipalertinib hydrochloride. In some embodiments of the disclosure, the described pure or purified Zipalertinib or of Zipalertinib salt,such as Zipalertinib hydrochloride may contain from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), or from about 5% to about 10% (w / w) of one or more other compounds. Particularly, according to any aspect or embodiment, Zipalertinib or Zipalertinib salt (particularly Zipalertinib hydrochloride), which is substantially free of any other compounds, may contain no more than about 5%, no more than about 3%, no more than about 2%, no more than about 1%, no more than about 0.5%, no more than about 0.2%, no more than about 0.1% or no more than about 0.05%, of any other compounds.

[0025] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of Zipalertinib or of Zipalertinib salt, such as Zipalertinib hydrochloride of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and / or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.

[0026] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data includes, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Zipalertinib referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Zipalertinib or of Zipalertinib salt, such as Zipalertinib hydrochloride, characterized with thegraphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0027] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline forms of Zipalertinib or of Zipalertinib salt, such as Zipalertinib hydrochloride, relates to a crystalline form of Zipalertinib or Zipalertinib hydrochloride, which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, unless otherwise indicated, an “anhydrous” form would generally not contain more than 1% (w / w), of either water or organic solvents as measured for example by TGA.

[0028] The term “solvate,” as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a “hydrate.” The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0029] Co-Crystal” or “Co-crystal” as used herein is defined as a crystalline material including two or more molecules in the same crystalline lattice and associated by non-ionic and non-covalent bonds. In some embodiments, the co-crystal includes two molecules which are in natural state.

[0030] As used herein, the term “isolated” in reference to crystalline polymorph of Zipalertinib of the present disclosure corresponds to a crystalline polymorph of Zipalertinib or of Zipalertinib complex that is physically separated from the reaction mixture in which it is formed.

[0031] As used herein, unless stated otherwise, the XRPD measurements are taken using copper Ka radiation wavelength 1.54187 A. XRPD peaks reported herein are measured using CuK a radiation, X = 1.54187 A, typically at a temperature of 25 ± 3 °C.

[0032] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” or “ambient temperature,” often abbreviated as “RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20 °C to about 30 °C, or about 22 °C to about 27 °C, or about 25 °C.

[0033] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solventper gram of the material being suspended, such that suspending 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term “v / v” may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v / v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added.

[0034] A process or step may be referred to herein as being carried out “overnight.” This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.

[0035] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.

[0036] As used herein and unless indicated otherwise, the term “ambient conditions” refer to atmospheric pressure and a temperature of 22-24 °C.

[0037] The present disclosure describes amorphous Zipalertinib hydrochloride. A characteristic XRPD pattern of amorphous Zipalertinib hydrochloride is shown in Figure 1.

[0038] In some embodiments, the present disclosure includes a process for preparation of amorphous Zipalertinib hydrochloride. The process comprises precipitating amorphous Zipalertinib hydrochloride from a mixture comprising ethanol and heptane, preferably a mixture of ethanol, water and heptane. The process may comprise adding heptane to a solution of Zipalertinib hydrochloride in a mixture of ethanol and water. Preferably the solution of Zipalertinib hydrochloride in ethanol and water is cooled prior to the addition of heptane. The heptane may also be cooled prior to the addition. Typically, the process may comprise dissolving Zipalertinib in a mixture of ethanol and aqueous solution of hydrochloride (preferably concentrated hydrochloric acid) to form a solution and adding n-heptane to form a suspension. The dissolution is aided by heating, for example to a temperature of about 40 °C to about 60 °C, preferably about 50 °C. Particularly, the heating may be to a temperature of: about 40 °C to about 80 °C, about 40 °C to about 75 °C, about 45 °C to about 60 °C, about 45 °C to about 55 °C, or about 50 °C. After a clear solution is formed, it may be cooled down, for example to a temperature of about 0 °C. Particularly, the cooling may be to a temperature of: about -5 °C to about 15 °C, about -2 °C to about 10 °C, about -2 °C to about 5 °C, about -2 °C to about 2 °C, orabout 0 °C. The heptane is typically added to the cooled solution, thus forming a suspension, from which the amorphous form can be isolated. This suspension may be maintained, preferably at the cooled temperature, and may be maintained while stirring. To aid precipitation, additional portions of heptane may be added. The amorphous form can be isolated, for example by filtration, and can be dried, for example by vacuum drying, possibly with nitrogen flow, preferably at room temperature. The amorphous form can be used to prepare crystalline forms of Zipalertinib hydrochloride, for example crystalline Zipalertinib form A, which is described herein below.

