Solid state forms of azenosertib

Abstract

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

Description

Attorney Docket: API080-WO01 (2222-235 PCT) SOLID STATE FORMS OF AZENOSERTIB CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, Indian Provisional Patent Application Serial No.202411078243 filed on October 15, 2024, and Indian Provisional Patent Application Serial No. 202411080785 filed October 23, 2024. The entire contents of the foregoing applications are incorporated by reference herein. FIELD OF THE DISCLOSURE

[0002] The present disclosure encompasses solid state forms of Azenosertib, in embodiments crystalline polymorphs of Azenosertib, processes for preparation thereof, and pharmaceutical compositions thereof. BACKGROUND OF THE DISCLOSURE

[0003] Azenosertib, (R)-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H- cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H- pyrazolo[3,4-d]pyrimidin-3-one, has the following chemical structure:

[0004] small molecule Wee1 inhibitor, and it is developed for the treatment of Ovarian cancer, Pancreatic cancer; Solid tumours, Uterine cancer, Acute myeloid leukaemia, Colorectal cancer; Fallopian tube cancer; Osteosarcoma, Peritoneal cancer, Triple negative breast cancer and Breast cancer.

[0005] The compound is described in International Publication No. WO2019 / 173082. International Publication No. WO 2022 / 011391 discloses crystalline forms of Azenosertib and salts of Azenosertib such as adipate salt Form A, HCl salt Form A, HCl salt Form B, sulfateAttorney Docket: API080-WO01 (2222-235 PCT) salt Form A, sulfate salt Form B, mesylate salt Form A, maleate salt Form A, phosphate salt Form A, tartrate salt Form A, tosylate salt Form A, mucate salt Form A and hippurate salt Form A. The entire contents of the foregoing publications are incorporated by reference herein.

[0006] 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.

[0007] 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.

[0008] Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical / physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Azenosertib.Attorney Docket: API080-WO01 (2222-235 PCT) SUMMARY OF THE DISCLOSURE

[0009] The present disclosure provides crystalline polymorphs of Azenosertib, processes for preparation thereof, and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other solid state forms of Azenosertib, Azenosertib salts and their solid state forms.

[0010] The present disclosure also provides uses of the said solid state forms of Azenosertib in the preparation of other solid state forms of Azenosertib or salts thereof.

[0011] The present disclosure provides crystalline polymorphs of Azenosertib for use in medicine, including for the treatment of Ovarian cancer, Pancreatic cancer; Solid tumours, Uterine cancer, Acute myeloid leukaemia, Colorectal cancer; Fallopian tube cancer; Osteosarcoma, Peritoneal cancer, Triple negative breast cancer and Breast cancer.

[0012] The present disclosure also encompasses the use of crystalline polymorphs of Azenosertib of the present disclosure for the preparation of pharmaceutical compositions and / or formulations.

[0013] In another aspect, the present disclosure provides pharmaceutical compositions comprising crystalline polymorphs of Azenosertib according to the present disclosure.

[0014] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes includes combining any one or a combination of the crystalline polymorphs of Azenosertib with at least one pharmaceutically acceptable excipient.

[0015] The crystalline polymorph of Azenosertib as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorph of Azenosertib may be used as medicaments, such as for the treatment of Ovarian cancer, Pancreatic cancer; Solid tumours, Uterine cancer, Acute myeloid leukaemia, Colorectal cancer; Fallopian tube cancer; Osteosarcoma, Peritoneal cancer, Triple negative breast cancer and Breast cancer.

[0016] The present disclosure also provides methods of treating Ovarian cancer, Pancreatic cancer; Solid tumours, Uterine cancer, Acute myeloid leukaemia, Colorectal cancer; Fallopian tube cancer; Osteosarcoma, Peritoneal cancer, Triple negative breast cancer and Breast cancer., by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Azenosertib of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from Ovarian cancer, Pancreatic cancer; Solid tumours, Uterine cancer, Acute myeloid leukaemia, Colorectal cancer; Fallopian tube cancer; Osteosarcoma, Peritoneal cancer, Triple negative breast cancer and Breast cancer, or otherwise in need of the treatment.Attorney Docket: API080-WO01 (2222-235 PCT)

[0017] The present disclosure also provides uses of crystalline polymorphs of Azenosertib of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g. Ovarian cancer, Pancreatic cancer; Solid tumours, Uterine cancer, Acute myeloid leukaemia, Colorectal cancer; Fallopian tube cancer; Osteosarcoma, Peritoneal cancer, Triple negative breast cancer and Breast cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 shows a characteristic X-ray powder diffraction (“XRPD”) pattern of Azenosertib Form AZ1;

[0019] Figure 2 shows a characteristic XRPD pattern of a Azenosertib Amorphous Form;

[0020] Figure 3 shows a characteristic XRPD pattern of Azenosertib Form AZ2;

[0021] Figure 4a shows solid state13C NMR spectrum of Azenosertib Form AZ1 (full scan);

[0015] Figure 4b shows solid state13C NMR spectrum of Azenosertib Form AZ1 (at the range of 0-90 ppm); and

[0022] Figure 4c shows solid state13C NMR spectrum of Azenosertib Form AZ1 (at the range of 90-200 ppm). DETAILED DESCRIPTION OF THE DISCLOSURE

[0023] The present disclosure encompasses solid state forms of Azenosertib, including crystalline polymorphs of Azenosertib, processes for preparation thereof, and pharmaceutical compositions thereof. In embodiments, the present disclosure provides crystalline form of Azenosertib designated as Form AZ1 and Form AZ2 (defined herein).

[0024] Solid state properties of Azenosertib and crystalline polymorphs thereof can be influenced by controlling the conditions under which Azenosertib and crystalline polymorphs thereof are obtained in solid form.

[0025] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" will be understood to mean that the solid state form contains about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. Thus, a crystalline polymorph of Azenosertib 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), greaterAttorney Docket: API080-WO01 (2222-235 PCT) 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 Azenosertib. In some embodiments of the disclosure, the described crystalline polymorph of Azenosertib 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 Azenosertib. Thus, for example, a crystalline polymorph of Azenosertib, as described in any aspect or embodiment herein, which is polymorphically pure, may contain: 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 Azenosertib. As another example, a crystalline polymorph of Azenosertib, as described in any aspect or embodiment herein, which is polymorphically pure, may contain: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of the Azenosertib. Thus, a crystalline polymorph of Azenosertib as described in any aspect or embodiment herein, which is polymorphically pure, may contain: 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 Azenosertib. Alternatively, a crystalline polymorph of Azenosertib according to any aspect or embodiment of the present invention may be polymorphically pure and may 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 crystalline polymorph of Azenosertib.

[0026] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of Azenosertib 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.

