Solid state forms of samuraciclib

Abstract

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

Description

Attorney Docket: API031-WO01 (2222-189 PCT) SOLID STATE FORMS OF SAMURACICLIB CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S. Provisional Patent Application Serial No.63 / 581,730 filed on September 11, 2023; U.S. Provisional Patent Application Serial No.63 / 590,801 filed on October 17, 2023; U.S. Provisional Patent Application Serial No.63 / 599,586 filed on November 16, 2023, and U.S. Provisional Patent Application Serial No.63 / 618,962 filed on January 9, 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 Samuraciclib and / or of Samuraciclib salts, in embodiments crystalline polymorphs of Samuraciclib and / or of Samuraciclib salts, processes for preparation thereof, and pharmaceutical compositions thereof. BACKGROUND OF THE DISCLOSURE

[0003] Samuraciclib, (3R,4R)-4-[[[7-(benzylamino)-3-propan-2-ylpyrazolo[1,5-a]pyrimidin- 5-yl]amino]methyl]piperidin-3-ol, has the following chemical structure:

[0004] Samuraciclib is an orallyof cyclin-dependent kinase 7 (CDK7) with potential antineoplastic activity and it is currently in clinical trial for treating breast cancer. The compound is described in International Publication No. WO2015 / 124941.

[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 solidAttorney Docket: API031-WO01 (2222-189 PCT) 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 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 Samuraciclib and / or of Samuraciclib salts. SUMMARY OF THE DISCLOSURE

[0008] The present disclosure provides crystalline polymorphs of Samuraciclib and / or of Samuraciclib salts, in embodiments crystalline polymorphs of Samuraciclib and / or of Samuraciclib salts, processes for preparation thereof, and pharmaceutical compositions thereof. These crystalline forms can be used to prepare other solid state forms of Samuraciclib and salts thereof.Attorney Docket: API031-WO01 (2222-189 PCT)

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

[0010] The present disclosure provides said crystalline forms of Samuraciclib and / or of Samuraciclib salts for use in medicine, including for the treatment of cancer, in particular, breast cancer.

[0011] The present disclosure also encompasses the use of said crystalline polymorphs of Samuraciclib and / or of Samuraciclib salts for the preparation of pharmaceutical compositions and / or formulations.

[0012] In another aspect, the present disclosure provides pharmaceutical compositions comprising said crystalline polymorphs of Samuraciclib and / or of Samuraciclib salts according to the present disclosure.

[0013] The present disclosure includes processes for preparing the above-mentioned pharmaceutical compositions. The processes include combining said crystalline polymorphs of Samuraciclib and / or of Samuraciclib salts with at least one pharmaceutically acceptable excipient.

[0014] The crystalline polymorphs of Samuraciclib and / or of Samuraciclib salts as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorphs of Samuraciclib and / or of Samuraciclib salts may be used as medicaments, such as for the treatment of cancer, and in particular breast cancer.

[0015] The present disclosure also provides methods for the treatment of patients with cancer by administering a therapeutically effective amount of said crystalline polymorph of Samuraciclib of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from cancer or otherwise in need of the treatment.

[0016] The present disclosure also provides uses of crystalline polymorphs of Samuraciclib of the present disclosure and / or of Samuraciclib salts, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g., cancer, in particular, breast cancer.Attorney Docket: API031-WO01 (2222-189 PCT) BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Samuraciclib Form B1.

[0018] Figure 2 shows a characteristic X-ray powder diffraction pattern (XRPD) of Samuraciclib hydrochloride salt Form H1.

[0019] Figure 3 shows a characteristic X-ray powder diffraction pattern (XRPD) of Samuraciclib hydrochloride salt Form H3.

[0020] Figure 4 shows a characteristic X-ray powder diffraction pattern (XRPD) of Samuraciclib hydrochloride salt Form H4.

[0021] Figure 5 shows a characteristic X-ray powder diffraction pattern (XRPD) of Samuraciclib Form B2.

[0022] Figure 6 shows a characteristic X-ray powder diffraction pattern (XRPD) of amorphous Samuraciclib.