[0039] The present disclosure includes a crystalline polymorph of Zipalertinib hydrochloride, designated Form A. Crystalline Form A may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 9.9, 12.0, 15.6, 21.7, and 26.3 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 2; or by combinations thereof. Crystalline Form A may be further characterized by an XRPD pattern having characteristic peaks at 9.9, 12.0, 15.6, 21.7, and 26.3 degrees 2-theta ± 0.2 degrees 2- theta, and also having any one, two or three additional peaks at 13.2, 23.3 and 27.8 degrees 2- theta ± 0.2 degrees 2-theta.

[0040] According to any aspect or embodiment of the disclosure, crystalline Form A of Zipalertinib hydrochloride may be characterized by an XRPD pattern having characteristic peaks at 9.9, 12.0, 15.6, 21.7, and 26.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having one peak selected from: 13.2, 23.3, or 27.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0041] Crystalline Form A may be described by an XRPD pattern having characteristic peaks at 9.9, 12.0, 13.2, 15.6, 21.7, 23.3, 26.3, and 27.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0042] Alternatively, Crystalline Form A may be described by an XRPD pattern having characteristic peaks at 9.9, 12.0, 13.2, 15.6, 17.3, 18.2, 19.2, 20.0, 21.7, 22.7, 23.3, 24.6, 25.1, 26.3, 27.8, 28.9, 31.3, 31.8, 32.5, 33.5, 34.6, and 35.1 degrees 2-theta ± 0.2 degrees 2-theta

[0043] According to any aspect or embodiment, crystalline Form A of Zipalertinib hydrochloride may be further characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at the area from 3.0 to 9.0 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively, or additionally, crystalline Form A of Zipalertinib hydrochloride according to any aspect or embodiment may be further characterized by an XRPD pattern having an absence of peaks at 10.5 to 11.5 degrees 2-theta ±0.2 degrees 2-theta. Alternatively or additionally, crystalline Form A of Zipalertinib hydrochloride according to any aspect or embodiment may be further characterized by an XRPD pattern having an absence of peaks at 13.7 to 15.0 degrees 2-theta ± 0.2 degrees 2-theta.Optionally, Form A of Zipalertinib hydrochloride according to any aspect or embodiment may be further characterized by an XRPD pattern having an absence of peaks: at 3.0 to 9.0 degrees 2- theta ± 0.2 degrees 2-theta, at 10.5 to 11.5 degrees 2-theta ± 0.2 degrees 2-theta, and at 13.7 to 15.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0044] According to any aspect or embodiment of the present disclosure, crystalline Form A of Zipalertinib hydrochloride is preferably isolated.

[0045] According to any aspect or embodiment of the disclosure, crystalline Form A of Zipalertinib hydrochloride may be a dihydrochloride salt. According to any aspect or embodiment, Form A of Zipalertinib hydrochloride, and it can be a hydrate form. According to any aspect or embodiment, Typically, the amount of water present in crystalline form A are may be: from about 13.5%(v / v) to about 16.0% (w / w), from about 13.5% (w / w) to about 15.5% v / v, from about 13.8% (v / v) to about 15.0% (w / w), from about 14.1% (w / w) to about 15.0%, or about 14.85% as determined by KF; and / or of about 14.1 to about 15.0%, or about 14.4% (w / w) as determined by TGA.

[0046] Crystalline Form A of Zipalertinib hydrochloride may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 9.9, 12.0, 15.6, 21.7 and 26.3 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2, and combinations thereof.

[0047] According to any aspect or embodiment of the disclosure, crystalline Form A of Zipalertinib hydrochloride may be polymorphically pure or may be substantially free of any other solid-state forms of Zipalertinib hydrochloride.

[0048] Crystalline Form A of Zipalertinib hydrochloride of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and / or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.