[0027] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone.Attorney Docket: API080-WO01 (2222-235 PCT) 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 Azenosertib 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 Azenosertib characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0028] A compound may be referred to herein as chemically pure or purified compound or as substantially free of any other compounds. As used herein, the terms “chemically pure” or “purified” or “substantially free of any other compounds” refer to a compound that is substantially free of any impurities including enantiomers of the subject compound, diastereomers or other isomers. A chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% (w / w) or less, about 5% (w / w) or less, about 4% (w / w) or less, about 3% (w / w) or less, about 2% (w / w) or less, about 1.5% (w / w) or less, about 1% (w / w), about 0.8% (w / w) or less, about 0.6% (w / w) or less, about 0.4% (w / w) or less, about 0.2% (w / w) or less, about 0.1% (w / w) or less, or about 0% of any other compound as measured, for example, by HPLC. Alternatively, A chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% area percent or less, about 5% area percent or less, about 4% area percent or less, about 3% area percent or less, about 2% area percent or less, about 1.5% area percent or less, about 1% area percent or less, about 0.8% area percent or less, about 0.6% area percent or less, about 0.4% area percent, or less about 0.2% area percent or less,, about 0.1% area percent or less or about 0% of any other compound as measured by HPLC. Thus, pure or purified Azenosertib described herein as substantially free of any compounds would be understood to contain greater than about 90% (w / w), greater than about 95% (w / w), greater than about 96% (w / w), greater than about 97% (w / w), greater than about 98% (w / w), greater than about 98.5% (w / w), greater than about 99% (w / w), greater than about 99.2%,(w / w) greater than about 99.4% (w / w), greater than about 99.6% (w / w), greater than about 99.8% (w / w), greater than about 99.9% (w / w), or about 100% of the subject Azenosertib. Alternatively, pure or purified Azenosertib described herein asAttorney Docket: API080-WO01 (2222-235 PCT) substantially free of any compounds would be understood to contain greater than about 90% area percent, greater than about 95% area percent, greater than about 96% area percent, greater than about 97% area percent, greater than about 98% area percent, greater than about 98.5% area percent, greater than about 99% area percent, greater than about 99.2%, area percent, greater than about 99.4% area percent, greater than about 99.6% area percent, greater than about 99.8% (area percent, greater than about 99.9% area percent, or about 100% of the subject Azenosertib.

[0029] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline forms of Azenosertib, relates to a crystalline form of Azenosertib which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would generally not contain more than 1% (w / w), of either water or organic solvents as measured for example by TGA.

[0030] 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.

[0031] As used herein, the term "isolated" in reference to crystalline polymorph of Azenosertib of the present disclosure corresponds to a crystalline polymorph of Azenosertib that is physically separated from the reaction mixture in which it is formed.

[0032] As used herein, unless stated otherwise, the XRPD measurements are taken using copper K^ radiation wavelength 1.5418 Å. XRPD peaks reported herein are measured using CuK α radiation, λ = 1.5418 Å, typically at a temperature of 25 ± 3°C.

[0033] As used herein, unless stated otherwise,13C NMR reported herein are measured at 125 MHz at a magic angle spinning frequency ^r / 2^ = 11 kHz, preferably at a temperature of at 293 K ± 3°C. More particularly,13C NMR reported herein are referenced to glycine (176.03 ppm).

[0034] 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.

[0035] 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.” ForAttorney Docket: API080-WO01 (2222-235 PCT) example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 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.

[0036] 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.

[0037] 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.

[0038] As used herein and unless indicated otherwise, the term "ambient conditions" refer to atmospheric pressure and a temperature of 22-24°C.

[0039] The present disclosure includes a crystalline polymorph of Azenosertib, designated AZ1. The crystalline Form AZ1 of Azenosertib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 5.4, 10.8, 16.6, 17.6 and 18.8 degrees 2-theta ± 0.2 degrees 2-theta; a solid state13C NMR spectrum having peaks at 9.8, 27.2, 36.0, 45.0 and 146.9 ppm ± 0.2 ppm; a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 81.0 ppm ± 2 ppm of 71.3, 53.9, 45.1, 36.1 and 65.8 ppm ± 0.1 ppm; a solid state13C NMR spectrum substantially as depicted in Figures 4a, 4b or 4c; and combinations of these data.

[0040] Crystalline Form AZ1 of Azenosertib may be further characterized by an X-ray powder diffraction pattern having peaks at 5.4, 10.8, 16.6, 17.6 and 18.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 9.4, 11.7 and 20.4 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form AZ1 of Azenosertib according to any aspect or embodiment as described herein, may be further characterised by an XRPD pattern having an absence of peaks at: 6.1 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form AZ1 of Azenosertib according to any aspect or embodiment as described herein, may be further characterised by an XRPD pattern having an absence of peaks at: 6.7 degrees 2-theta ±Attorney Docket: API080-WO01 (2222-235 PCT) 0.2 degrees 2-theta. Crystalline Form AZ1 of Azenosertib according to any aspect or embodiment as described herein, may be further characterised by an XRPD pattern having an absence of peaks at 4.1 to 4.2 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form AZ1 of Azenosertib according to any aspect or embodiment as described herein, may be further characterised by an XRPD pattern having an absence of peaks at 6.5 to 7.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form AZ1 of Azenosertib according to any aspect or embodiment as described herein, may be further characterised by an XRPD pattern having an absence of peaks at 6.3 to 7.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0041] Crystalline Form AZ1 of Azenosertib according to any aspect or embodiment as described herein, may be further characterised by an XRPD pattern having an absence of peaks at 6.0 to 7.5 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form AZ1 of Azenosertib according to any aspect or embodiment as described herein, may be further characterised by an XRPD pattern having an absence of peaks at 23.6 to 23.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0042] In one embodiment of the present disclosure, crystalline Form AZ1 of Azenosertib is isolated. Particularly, crystalline Form AZ1 of Azenosertib according to any aspect or embodiment as described herein, may be isolated.

[0043] Crystalline Form AZ1 of Azenosertib may be anhydrous form. Crystalline Form AZ1 of Azenosertib according to any aspect or embodiment as described herein, is preferably an anhydrous form.

[0044] Crystalline Form AZ1 of Azenosertib may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 5.4, 10.8, 16.6, 17.6 and 18.8 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1, and combinations thereof.

[0045] Form AZ1 of Azenosertib according to any aspect or embodiment of the disclosure, may be prepared by crystallization from a mixture comprising isopropyl alcohol and petroleum ether. The process may comprise combining a solution of Azenosertib in isopropyl alcohol with petroleum ether. According to any aspect or embodiment of the process, petroleum ether may be added to the solution of Azenosertib in isopropanol, or preferably, the solution of Azenosertib in isopropanol may be added to petroleum ether. According to any aspect or embodiment of the process, the solution of Azenosertib in isopropanol may be at room temperature, preferably at a temperature of: about 18°C to about 28 °C, or about 22°C to about 26°C, or about 25°C. According to any aspect or embodiment of the process, the petroleum ether may be at a temperature of: about -10°C to about 15 °C, about -5°C to about 10°C, or about 0°C to about 5°C. The process may comprise maintaining the reaction mixture atAttorney Docket: API080-WO01 (2222-235 PCT) increased temperatures, by staged heating and stirring steps. Thus, following the combining of the petroleum ether and the solution of Azenosertib in isopropanol, the reaction mixture may be stirred at a temperature of: about -10°C to about 15°C, about -5°C to about 10°C, or about 0°C to about 5°C (preferably for about 15 minutes to about 3 hours, about 15 minutes to about 2 hours, about 15 minutes to about 1 hour, or about 30 minutes). The mixture may then be stirred at a temperature of: about 15°C to about 28°C, about 20°C to about 28°C, or about 25°C (preferably for a period of: about 15 minutes to about 3 hours, about 15 minutes to about 2 hours, about 15 minutes to about 1 hour, or about 30 minutes). The mixture may then be stirred at a temperature of: about 30°C to 45°C, about 35°C to about 45°C, or about 40°C (preferably for a period of: about 15 minutes to about 3 hours, about 15 minutes to about 2 hours, about 15 minutes to about 1 hour, or about 30 minutes). The mixture may then be stirred at a temperature of: about 48°C to about 70°C, about 50°C to about 68°C, about 55°C to about 65°C, or about 60°C, preferably for a period of: about 4 hours to about 72 hours, about 10 hours to about 65 hours, about 20 hours to about 60 hours, about 35 hours to about 55 hours, about 40 hours to about 50 hours, or about 46 hours. Form AZ1 of Azenosertib may be isolated and optionally dried.