[0049] According to any aspect or embodiment, crystalline Form A of Zipalertinib hydrochloride of the present disclosure may be polymorphically stable at a relative humidity (RH) of 0%-100% for at least 7 days. In addition, crystalline Form A of Zipalertinib hydrochloride is freely soluble in water.

[0050] The present disclosure includes a process for preparation of Crystalline Form A of Zipalertinib. Crystalline Form A of Zipalertinib according to any aspect or embodiment of the disclosure may be prepared by a process comprising crystallizing Zipalertinib hydrochloride from water or from a mixture of ethanol and water.

[0051] In a first embodiment, the process comprises crystallizing Zipalertinib hydrochloride from water. The process may be carried out by cooling a solution of Zipalertinib hydrochloride in water. The solution of Zipalertinib hydrochloride in water may be obtained by dissolving Zipalertinib hydrochloride in water, optionally by heating. Particularly, the solution of Zipalertinib hydrochloride in water may be prepared by a process comprising combining Zipalertinib hydrochloride with water to form a suspension, heating the suspension to form a solution, and cooling to precipitate crystalline Zipalertinib hydrochloride. The water may be used in an amount of: about 0.8 ml to about 5 ml, about 1 ml to about 4 ml, about 1 ml to about 3 ml, about 1 ml to about 2 ml, about 1 ml to about 1.5 ml, about 1.1 ml to about 1.4 ml, or about 1.3 ml, per gram of Zipalertinib hydrochloride. The heating may be carried out to a temperature of: about 40 °C to about 80 °C, about 45 °C to about 75 °C, about 50 °C to about 70 °C, about 55 °C to about 65 °C, or about 60 °C. The heating may be carried out for a sufficient time to dissolve the Zipalertinib hydrochloride. Optionally, the heating may be carried out for a period of: about 2 minutes to about 1 hour, 10 minutes to about 1 hour, or about 20 minutes to about 45 minutes, or about 25 minutes to about 40 minutes, or about 30 to 35 minutes. The solution may then be cooled, optionally to a temperature of: about 2 °C to about 10 °C, about 3 °C to about 8 °C, about 4 °C to about 6 °C, or about 5 °C. The cooling is preferably carried out gradually, typically over a period of: about 15 minutes to about 4 hours, about 30 minutes to about 3 hours, about 45 minutes to about 2 hours, about 45 minutes to about 1.5 hours, or about 1 hour. Crystalline Form A of Zipalertinib hydrochloride may then be isolated from the suspension by any suitable method, such as decantation, filtration or centrifugation, preferably by filtration. The isolated product can optionally be dried, for example under vacuum. Drying can be done under inert atmosphere, for example, under nitrogen stream. The drying may be carried out over a period ofabout 0.5 hours to about 6 hours, about 0.5 hours to about 4 hours, about 0.5 hours to about 3 hours, about 1 hour to about 2 hours, or about 1.5 hours. The drying may preferably be carried out at room temperature.