[0046] According to any aspect or embodiment of the disclosed process, the process for preparing Form AZ1 of Azenosertib may comprise: (i) dissolving Azenosertib in isopropyl alcohol; (ii) adding precooled petroleum ether; (iii) optionally isolating; and (iii) optionally drying. According to any aspect or embodiment of the disclosed processes for preparing Form AZ1 of Azenosertib, isopropyl alcohol may be used in step (i) in an amount of: about 2 ml to about 5 ml, about 2.5 ml to about 4.5 ml, or about 3.33 ml, per gram of Azenosertib. Preferably, according to any aspect or embodiment of the disclosed process for preparing Form AZ1 of Azenosertib, the isopropyl alcohol may be at temperature of about 15°C to about 35°C, about 20°C to about 30°C, or about 25°C. Petroleum ether may be used in step (ii) in an amount of: about 400 ml to about 500 ml, about 410 ml to about 450 ml, or about 433.3 ml, per gram of Azenosertib. Preferably, according to any aspect or embodiment of the disclosed process, the v / v ratio of isopropyl alcohol to petroleum ether is: about 1:30 to about 1:300, about 1:50 to about 1:250, about 1:100 to about 1:200, about 1:120 to about 1:150, about 1:120 to about 1:140, or about 1:130. Preferably, according to any aspect or embodiment of the disclosed process for preparing Form AZ1 of Azenosertib, the petroleum ether may be at temperature ofAttorney Docket: API080-WO01 (2222-235 PCT) -5°C to about 15°C, about -2°C to about 10°C, or about 0°C to about 5°C. The reaction mixture may be maintained at temperature of about -5°C to about 15°C, about -2°C to about 10°C, or about 0°C to about 5°C, preferably for period of: about 15 minutes to about 3 hours, about 15 minutes to about 2 hours, about 15 minutes to about 1 hour, or about 30 minutes. The reaction mixture may be further maintained at a temperature of: about 15°C to about 28°C, about 20°C to about 28°C, or about 25°C, preferably for a period of: about 15 minutes to about 3 hours, about 15 minutes to about 2 hours, about 15 minutes to about 1 hour, or about 30 minutes. For example, following maintaining the reaction mixture at the cooled temperature, the temperature of the reaction mixture may be raised to 15°C to about 28°C, about 20°C to about 28°C, or about 25°C,, preferably over a period of about 2 mins to about 30 mins, about 2 mins to about 15 mins, or about 5 minutes. The mixture may be maintained at this temperature for a period of: about 15 minutes to about 3 hours, about 15 minutes to about 2 hours, about 15 minutes to about 1 hour, or about 30 minutes. The reaction mixture may be additionally maintained at a temperature of: 30°C to 45°C, about 35°C to about 45°C, or about 40°C, preferably for a period of: about 15 minutes to about 3 hours, about 15 minutes to about 2 hours, about 15 minutes to about 1 hour, or about 30 minutes. For example, the temperature of the reaction mixture may be raised to: 30°C to 45°C, about 35°C to about 45°C, or about 40°C, preferably over a period of about 2 mins to about 30 mins, about 2 mins to about 20 mins, or about 10 minutes. The mixture may be maintained at the raised temperature for a period of: about 15 minutes to about 3 hours, about 15 minutes to about 2 hours, about 15 minutes to about 1 hour, or about 30 minutes. The reaction mixture may be additionally further maintained at a temperature of: about 48°C to about 70°C, about 50°C to about 68°C, about 55°C to about 65°C, or about 60°C, preferably for a period of: about 4 hours to about 72 hours, about 10 hours to about 65 hours, about 20 hours to about 60 hours, about 35 hours to about 55 hours, about 40 hours to about 50 hours, or about 46 hours. For example, the temperature of the reaction mixture may be raised to: 48°C to about 70°C, about 50°C to about 68°C, about 55°C to about 65°C, or about 60°C, preferably over a period of: about 2 mins to about 30 mins, about 2 mins to about 20 mins, or about 10 minutes. The mixture may be maintained at the raised temperature for a period of: about 4 hours to about 72 hours, about 10 hours to about 65 hours, about 20 hours to about 60 hours, about 35 hours to about 55 hours, about 40 hours to about 50 hours, or about 46 hours. The product may be isolated, preferably by cooling, and filtering. Preferably the product is isolated by cooling to a temperature of: about 15°C to about 35°C, about 20°C to about 30°C, or about 25°C, preferably over a period of: about 2 mins to about 30 mins, about 5 mins to about 20 mins, or about 10 minutes to about 20 minutes, or about 15 minutes. The process mayAttorney Docket: API080-WO01 (2222-235 PCT) further include isolating the obtained Form AZ1 of Azenosertib, by any suitable procedure, such as filtration, decantation, or by centrifuge. Particularly the product may be isolated by vacuum filtration and dried, preferably under vacuum (for example under vacuum suction during filtration). The drying may preferably be conducted at temperature of about 15°C to about 35°C, about 20°C to about 30°C, or about 25°C.

[0047] According to any aspect or embodiment, the processes for preparing form AZ1 Azenosertib as described herein, may further comprise combining the form AZ1 Azenosertib with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.

[0048] The present disclosure includes a crystalline polymorph of Azenosertib, designated AZ2. The crystalline Form AZ2 of Azenosertib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 3; an X-ray powder diffraction pattern having peaks at 4.5, 5.8, 12.1, 15.5 and 16.9 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0049] Crystalline Form AZ2 of Azenosertib may be further characterized by an X-ray powder diffraction pattern having peaks at 4.5, 5.8, 12.1, 15.5 and 16.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 10.2, 13.2 and 20.5 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form AZ2 of Azenosertib may be characterized by an X-ray powder diffraction pattern having peaks at 4.5, 5.8, 10.2, 12.1, 13.2, 15.5, 16.9, and 20.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0050] Crystalline Form AZ2 of Azenosertib according to any aspect or embodiment of the present disclosure may be further characterised by an XRPD pattern having a peak at 7.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0051] Crystalline Form AZ2 of Azenosertib according to any aspect or embodiment of the present disclosure may be further characterized by an XRPD pattern having an absence of peaks at 5.0 to 5.3 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form AZ2 of Azenosertib according to any aspect or embodiment of the present disclosure may be further characterised by an XRPD pattern having an absence of peaks at 6.3 to 6.8 degrees 2-theta ± 0.2 degrees 2- theta. Crystalline Form AZ2 of Azenosertib according to any aspect or embodiment of the present disclosure may be further characterised by an XRPD pattern having an absence of peaks at 7.8 to 8.4 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form AZ2 of Azenosertib according to any aspect or embodiment of the present disclosure may be further characterised by an XRPD pattern having an absence of peaks at 11.0 to 11.4 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form AZ2 of Azenosertib according to any aspect or embodiment of the present disclosure may be further characterised by an XRPD pattern having an absence of peaksAttorney Docket: API080-WO01 (2222-235 PCT) at 10.7 to 11.6 degrees 2-theta ± 0.2 degrees 2-theta.In one embodiment of the present disclosure, crystalline Form AZ2 of Azenosertib is isolated. Particularly, crystalline Form AZ2 of Azenosertib according to any aspect or embodiment as described herein, may be isolated.

[0052] Crystalline Form AZ2 of Azenosertib may be anhydrous form. Crystalline Form AZ2 of Azenosertib according to any aspect or embodiment as described herein, is preferably an anhydrous form.

[0053] Crystalline Form AZ2 of Azenosertib may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 4.5, 5.8, 12.1, 15.5 and 16.9 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 3, and combinations thereof.

[0054] Crystalline Form AZ2 of Azenosertib as described in any aspect or embodiment of the disclosure, may be prepared by a process comprising stirring Azenosertib (preferably amorphous Azenosertib) in cyclohexane for a suitable period of time. The cyclohexane may preferably be used in an amount of: about 8 ml to about 60 ml, about 12 ml to about 50 ml, about 18 ml to about 40 ml, about 20 ml to about 30 ml, or about 27 ml, per gram of Azenosertib. Particularly, the process may comprise heating a mixture of Azenosertib (preferably amorphous Azenosertib) and cyclohexane, preferably to a temperature of: about 40°C to about 75°C, about 45°C to about 70°C, about 50°C to about 65°C, or about 55°C to about 60°C, and stirring. Preferably, the mixture may be stirred for a period of: about 4 hours to about 36 hours, about 8 hours to about 30 hours, about 12 hours to about 24 hours, about 14 hours to about 18 hours, or about 16 hours. Form AZ2 of Azenosertib may be isolated by any suitable procedure, such as decantation, centrifuge or filtration, preferably by filtration. The solid may be dried, for example by suction on the filter, preferably at room temperature, preferably for a period of: about 5 minutes to about 60 minutes, about 10 minutes to about 40 minutes, or about 15 minutes to about 30 minutes. Alternatively, or additionally, the solid may be dried or further dried under vacuum, preferably at a temperature of: 40°C to about 75°C, about 45°C to about 70°C, about 50°C to about 65°C, or about 60°C, preferably for a period of: about 4 hours to about 36 hours, about 8 hours to about 24 hours, about 12 hours to about 20 hours, about 14 hours to about 18 hours, or about 16 hours. Crystalline Form AZ2 of Azenosertib as described in any aspect or embodiment, may particularly be prepared by a process comprising: (i) heating a mixture of amorphous Azenosertib and cyclohexane (preferably about 18 ml to about 40 ml, and more preferably about 20 ml to about 30 ml per gramAttorney Docket: API080-WO01 (2222-235 PCT) of Azenosertib), to a temperature of about 50°C to about 65°C (preferably about 55°C to about 60°C); (ii) stirring the mixture for about 12 hours to about 24 hours (preferably about 14 hours to about 18 hours); (iii) optionally isolating Azenosertib Form AZ2, preferably by filtration; (iv) optionally drying the Azenosertib Form AZ2, preferably by suction on the filter (preferably for about 15 minutes to about 30 minutes); and (v) optionally drying the Azenosertib Form AZ2 under vacuum (preferably at a temperature of: about 50°C to about 65°C, more preferably about 55°C to about 60°C).

[0055] According to any aspect or embodiment, the processes for preparing form AZ2 Azenosertib as described herein, may further comprise combining the form AZ2 Azenosertib with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.

[0056] Alternatively, crystalline Form AZ2 of Azenosertib as described in any aspect or embodiment of the disclosure, may be prepared by a process comprising crystallization of Azenosertib from a mixture of ethanol and cyclohexane. According to any aspect or embodiment, the process may comprise combining a solution of Azenosertib in ethanol with cyclohexane to form a mixture. According to any aspect or embodiment of the process, the process may comprise adding the solution of Azenosertib in ethanol to cyclohexane, or adding cyclohexane to the solution of Azenosertib; preferably the process comprises adding the solution of Azenosertib in ethanol to cyclohexane. Preferably, the cyclohexane contains seeds of Azenosertib form AZ2. In any aspect or embodiment, the ethanol is used in an amount of: about 0.5 ml to about 8 ml, about 0.8 ml to about 6 ml, about 1 ml to about 4 ml, about 1.5 ml to about 3 ml, about 1.5 ml to about 2.5 ml, or about 2 ml, per gram of Azenosertib. In any aspect or embodiment, the cyclohexane is used in an amount of: about 50 ml to about 600 ml, about 100 ml to about 550 ml, about 150 ml to about 500 ml, about 200 ml to about 480 ml, about 300 ml to about 450 ml, about 350 ml to about 420 ml, or about 400 ml, per gram of Azenosertib. In any aspect or embodiment, the v / v ratio of ethanol to cyclohexane is: about 1:50 to about 1:500, about 1:100 to about 1:400, about 1:150 to about 1:300, about 1:180 to about 1:250, about 1:180 to about 1:220, or about 1:200. In any aspect or embodiment, the seeds of Azenosertib form AZ2 are used in an amount (w / w %) of: about 1% to about 10%, about 2% to about 8%, about 4% to about 6%, or about 5% relative to the Azenosertib starting material.Attorney Docket: API080-WO01 (2222-235 PCT)

[0057] According to any aspect or embodiment, the cyclohexane (or mixture of cyclohexane and form AZ2 seeds) may be heated, preferably to a temperature of: about 40°C to about 75°C, about 45°C to about 70°C, about 50°C to about 65°C, about 55°C to about 65°C, or about 60°C. The mixture may be stirred, preferably at a temperature of: about 40°C to about 75°C, about 45°C to about 70°C, about 50°C to about 65°C, about 55°C to about 65°C, or about 60°C. The mixture may be stirred for a period of: about 4 hours to about 36 hours, about 8 hours to about 30 hours, about 12 hours to about 24 hours, about 14 hours to about 18 hours, or about 16 hours. Form AZ2 of Azenosertib may be isolated from the mixture (preferably after cooling to room temperature) by any suitable procedure, such as decantation, centrifuge or filtration, preferably by filtration. The solid may be dried, for example by suction on the filter, preferably at room temperature, preferably for a period of: about 5 minutes to about 60 minutes, about 10 minutes to about 40 minutes, or about 15 minutes to about 30 minutes. Alternatively, or additionally, the solid may be dried or further dried under vacuum, preferably at a temperature of: 40°C to about 75°C, about 45°C to about 70°C, about 50°C to about 65°C, or about 60°C, preferably for a period of: about 4 hours to about 36 hours, about 8 hours to about 24 hours, about 12 hours to about 20 hours, about 14 hours to about 18 hours, or about 16 hours. Crystalline Form AZ2 of Azenosertib as described in any aspect or embodiment, may particularly be prepared by a process comprising: (i) adding a solution of Azenosertib in ethanol (preferably wherein the solution is at room temperature) to cyclohexane, wherein the cyclohexane is heated to a temperature of about 50°C to about 65°C (preferably about 55°C to about 65°C), and preferably wherein the cyclohexane is seeded with Azenosertib form AZ2; (ii) stirring the mixture for about 12 hours to about 24 hours (preferably about 14 hours to about 18 hours); (iii) optionally isolating Azenosertib Form AZ2, preferably by filtration; (iv) optionally drying the Azenosertib Form AZ2, preferably by suction on the filter (preferably for about 15 minutes to about 30 minutes); and (v) optionally drying the Azenosertib Form AZ2 under vacuum (preferably at a temperature of: about 50°C to about 65°C, more preferably about 55°C to about 60°C).