[0052] In a second embodiment, Zipalertinib hydrochloride Form A may be prepared by a process comprising crystallizing Zipalertinib hydrochloride from a mixture of ethanol and water. The process may be carried out by cooling a solution of Zipalertinib hydrochloride in a mixture of ethanol and water. The solution of Zipalertinib hydrochloride in a mixture of ethanol and water may be obtained by dissolving Zipalertinib hydrochloride in a mixture of ethanol and water, optionally by heating. Particularly, the solution of Zipalertinib hydrochloride in a mixture of ethanol and water may be prepared by a process comprising combining Zipalertinib hydrochloride in a mixture of ethanol and water, and heating to form a solution. . Preferably, the solution of Zipalertinib hydrochloride in ethanol and water may be prepared by a process comprising combining Zipalertinib in a mixture of ethanol and water to obtain a first suspension, adding concentrated aqueous solution of HC1 to form a second suspension, and heating the second suspension to form the solution. The mixture of ethanol and water used to form the first suspension may comprise ethanol and water in a ratio (v / v) of about 95:5. The hydrochloric acid is preferably used in an amount of about 2.0 to about 2.3 mole equivalents or about 2.0 to 2.2 mole equivalents, or about 2.1 mole equivalents relative to Zipalertinib. The solution may be cooled to precipitate Zipalertinib hydrochloride Form A. Typically, the first suspension is formed at about room temperature and then the concentrated hydrochloric acid is added. The obtained second suspension is typically heated, until a solution is formed. Preferably, the heating is to a temperature above 40 °C, Particularly, the heating may be carried out to a temperature of: about 40 °C to about 80 °C, about 40 °C to about 75 °C, about 45 °C to about 60 °C, about 45 °C to about 55 °C, or about 50 °C. The heating may be carried out for a sufficient time to dissolve the Zipalertinib hydrochloride. For example, the heating may be carried out for a period of: about 2 minutes to about 1 hour, 10 minutes to about 1 hour, or about 20 minutes to about 45 minutes, or about 25 minutes to about 40 minutes, or about 30 to 35 minutes. The solution may then be cooled, optionally to a temperature of: about -5 °C to about 15 °C, about -2 °C to about 10 °C, about -2 °C to about 5 °C, about -2 °C to about 2 °C, or about 0 °C to precipitate Zipalertinib hydrochloride Form A. The cooling may be carried over a period of about 0.5 hours to about 5 hours, about 0.5 hours to about 4 hours, about 1 hour to about 3 hours, or about 2 hours. Aftercooling the mixture may be further maintained at the cooling temperature for a period of about 5 minutes to about 120 minutes, about 20 minutes to about 80 minutes, about 30 minutes to about 60 minutes, or about 45 minutes.

[0053] Crystalline Form A of Zipalertinib hydrochloride may be then isolated from the suspension by any suitable method, such as decantation, filtration or centrifugation, preferably by filtration. The product can be optionally dried. The isolated product can optionally be dried, for example under vacuum. The drying may preferably be carried out at room temperature. Preferably, the product may be further dried under a nitrogen stream, more preferably a stream of wet nitrogen, optionally at room temperature. The further drying may be carried out over a period of about 5 minutes to about 60 minutes, about 5 minutes to about 45 minutes, about 10 minutes to about 30 minutes, or about 15 minutes.

[0054] In any aspect or embodiment of the disclosed processes for preparing Form A of Zipalertinib hydrochloride, the process may further comprise combining the Form A of Zipalertinib hydrochloride with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition or formulation.

[0055] The above crystalline polymorphs can be used to prepare other crystalline polymorphs of Zipalertinib, other Zipalertinib salts or co-crystals and their solid-state forms. Solid state forms may be crystalline polymorphs, co-crystals and complexes of Zipalertinib or of Zipalertinib salt.

[0056] The present disclosure encompasses a process for preparing other solid-state forms of Zipalertinib or of Zipalertinib salts, such as Zipalertinib hydrochloride. The process includes preparing any one of the crystalline polymorphs of Zipalertinib hydrochloride by the processes of the present disclosure. The process may further comprise converting said crystalline polymorph of Zipalertinib hydrochloride to other crystalline polymorph of Zipalertinib hydrochloride or to other Zipalertinib salt or co-crystal.

[0057] The present disclosure provides the above-described crystalline polymorphs of Zipalertinib salts, particularly of Zipalertinib hydrochloride for use in the preparation of pharmaceutical compositions comprising Zipalertinib or Zipalertinib complexes and / or crystalline polymorphs thereof.

[0058] The present disclosure also encompasses the use of crystalline polymorphs of Zipalertinib or of Zipalertinib salts, such as Zipalertinib hydrochloride of the present disclosurefor the preparation of pharmaceutical compositions of crystalline polymorph Zipalertinib and of Zipalertinib salts, such as Zipalertinib hydrochloride and / or crystalline polymorphs thereof. Particularly, the pharmaceutical compositions may be used for oral administration.

[0059] The present disclosure includes processes for preparing the above-mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorphs of Zipalertinib or of Zipalertinib salts, such as Zipalertinib hydrochloride, of the present disclosure with at least one pharmaceutically acceptable excipient. Particularly, the pharmaceutical compositions may comprise pharmaceutically acceptable excipient suitable for making formulations for oral administration. Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the solid-state forms of Zipalertinib or Zipalertinib hydrochloride of the present disclosure. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes. For example, excipients may be added to assist in formation of formulation suitable for oral administration.