[0058] According to any aspect or embodiment, the processes for preparing form AZ2 Azenosertib as described herein, may further comprise combining the form AZ2 Azenosertib with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.Attorney Docket: API080-WO01 (2222-235 PCT)

[0059] The above crystalline polymorphs can be used to prepare other crystalline polymorphs of Azenosertib, Azenosertib salts and their solid state forms.

[0060] The present disclosure encompasses a process for preparing other solid state forms of Azenosertib, Azenosertib salts and their solid state forms thereof.

[0061] The present disclosure provides the above described crystalline polymorphs of Azenosertib for use in the preparation of pharmaceutical compositions comprising Azenosertib and / or crystalline polymorphs thereof.

[0062] The present disclosure also encompasses the use of crystalline polymorphs of Azenosertib of the present disclosure for the preparation of pharmaceutical compositions of crystalline polymorph Azenosertib and / or crystalline polymorphs thereof.

[0063] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes includes combining any one or a combination of the crystalline polymorphs of Azenosertib of the present disclosure with at least one pharmaceutically acceptable excipient.

[0064] Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the solid state forms of Azenosertib 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.

[0065] 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.

[0066] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose,Attorney Docket: API080-WO01 (2222-235 PCT) polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] In liquid pharmaceutical compositions of the present invention, Azenosertib 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.

[0073] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not solubleAttorney Docket: API080-WO01 (2222-235 PCT) in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0074] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and / or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.

[0075] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[0076] 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.

[0077] 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.

[0078] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

[0079] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0080] 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.Attorney Docket: API080-WO01 (2222-235 PCT)

[0081] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] A pharmaceutical formulation of Azenosertib can be administered. Azenosertib may be formulated for administration to a mammal, in embodiments to a human, by injection. Azenosertib can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection. The formulation can contain one or more solvents. A suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

[0087] The crystalline polymorphs of Azenosertib and the pharmaceutical compositions and / or formulations of Azenosertib of the present disclosure can be used as medicaments, inAttorney Docket: API080-WO01 (2222-235 PCT) embodiments in the treatment of Ovarian cancer, Pancreatic cancer; Solid tumours, Uterine cancer, Acute myeloid leukaemia, Colorectal cancer; Fallopian tube cancer; Osteosarcoma, Peritoneal cancer, Triple negative breast cancer and Breast cancer.

[0088] The present disclosure also provides methods of treating Ovarian cancer, Pancreatic cancer; Solid tumours, Uterine cancer, Acute myeloid leukaemia, Colorectal cancer; Fallopian tube cancer; Osteosarcoma, Peritoneal cancer, Triple negative breast cancer and Breast cancer. by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Azenosertib of the present disclosure, or at least one of the above pharmaceutical compositions and / or formulations, to a subject in need of the treatment.

[0089] 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

[0090] X-ray diffraction was performed on X-Ray powder diffractometer: Bruker D8 Advance; Copper Kα radiation (λ = 1.5418 Å); Lynx eye detector; laboratory temperature 22-25 °C; PMMA specimen holder ring. Prior to analysis, the samples were gently ground by means of mortar and pestle in order 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 by means of a cover glass. Measurement parameters: Scan range: 2 – 40 degrees 2-theta; Scan mode: continuous; Step size: 0.05 degrees; Time per step: 0.5 s; Sample spin: 30 rpm; Sample holder: PMMA specimen holder ring with silicon low background. All X-Ray Powder Diffraction peak values are calibrated with regard to standard silicon spiking in the sample. 13C CP / MAS NMR Method:

[0091] Solid-state NMR spectra were measured at 11.7 T using a Bruker Avance III HD 500 US / WB NMR spectrometer (Karlsruhe, Germany, 2013) with 3.2 mm probehead. The13CAttorney Docket: API080-WO01 (2222-235 PCT) CP / MAS NMR spectra employing cross-polarization were acquired using the standard pulse scheme at spinning frequency of 18 kHz and a room temperature (300 K). The recycle delay was 8 s and the cross-polarization contact time was 2 ms. The13C scale was referenced to α- glycine (176.03 ppm for13C). Frictional heating of the spinning samples was offset by active cooling, and the temperature calibration was performed with Pb(NO3)2.The NMR spectrometer was completely calibrated and all experimental parameters were carefully optimized prior the investigation. Magic angle was set using KBr during standard optimization procedure and homogeneity of magnetic field was optimized using adamantane sample (resulting line-width at half-height Δυ1 / 2 was less than 3.5 Hz at 250 ms of acquisition time). EXAMPLES Preparation of starting materials

[0092] Azenosertib can be prepared according to methods known from the literature, for example WO2019 / 173082 and WO 2022 / 011391. Example 1: Preparation of Azenosertib Form AZ1

[0093] Azenosertib (0.03 g) was dissolved in isopropyl alcohol (0.1 ml) at temperature of about 25°C to get clear solution. The clear solution was immediately added to petroleum ether (13 ml) which was precooled to temperature of about 0°C to about 5°C. The reaction mixture was maintained at temperature of about 0°C to about 5°C for about 30 minutes. The temperature of the reaction mixture was raised to 25°C in 5 minutes and stirred for an additional 30 minutes. Further the temperature of the reaction mixture was raised up to 40°C in 10 minutes and stirred for another 30 minutes and then heated to 60°C in 10 minutes and maintained at 60°C under stirring for period of about 46 hours. After 46 hours, the reaction mixture was cooled down to temperature of about 20°C to about 25°C in 15 minutes and filtered and dried under vacuum suction at 25°C. The obtained solid was analyzed by XRPD. Crystalline Azenosertib Form AZ1 was obtained. An XRPD pattern is shown in Figure 1. Example 2: Preparation of Azenosertib Amorphous Form

[0094] Azenosertib (0.5g) was dissolved in Methyl Acetate (0.6 ml) at temperature of about 25°C. The clear solution was subjected to distillation under reduced pressure (below 150 mbar) at temperature of about 45°C for period of about 15 minutes. The obtained solid was analyzed by XRPD. Amorphous form of Azenosertib was obtained. An XRPD pattern is shown in Figure 2. Example 3: Preparation of Azenosertib Form AZ2Attorney Docket: API080-WO01 (2222-235 PCT)

[0095] Azenosertib (0.15 g) (Amorphous) was charged in 10ml Vial and Cyclohexane (4 ml) was added at temperature of about 25°C. The reaction mixture was heated to temperature of about 55°C to about 60°C. The slurry mass was maintained under stirring for about 16 hours at temperature of about 55°C to about 60°C. The slurry mass was filtered and suck dried for period of about 15 minutes to about 30 minutes at temperature of about 25°C. The sample was further dried in a Vacuum tray dryer (VTD) at temperature of about 60°C for period of about 16 hours. The obtained solid was analyzed by XRPD. Crystalline Azenosertib Form AZ2 was obtained. Example 4: Preparation of Azenosertib Form AZ2

[0096] Azenosertib (0.1g) was dissolved in ethanol (0.2 ml) at temperature about 25°C. The clear solution was slowly added into preheated Cyclohexane (40 ml) with seeds of Azenosertib form AZ2 (5%) (Seed of Azenosertib form AZ2 was prepared as per example 3) at temperature of about 60°C. The reaction was maintained under stirring at temperature of about 60°C for period of about 16 hours. Then reaction mass cooled to 25°C and filtered and suck dried for about 30 minutes. The obtained solid further dried under Vacuum tray dryer (VTD) at temperature of about 60°C for period of about 16 hours. The obtained solid was analyzed by XRPD. Crystalline Azenosertib Form AZ2 was obtained. An XRPD pattern is shown in Figure 3. Example 5: Stability Studies Forms AZ1 and AZ2 of Azenosertib Storage stability at different relative humidities

[0097] Samples of Form AZ1 and Form AZ2 of Azenosertib were subjected to conditions of different relative humidities at ambient temperature. XRPD analysis was performed on the samples after 7 days. The results are shown in Table 1 below: XRPD analysis results Starting material Relative humidity 20% 40% 60% 80% Form AZ1 Form Form Form Form Azenosertib AZ1 AZ1 AZ1 AZ1 Form AZ2 Form Form Form Form Azenosertib AZ2 AZ2 AZ2 AZ2 Table 1

[0098] These results demonstrate that Form AZ1 and Form AZ2 of Azenosertib are stable after exposure to high and low relative humidity for at least 7 days.Attorney Docket: API080-WO01 (2222-235 PCT)

[0099] Samples of Form AZ1 and Form AZ2 of Azenosertib were subjected to conditions of different relative humidities at different temperatures. XRPD analysis was performed on the samples after 6 months. The results are shown in Table 2 below: XRPD analysis results Starting material Conditions (6 months) 25°C, 60% 40°C, 75% RH RH Form AZ1 Azenosertib Form AZ1 Form AZ1 Form AZ2 Azenosertib Form AZ2 Form AZ2 Table 2

[0100] The results demonstrate that Form AZ1 and Form AZ2 of Azenosertib are stable after exposure to high and low relative humidity at different temperatures for at least 6 months, indicating that these crystalline forms have good storage stability. Grinding experiments

[0101] Samples of Form AZ1 and Form AZ2 of Azenosertib were subjected to strong grinding, and to solvent drop grinding in water. Grinding was carried out on the samples alone, or in the presence of water. In these experiments, about 20 mg of the sample is placed in a mortar and ground with a pestle for 2 minutes. Water, when used, was added to the crystalline material before grinding, in a volume of 20 microlitres. XRPD analysis performed on each of the samples after the grinding experiment, confirmed no change in the starting material (Table 3): XRPD analysis results Starting material Condition Strong grinding Grinding in water Form AZ1 Azenosertib Form AZ1 Form AZ1 Form AZ2 Azenosertib Form AZ2 Form AZ2 Table 3

[0102] The results demonstrate that Form AZ1 and Form AZ2 of Azenosertib are resistant to polymorphic changes when subjected to grinding, including in the presence of water, aAttorney Docket: API080-WO01 (2222-235 PCT) typical solvent used for processing pharmaceutical compositions. Accordingly, Forms A1 and A2 are highly suitable for preparing pharmaceutical formulations. Thermal stability

[0103] Samples of Form AZ1 and Form AZ2 of Azenosertib were subjected to heating up to 100°C for 30 minutes. XRPD analysis of the samples confirmed no change in the starting material (Table 4): Starting material XRPD analysis Heating 100ºC, 30 minutes Form AZ1 Azenosertib Form AZ1 Form AZ2 Azenosertib Form AZ2 Table 4 Stability to compression

[0104] Samples of Form AZ1 and Form AZ2 of Azenosertib were subjected to a pressure of 2 tons. (Atlas® Autopress hydraulic press, set to 2 tons). XRPD analysis was performed on the samples after 1 minute. The result is shown in Table 5 below: Starting material XRPD analysis Compression (2 tons for 1 min) Form AZ1 Azenosertib Form AZ1 Form AZ2 Azenosertib Form AZ2 Table 5

[0105] Accordingly Form AZ1 and Form A2 of Azenosertib are stable under high pressure conditions, making these forms highly suitable for pharmaceutical processing.