[0060] Diluents increase the bulk of a solid pharmaceutical composition and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0061] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxy ethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0062] The dissolution rate of a compacted solid pharmaceutical composition in the patient’s stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac- Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[0063] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0064] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[0065] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0066] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and / or facilitate patient identification of the product and unit dosage level.

[0067] In liquid pharmaceutical compositions of the present invention, Zipalertinib and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0068] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not solublein the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0069] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouthfeel of the product and / or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.

[0070] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[0071] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

[0072] According to the present disclosure, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[0073] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, intranasal and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

[0074] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0075] The dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the disclosure, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and / or sorbitol, an opacifying agent and / or colorant.

[0076] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0077] A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and / or milled, dried, and then screened and / or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and / or a lubricant.

[0078] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.

[0079] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

[0080] A capsule filling of the present disclosure can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.

[0081] A pharmaceutical formulation of Zipalertinib can be administered. For example, it can be administrated orally. Zipalertinib may be formulated for administration to a mammal, in embodiments to a human. Zipalertinib can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection. The formulation can contain one or more solvents. A suitable solvent can be selected by considering the solvent’s physical andchemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7thed.

[0082] The crystalline polymorphs of Zipalertinib and of Zipalertinib salts, such as Zipalertinib hydrochloride, and the pharmaceutical compositions and / or formulations of Zipalertinib of the present disclosure can be used as medicaments, in embodiments in the treatment of cancer, particularly NSCLC. The medicament may preferably be administrated in oral form.

[0083] The present disclosure also provides methods of treating cancer, particularly NSCLC by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Zipalertinib or Zipalertinib salts, such as Zipalertinib hydrochloride, of the present disclosure, or at least one of the above pharmaceutical compositions and / or formulations, to a subject in need of the treatment.

[0084] Having thus described the disclosure with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure as disclosed in the specification. The Examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way.Powder X-ray Diffraction (“XRPD”) method

[0085] Powder X-ray Diffraction was performed on an X-Ray powder diffractometer PanAlytical EMPYREAN; CuKa radiation (A. = 1.54187 A); pixCel detector with active length 2.140 degrees 2-theta; laboratory temperature 25 ± 3 °C; zero background sample holders. Prior to analysis, the samples were gently ground using a mortar and pestle to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed using a cover glass.Measurement parameters:Scan range: 3 - 40 degrees 2-thetaScan mode: continuousStep size: 0.0131 degreesStep size: 41.4 sSample spin: 60 rpmSample holder: zero background silicon plateEXAMPLESPreparation of starting materials

[0086] Zipalertinib can be prepared according to methods known from the literature, for example International Publication No. WO 2015025936 (and the corresponding U.S. counterpart, U.S. Patent No. 9,650,386).Example 1: Preparation of amorphous Zipalertinib hydrochloride

[0087] Zipalertinib (5 grams) was suspended in ethanol (85 ml) and 35% HC1 (aqueous solution, 2.34 ml, 2.1 mol. eq) at room temperature. The suspension was heated to a temperature of about 50 °C over a period of 30 minutes to obtain clear solution. The solution was filtered to remove foreign particles. The solution was cooled down to a temperature of about 0 °C over a period of 2 hours. Heptane (20 ml) was added gradually at a temperature of about 0 °C. The solution was stirred for 17.5 hours at a temperature of about 0 °C. The sample slightly precipitated. Then, additional portion of heptane (60 ml) was added and a suspension formed. The suspension was stirred for 6 hours and then filtered and dried under the vacuum with nitrogen flow for about 6 hours. The sample was analyzed by XRPD: amorphous form of Zipalertinib Hydrochloride was obtained. A characteristic XRPD pattern is shown in Figure 1.Example 2: Preparation of Zipalertinib hydrochloride Form A

[0088] Zipalertinib Hydrochloride (1.18 grams) was suspended in water (1.5 ml) at room temperature and the suspension was heated to at a temperature of about 60 °C over a period of about 30 minutes to obtain a clear solution, which was further stirred at a temperature of about 60 °C for about 4 minutes. The clear solution was cooled down to at a temperature of about 5 °C during a period of about 1 hour. The sample crystallized during cooling. The obtained suspension was stirred at 5 °C for about 2 hours. The suspension was filtered and the sample was dried by vacuum under the nitrogen flow for 1.5 hours. The sample was analyzed by XRPD, Form A was obtained. A characteristic XRPD pattern is shown in Figure 2.Example 3: Preparation of Zipalertinib hydrochloride Form A

[0089] Zipalertinib (150 mg) was suspended in a mixture of ethanol water (95% ethanol, v / v) and then a concentrated aqueous solution of HC1 (70 pl; 2.1 moleq.) was added to the suspension. The suspension was heated to a temperature of about 50 °C and dissolution occurred. The obtained clear solution was cooled down using a cooling ramp over a period of about 120 minutes to about 0 °C and was stirred for about 45 minutes at about 0 °C. The obtained suspension was filtered and the solid was dried under vacuum at room temperature for about 15 minutes. The material was further dried under stream of wet nitrogen for about 30 min. The sample was analyzed by XRPD, Form A was obtained.Example 4: Polymorphic stability in different humidities

[0090] Zipalertinib Hydrochloride Form A was exposed to different relative humidity (“RH”) at room temperature, for a period of 7 days. The results are summarized in the table below.Table 1:

[0091] As seen in the results shown in Table 1, Zipalertinib Hydrochloride Form A is polymorphically stable when exposure to different humidity for 7 days. Accordingly, Zipalertinib Hydrochloride Form A is stable to storage under high and low relative humidities.Example 5: Solubility in water

[0092] Solubility of Zipalertinib Hydrochloride Form A was determined using the method described in the European Pharmacopoeia, 6.0. section EP 5.11. The results are summarized in the table below.Table 2:

[0093] Based on the data shown in Table 2, Zipalertinib hydrochloride Form A was classified as freely soluble in water.

Claims

CLAIMS1. Crystalline Zipalertinib hydrochloride Form A, which is characterized by data selected from one or more of the following:(a) an XRPD pattern having characteristic peaks at 9.9, 12.0, 15.6, 21.7 and 26.3 degrees 2-theta ± 0.2 degrees 2-theta;(b) an XRPD pattern as depicted in Figure 2; or(c) any combinations thereof.

2. The crystalline Zipalertinib hydrochloride Form A according to Claim 1, which is characterised by an X-ray powder diffraction pattern having peaks at 9.9, 12.0, 15.6, 21.7, and 26.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks at 13.2, 23.3, and 27.8 degrees 2-theta ± 0.2 degrees 2-theta.

3. The crystalline Zipalertinib hydrochloride Form A according to Claim 1 or Claim 2, which is characterized by an XRPD pattern having characteristic peaks at 9.9, 12.0, 13.2, 15.6, 21.7, 23.3, 26.3, and 27.8 degrees 2-theta ± 0.2 degrees 2-theta.

4. The crystalline Zipalertinib hydrochloride Form A according to any of Claim 1, Claim 2, or Claim 3, which is characterized by an XRPD pattern having characteristic peaks at 9.9, 12.0, 13.2, 15.6, 17.3, 18.2, 19.2, 20.0, 21.7, 22.7, 23.3, 24.6, 25.1, 26.3, 27.8, 28.9, 31.3, 31.8, 32.5, 33.5, 34.6, and 35.1 degrees 2-theta ± 0.2 degrees 2-theta.

5. The crystalline Zipalertinib hydrochloride Form A according to any of Claims 1, 2, 3, or 4, which is further characterized by an XRPD pattern having an absence of peaks at: 3.0 to 9.0 ± 0.2 degrees 2-theta.

6. The crystalline Zipalertinib hydrochloride Form A according to any preceding claim, which is Zipalertinib dihydrochloride.

7. The crystalline Zipalertinib hydrochloride Form A according to any preceding claim, which is isolated.

8. The crystalline Zipalertinib hydrochloride Form A according to any preceding claim, which is a hydrate form.

9. The crystalline Zipalertinib hydrochloride Form A according to any preceding claim, which contains: no more than about 20%, no more than about 10%, no more than about 5%, nomore than about 2%, no more than about 1%, or about 0% of any other crystalline forms of Zipalertinib hydrochloride.