[0106] Further aspects and embodiments of the disclosure are set out in the numbered clause list A and B below: List A 1A. Crystalline Form AZ1 of Azenosertib characterized by data selected from one or more of the following:Attorney Docket: API080-WO01 (2222-235 PCT) a) an XRPD pattern having peaks at 5.4, 10.8, 16.6, 17.6 and 18.8 degrees 2-theta ± 0.2 degrees 2-theta; b) an XRPD pattern as depicted in Figure 1; c) a solid state 13C NMR spectrum having peaks at 9.8, 27.2, 36.0, 45.0 and 146.9 ppm ± 0.2 ppm; d) a solid state 13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 81.0 ppm ± 2 ppm of 71.3, 53.9, 45.1, 36.1 and 65.8 ppm ± 0.1 ppm; e) a solid-state 13C NMR spectrum substantially as depicted in Figures 4a, 4b or 4c; and f) combinations of two or more of: a, b, c, d, and e. A. Crystalline Form AZ1 of Azenosertib according to Clause 1A, which is characterized by an XRPD pattern having peaks at 5.4, 10.8, 16.6, 17.6 and 18.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, or three additional peaks selected from 9.4, 11.7 and 20.4 degrees 2-theta ± 0.2 degrees two theta. A. Crystalline Form AZ1 of Azenosertib according to any of Clauses 1A or 2A, which is characterized by an XRPD pattern having peaks at: 5.4, 9.4, 10.8, 11.7, 16.6, 17.6, 18.8 and 20.4 degrees 2-theta ± 0.2 degrees 2-theta. A. Crystalline Form AZ1 of Azenosertib according to any of Clauses 1A, 2A and 3A, which is characterised by XRPD pattern having an absence of peaks at: 6.1 degrees 2- theta ± 0.2 degrees 2-theta. A. Crystalline Form AZ1 of Azenosertib according to any of Clauses 1A, 2A, 3A, and 4A, which is characterised by XRPD pattern having an absence of peaks at: 6.7 degrees 2-theta ± 0.2 degrees 2-theta. A. Crystalline Form AZ1 of Azenosertib according to any of Clauses 1A, 2A, 3A, 4A, and 5A, which is characterised by XRPD pattern having an absence of peaks at 4.1 to 4.2 degrees 2-theta ± 0.2 degrees 2-theta. A. Crystalline Form AZ1 of Azenosertib according to any of Clauses 1A, 2A, 3A, 4A, 5A, and 6A, which is characterised by XRPD pattern having an absence of peaks at 6.5 to 7.0 degrees 2-theta ± 0.2 degrees 2-theta. A. Crystalline Form AZ1 of Azenosertib according to any of Clauses 1A, 2A, 3A, 4A, 5A, 6A, and 7A, which is characterised by XRPD pattern having an absence of peaks at 6.3 to 7.2 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API080-WO01 (2222-235 PCT) A. Crystalline Form AZ1 of Azenosertib according to any of Clauses 1A, 2A, 3A, 4A, 5A, 6A, 7A, and 8A, which is characterised by XRPD pattern having an absence of peaks at 6.0 to 7.5 degrees 2-theta ± 0.2 degrees 2-theta. 0A. Crystalline Form AZ1 of Azenosertib according to any of Clauses 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, and 9A, which is characterised by XRPD pattern having an absence of peaks at 23.6 to 23.9 degrees 2-theta ± 0.2 degrees 2-theta. 1A. Crystalline Form AZ1 of Azenosertib according to any of Clauses 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, and 10A, which is isolated. 2A. Crystalline Form AZ1 of Azenosertib according to any of Clauses 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, and 11A, which is an anhydrous form. 3A. Crystalline Azenosertib according to any of Clauses 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, and 12A, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Azenosertib. 4A. Crystalline Azenosertib according to any of Clauses 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, and 13A, 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 Azenosertib. 5A. A pharmaceutical composition comprising a crystalline Azenosertib according to any of Clauses 1A to 14A. 6A. A pharmaceutical formulation comprising a crystalline Azenosertib according to any of Clauses 1A to 14A or a pharmaceutical composition of Clause 15A, with at least one pharmaceutically acceptable excipient. 7A. A process for preparing a pharmaceutical formulation according to Clause 16A, comprising combining a crystalline Azenosertib according to any of Clauses 1A to 14A or a pharmaceutical composition of Clause 15A, with at least one pharmaceutically acceptable excipient. 8A. Crystalline Azenosertib according to any one of Clauses 1A to 14A, a pharmaceutical composition according to Clause 15A, or a pharmaceutical formulation according to Clause 16A, for use as a medicament. 9A. Crystalline Azenosertib according to any one of Clauses 1A to 14A, a pharmaceutical composition according to Clause 15A, or a pharmaceutical formulation according to Clause 16A, for use in the treatment of Ovarian cancer, Pancreatic cancer; Solid tumours, Uterine cancer, Acute myeloid leukaemia, Colorectal cancer; Fallopian tubeAttorney Docket: API080-WO01 (2222-235 PCT) cancer; Osteosarcoma, Peritoneal cancer, Triple negative breast cancer and Breast cancer. 20A. A method of treating Ovarian cancer, Pancreatic cancer; Solid tumours, Uterine cancer, Acute myeloid leukaemia, Colorectal cancer; Fallopian tube cancer; Osteosarcoma, Peritoneal cancer, Triple negative breast cancer and Breast cancer, comprising administering a therapeutically effective amount of a crystalline Azenosertib according to any one of Clauses 1A to 14A, a pharmaceutical composition according to Clause 15A, or a pharmaceutical formulation according to Clause 16A, to a subject in need of the treatment. 21A. Crystalline Azenosertib, according to any one of Clauses 1A to 14A, a pharmaceutical composition according to Clause 15A, or a pharmaceutical formulation according to Clause 16A, for the manufacture of a medicament for treating Ovarian cancer, Pancreatic cancer; Solid tumours, Uterine cancer, Acute myeloid leukaemia, Colorectal cancer; Fallopian tube cancer; Osteosarcoma, Peritoneal cancer, Triple negative breast cancer and Breast cancer. 22A. Use of a crystalline Azenosertib according to any one of Clauses 1A to 14A, in the preparation of another solid state form of Azenosertib, or another Azenosertib salt or solid state form thereof. List B 1B. Crystalline Form AZ2 of Azenosertib characterized by data selected from one or more of the following: a) an XRPD pattern having peaks at 4.5, 5.8, 12.1, 15.5 and 16.9 degrees 2-theta ± 0.2 degrees 2-theta; and b) an XRPD pattern as depicted in Figure 3. 2B. Crystalline Form AZ2 of Azenosertib according to Clause 1B, which is characterized by an XRPD pattern having peaks at 4.5, 5.8, 12.1, 15.5 and 16.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 10.2, 13.2 and 20.5 degrees 2-theta ± 0.2 degrees 2-theta. 3B. Crystalline Form AZ2 of Azenosertib according to any of Clauses 1B or 2B, which is characterized by an XRPD pattern having peaks at: 4.5, 5.8, 10.2, 12.1, 13.2, 15.5, 16.9, and 20.5 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API080-WO01 (2222-235 PCT) B. Crystalline Form AZ2 of Azenosertib according to any of Clause 1B, 2B or 3B, which is further characterized by an XRPD pattern having a peak at 7.3 degrees 2-theta ± 0.2 degrees 2-theta. B. Crystalline Form AZ2 of Azenosertib according to any of Clauses 1B, 2B, 3B, and 4B, which is characterised by XRPD pattern having an absence of peaks at 5.0 to 5.3 degrees 2-theta ± 0.2 degrees 2-theta. B. Crystalline Form AZ2 of Azenosertib according to any of Clauses 1B, 2B, 3B, 4B, and 5B, which is characterised by XRPD pattern having an absence of peaks at 6.3 to 6.8 degrees 2-theta ± 0.2 degrees 2-theta. B. Crystalline Form AZ2 of Azenosertib according to any of Clauses 1B, 2B, 3B, 4B, 5B, and 6B, which is characterised by XRPD pattern having an absence of peaks at 7.8 to 8.4 degrees 2-theta ± 0.2 degrees 2-theta. B. Crystalline Form AZ2 of Azenosertib according to any of Clauses 1B, 2B, 3B, 4B, 5B, 6B, and 7B, which is characterised by XRPD pattern having an absence of peaks at 11.0 to 11.4 degrees 2-theta ± 0.2 degrees 2-theta. B. Crystalline Form AZ2 of Azenosertib according to any of Clauses 1B, 2B, 3B, 4B, 5B, 6B, 7B, and 8B, which is characterised by XRPD pattern having an absence of peaks at 10.7 to 11.6 degrees 2-theta ± 0.2 degrees 2-theta. 0B. Crystalline Form AZ2 of Azenosertib according to any of Clauses 1B, 2B, 3B, 4B, 5B, 6B, 7B, 8B, and 9B, which is isolated. 1B. Crystalline Form AZ2 of Azenosertib according to any of Clauses 1B, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, and 10B, which is an anhydrous form. 2B. Crystalline Azenosertib Form AZ2 according to any of Clauses 1B, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, and 11B, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Azenosertib. 3B. Crystalline Azenosertib Form AZ2 according to any of Clauses 1B, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, and 12B, 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 Azenosertib. 4B. A pharmaceutical composition comprising a crystalline Azenosertib according to any of Clauses 1B to 13B.Attorney Docket: API080-WO01 (2222-235 PCT) B. A pharmaceutical formulation comprising a crystalline Azenosertib according to any of Clauses 1B to 13B or a pharmaceutical composition of Clause 14B, with at least one pharmaceutically acceptable excipient. B. A process for preparing a pharmaceutical formulation according to Clause 15B, comprising combining a crystalline Azenosertib according to any of Clauses 1B to 13B or a pharmaceutical composition of Clause 14B, with at least one pharmaceutically acceptable excipient. B. Crystalline Azenosertib according to any one of Clauses 1B to 13B, a pharmaceutical composition according to Clause 14B, or a pharmaceutical formulation according to Clause 15B, for use as a medicament. B. Crystalline Azenosertib according to any one of Clauses 1B to 13B, a pharmaceutical composition according to Clause 14B, or a pharmaceutical formulation according to Clause 15B, for use in the treatment of Ovarian cancer, Pancreatic cancer; Solid tumours, Uterine cancer, Acute myeloid leukaemia, Colorectal cancer; Fallopian tube cancer; Osteosarcoma, Peritoneal cancer, Triple negative breast cancer and Breast cancer. B. A method of treating Ovarian cancer, Pancreatic cancer; Solid tumours, Uterine cancer, Acute myeloid leukaemia, Colorectal cancer; Fallopian tube cancer; Osteosarcoma, Peritoneal cancer, Triple negative breast cancer and Breast cancer, comprising administering a therapeutically effective amount of a Crystalline Azenosertib according to any one of Clauses 1B to 13B, a pharmaceutical composition according to Clause 14B, or a pharmaceutical formulation according to Clause 15B, to a subject in need of the treatment. B. Crystalline Azenosertib, according to any one of Clauses 1B to 13B, a pharmaceutical composition according to Clause 14B, or a pharmaceutical formulation according to Clause 15B, for the manufacture of a medicament for treating Ovarian cancer, Pancreatic cancer; Solid tumours, Uterine cancer, Acute myeloid leukaemia, Colorectal cancer; Fallopian tube cancer; Osteosarcoma, Peritoneal cancer, Triple negative breast cancer and Breast cancer. B. Use of a crystalline Azenosertib according to any one of Clauses 1B to 13B, in the preparation of another solid state form of Azenosertib, or another Azenosertib salt or solid state form thereof.