10. The crystalline Zipalertinib hydrochloride Form A according to any preceding claim, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Zipalertinib hydrochloride11. Use of the crystalline Zipalertinib hydrochloride Form A according to any of Claims 1-10 for the preparation of a pharmaceutical composition and / or formulation, preferably wherein the pharmaceutical formulation is a tablet or a capsule.

12. A pharmaceutical composition comprising the crystalline Zipalertinib hydrochloride Form A according to any of Claims 1-10.

13. A process for preparing the pharmaceutical composition according to Claim 12, comprising combining the crystalline Zipalertinib hydrochloride Form A according to any of Claims 1-10 with at least one pharmaceutically acceptable excipient.

14. The crystalline Zipalertinib hydrochloride Form A according to any of Claims 1-10, or a pharmaceutical composition according to Claim 12, for use as a medicament.

15. The crystalline Zipalertinib hydrochloride Form A according to any of Claims 1-10, or a pharmaceutical composition according to Claim 12, for use in the treatment of cancer, particularly Non-Small Cell Lung Cancer.

16. A method of treating cancer, particularly Non-Small Cell Lung Cancer, comprising administering a therapeutically effective amount of the crystalline Zipalertinib hydrochloride Form A according to any of Claims 1-10, or a pharmaceutical composition according to Claim 12, to a subject in need of the treatment.

17. Use of the crystalline Zipalertinib hydrochloride Form A according to any of Claims 1-10 in the preparation of another solid state form of Zipalertinib, Zipalertinib hydrochloride, Zipalertinib succinic acid or Zipalertinib succinate, Zipalertinib adipic acid or Zipalertinib adipate, Zipalertinib fumaric acid, or Zipalertinib fumarate.

18. A process for preparing a solid state form of Zipalertinib or Zipalertinib salt or Zipalertinib co-crystal comprising preparing the crystalline Zipalertinib hydrochloride Form A according to any one of Claims 1-10, and converting it to another a solid state form thereof.

19. A process for preparing a crystalline Zipalertinib hydrochloride Form A comprising crystallizing Zipalertinib hydrochloride from a solution in a solvent, wherein the solvent is selected from water or a mixture of ethanol and water.

20. A process according to Claim 19 wherein the solvent is water.

21. The process according to Claim 19 or Claim 20, comprising cooling a solution of Zipalertinib hydrochloride in water.

22. The process according to any of Claims 19, 20, or 21, comprising combining Zipalertinib hydrochloride in water and heating to obtain a solution; and cooling the solution to precipitate the crystalline Zipalertinib hydrochloride Form A.

23. The process according to any of Claims 19, 20, 21, or 22, wherein the water is used in an amount of: about 0.8 ml to about 5 ml, about 1 ml to about 4 ml, about 1 ml to about 3 ml, about 1 ml to about 2 ml, about 1 ml to about 1.5 ml, about 1.1 ml to about 1.4 ml, or about 1.3 ml, per gram of Zipalertinib hydrochloride.

24. The process according to Claim 22 or Claim 23, wherein the heating is to a temperature of: about 40 °C to about 80 °C, about 45 °C to about 75 °C, about 50 °C to about 70 °C, about 55 °C to about 65 °C, or about 60 °C.

25. The process according to any of Claims 21-24, wherein the solution is cooled to a temperature of: about 2 °C to about 10 °C, about 3 °C to about 8 °C, about 4 °C to about 6 °C, or about 5 °C.

26. The process according to any of Claims 21-25, wherein the cooling is carried out over a period of: about 15 minutes to about 4 hours, about 30 minutes to about 3 hours, about 45 minutes to about 2 hours, about 45 minutes to about 1.5 hours, or about 1 hour.

27. The process according to Claim 19 wherein the solvent is a mixture of ethanol and water.

28. The process according to Claim 19 or 27, comprising cooling a solution of Zipalertinib hydrochloride in ethanol and water to precipitate the crystalline Zipalertinib hydrochloride Form A.