Claims

Attorney Docket: API080-WO01 (2222-235 PCT) CLAIMS 1. A crystalline Form AZ1 of Azenosertib characterized by data selected from one or more of the following: a) an X-ray powder diffraction (“XRPD”) pattern having peaks at 5.4, 10.8, 16.6, 17.6 and 18.8 degrees 2-theta ± 0.2 degrees 2-theta; b) an XRPD pattern as depicted in Figure 1; c) a solid state 13C NMR spectrum having peaks at 9.8, 27.2, 36.0, 45.0 and 146.9 ppm ± 0.2 ppm; d) a solid state 13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 81.0 ppm ± 2 ppm of 71.3, 53.9, 45.1, 36.1 and 65.8 ppm ± 0.1 ppm; e) a solid-state 13C NMR spectrum substantially as depicted in Figures 4a, 4b or 4c; and f) combinations of two or more of: a, b, c, d, and e.

2. The crystalline Form AZ1 of Azenosertib according to Claim 1, which is characterized by an XRPD pattern having peaks at 5.4, 10.8, 16.6, 17.6 and 18.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, or three additional peaks selected from 9.4, 11.7 and 20.4 degrees 2-theta ± 0.2 degrees two theta.

3. The crystalline Form AZ1 of Azenosertib according to any of Claims 1 and 2, which is characterized by an XRPD pattern having peaks at: 5.4, 9.4, 10.8, 11.7, 16.6, 17.6, 18.8 and 20.4 degrees 2-theta ± 0.2 degrees 2-theta.

4. The crystalline Form AZ1 of Azenosertib according to any of Claims 1, 2, and 3, which is isolated.

5. The crystalline Form AZ1 of Azenosertib according to any of Claims 1, 2, 3 and 4, which is an anhydrous form.

6. A crystalline Form AZ2 of Azenosertib characterized by data selected from one or more of the following: a) an X-ray powder diffraction (“XRPD”) pattern having peaks at 4.5, 5.8, 12.1, 15.5 and 16.9 degrees 2-theta ± 0.2 degrees 2-theta; b) an XRPD pattern as depicted in Figure 3;Attorney Docket: API080-WO01 (2222-235 PCT) c) a combination of a and b.

7. The crystalline Form AZ2 of Azenosertib according to Claim 6, which is characterized by an XRPD pattern having peaks at 4.5, 5.8, 12.1, 15.5 and 16.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, or three additional peaks selected from 10.2, 13.2 and 20.5 degrees 2-theta ± 0.2 degrees two theta.

8. The crystalline Form AZ2 of Azenosertib according to any of Claims 6 and 7, which is characterized by an XRPD pattern having peaks at: 4.5, 5.8, 10.2, 12.1, 13.2, 15.5, 16.9 and 20.5 degrees 2-theta ± 0.2 degrees 2-theta.

9. The crystalline Form AZ2 of Azenosertib according to any of Claims 6, 7, and 8, which is isolated.

10. The crystalline Form AZ2 of Azenosertib according to any of Claims 6, 7, 8, and 9, which is an anhydrous form.

11. The crystalline Azenosertib according to any of Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Azenosertib.

12. The crystalline Azenosertib according to any of Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11, 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 Azenosertib.

13. A pharmaceutical composition comprising a crystalline Azenosertib according to any of Claims 1 to 12.

14. A pharmaceutical formulation comprising the crystalline Azenosertib according to any of Claims 1 to 12, or a pharmaceutical composition of Claim 13, with at least one pharmaceutically acceptable excipient.

15. A process for preparing a pharmaceutical formulation according to Claim 14, comprising combining a crystalline Azenosertib according to any of Claims 1 to 12, or a pharmaceutical composition of Claim 13, with at least one pharmaceutically acceptable excipient.Attorney Docket: API080-WO01 (2222-235 PCT) 16. The crystalline Azenosertib according to any one of Claims 1 to 12, a pharmaceutical composition according to Claim 13, or a pharmaceutical formulation according to Claim 14, for use as a medicament.

17. The crystalline Azenosertib according to any one of Claims 1 to 12, a pharmaceutical composition according to Claim 13, or a pharmaceutical formulation according to Claim 14, for use in the treatment of Ovarian cancer, Pancreatic cancer; Solid tumours, Uterine cancer, Acute myeloid leukaemia, Colorectal cancer; Fallopian tube cancer; Osteosarcoma, Peritoneal cancer, Triple negative breast cancer and Breast cancer.

18. A method of treating Ovarian cancer, Pancreatic cancer; Solid tumours, Uterine cancer, Acute myeloid leukaemia, Colorectal cancer; Fallopian tube cancer; Osteosarcoma, Peritoneal cancer, Triple negative breast cancer and Breast cancer, comprising administering a therapeutically effective amount of a Crystalline Azenosertib according to any one of Claims 1 to 12, a pharmaceutical composition according to Claim 13, or a pharmaceutical formulation according to Claim 14, to a subject in need of the treatment.

19. The crystalline Azenosertib, according to any one of Claims 1 to 12, a pharmaceutical composition according to Claim 13, or a pharmaceutical formulation according to Claim 14, for the manufacture of a medicament for treating Ovarian cancer, Pancreatic cancer; Solid tumours, Uterine cancer, Acute myeloid leukaemia, Colorectal cancer; Fallopian tube cancer; Osteosarcoma, Peritoneal cancer, Triple negative breast cancer and Breast cancer.

20. Use of a crystalline Azenosertib according to any one of Claims 1 to 12, in the preparation of another solid state form of Azenosertib, or another Azenosertib salt or solid state form thereof.

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