29. The process according to Claim 27 or Claim 28, wherein the process comprises preparing a mixture of Zipalertinib hydrochloride in ethanol and water; heating the mixture to obtain a solution; and cooling the solution to precipitate the crystalline Zipalertinib hydrochloride Form A.

30. The process according to Claim 28 or Claim 29, wherein the solution of Zipalertinib hydrochloride in ethanol and water is prepared by a process comprising combining Zipalertinib in a mixture of ethanol and water to obtain a first suspension, adding concentrated hydrochloric acid to form a second suspension, and heating the second suspension to form the solution.

31. The process according to any of Claims 27, 28, 29, or 30, wherein the mixture of ethanol and water used to form the first suspension contains ethanol and water in a ratio (v / v) of abouts 95:5.

32. The process according to Claim 30 or Claim 31, wherein the hydrochloric acid is used in an amount of about 2.0 to about 2.3 mole equivalents or about 2.0 to 2.2 mole equivalents, or about 2.0 or about 2.1 mole equivalents relative to Zipalertinib.

33. The process according to any of Claims 30-32, wherein the first suspension is formed at about room temperature.

34. The process according to any of Claims 30-33, wherein the concentrated hydrochloric acid is added at about room temperature.

35. The process according to any of Claims 29-34, wherein the heating is to a temperature above 40 °C, particularly wherein the heating is to a temperature of: about 40 °C to about 80 °C, about 40 °C to about 75 °C, about 45 °C to about 60 °C, about 45 °C to about 55 °C, or about 50 °C.

36. The process according to any of Claims 28-35, wherein the solution is cooled to a temperature of: about -5 °C to about 15 °C, about -2 °C to about 10 °C, about -2 °C to about 5 °C, about -2 °C to about 2 °C, or about 0 °C.

37. The process according to any of Claims 19-36, wherein the crystalline Zipalertinib hydrochloride Form A is isolated, preferably by filtration, decantation or centrifugation, and more preferably by filtration.

38. The process according to any of Claims 19-37, wherein the process further comprises drying the crystalline Zipalertinib hydrochloride Form A, preferably wherein the drying is performed under vacuum.

39. The process according to Claim 38, wherein the drying is carried out under inert gas, preferably nitrogen.

40. The process according to Claim 39, wherein the drying is carried using wet gas, preferably wet nitrogen.

41. A process for preparation of amorphous Zipalertinib hydrochloride comprising precipitating amorphous Zipalertinib hydrochloride from a mixture comprising ethanol and heptane.

42. The process according to Claim 41, comprising precipitating amorphous Zipalertinib hydrochloride from a mixture of ethanol, water and heptane.

43. The process according to Claim 42, comprising adding heptane to a solution of Zipalertinib hydrochloride in a mixture of ethanol and water.

44. The process according to Claim 43, wherein the solution of Zipalertinib hydrochloride in a mixture of ethanol and water is prepared by a process comprising dissolving Zipalertinib in a ethanol and adding hydrochloric acid, and optionally heating, to form a solution.

45. The process according to Claim 44 wherein heating is to a temperature of about the heating is to a temperature of: about 40 °C to about 80 °C, about 40 °C to about 75 °C, about 45 °C to about 60 °C, about 45 °C to about 55 °C, or about 40 °C to about 60 °C, preferably about 50 °C.

46. The process according to Claim 43 or Claim 44, wherein the solution is cooled down, prior to addition of n-heptane, preferably to a temperature of: about -5 °C to about 15 °C, about - 2 °C to about 10 °C, about -2 °C to about 5 °C, about -2 °C to about 2 °C, and more preferably about 0 °C.

47. The process according to any of Claims 41-46, wherein the amorphous Zipalertinib hydrochloride is isolated by filtration, decantation or centrifugation, and more preferably by filtration.

48. The process according to any of Claims 41-47, wherein the process further comprises drying the amorphous Zipalertinib hydrochloride, preferably wherein the drying is performed under vacuum.

49. The process according to any of Claim 48, wherein the drying is carried out at about room temperature.

50. The process according to any of Claims 19-49, further comprising combining the crystalline Zipalertinib hydrochloride Form A or Zipalertinib hydrochloride or amorphous Zipalertinib hydrochloride, with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition or a pharmaceutical formulation.

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