[0023] Figure 7 shows a characteristic X-ray powder diffraction pattern (XRPD) of Samuraciclib hydrochloride salt Form H5.

[0024] Figure 8 shows a characteristic X-ray powder diffraction pattern (XRPD) of Samuraciclib dihydrochloride salt Form H4 (Example10). DETAILED DESCRIPTION OF THE DISCLOSURE

[0025] The present disclosure encompasses solid state forms of Samuraciclib and / or of Samuraciclib salts, in embodiments crystalline polymorphs of Samuraciclib and / or of Samuraciclib salts, processes for preparation thereof, and pharmaceutical compositions thereof.

[0026] Solid state properties of Samuraciclib and / or of Samuraciclib salts and crystalline polymorphs thereof can be influenced by controlling the conditions under which Samuraciclib and crystalline polymorphs thereof are obtained in solid form.

[0027] The solid state forms of Samuraciclib and / or of Samuraciclib salts as described in any aspect or embodiment of the present disclosure may be polymorphically pure, or substantially free of any other solid state (or polymorphic) forms.

[0028] 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 thatAttorney Docket: API031-WO01 (2222-189 PCT) 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. For example, polymorphically pure Samuraciclib form B1 means that the solid state form is substantially free of other solid state forms of Samuraciclib. Thus, a crystalline polymorph of Samuraciclib 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 Samuraciclib. In some embodiments of the disclosure, the described crystalline polymorph of Samuraciclib, salt or cocrystal 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 Samuraciclib.

[0029] The solid state forms of Samuraciclib (e.g. Samuraciclib or Samuraciclib salts) as described in any aspect or embodiment of the present disclosure may be enantiomerically pure, or substantially free of any other enantiomer. As used herein in this context, the expression “substantially free of any other enantiomer” or “substantially free” of a particular enantiomer 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 enantiomer or of the particular enantiomer, of the subject compound as measured, for example, by chiral HPLC. Thus, a crystalline polymorph of Samuraciclib described herein as substantially free of any other enantiomer 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 enantiomer of crystalline polymorph of Samuraciclib.

[0030] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of Samuraciclib and / or of Samuraciclib salts 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 lowerAttorney Docket: API031-WO01 (2222-189 PCT) degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.

[0031] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Samuraciclib 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 Samuraciclib characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0032] As used herein, the term “isolated” in reference to crystalline polymorph of Samuraciclib of the present disclosure corresponds to a crystalline polymorph of Samuraciclib that is physically separated from the reaction mixture in which it is formed.

[0033] As used herein, unless stated otherwise, the XRPD measurements are taken using copper K α radiation wavelength 1.54184 Å. XRPD peaks reported herein are optionally measured using CuK α radiation, λ = 1.54184 Å, typically at a temperature of 25 ± 3 °C.

[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.Attorney Docket: API031-WO01 (2222-189 PCT)

[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.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending 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 solid state forms of Samuraciclib and of Samuracicib salts as described in any aspect or embodiment of the present disclosure may be chemically pure, or substantially free of any other compounds.

[0040] 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, 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) or less, 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 orAttorney Docket: API031-WO01 (2222-189 PCT) 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.

[0041] Thus, pure or purified Samuraciclib 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 Samuraciclib. Alternatively, pure or purified Samuraciclib, described herein as 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 Samuraciclib.

[0042] The present disclosure includes a crystalline polymorph Samuraciclib designated Form B1. The crystalline Form B1 of Samuraciclib 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 7.6, 9.4, 12.7, 19.0 and 20.2 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0043] Crystalline Form B1 of Samuraciclib may be further characterized by an X-ray powder diffraction pattern having peaks at 7.6, 9.4, 12.7, 19.0 and 20.2 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, four, or five additional peaks selected from 11.8, 16.2, 16.9, 17.3 and 21.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0044] Crystalline Form B1 of Samuraciclib may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 7.6, 9.4, 11.8, 12.7, 16.2, 16.9, 17.3, 19.0, 20.2 and 21.2 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API031-WO01 (2222-189 PCT)

[0045] Crystalline Form B1 of Samuraciclib according to any aspect or embodiment of the present disclosure may be additionally characterized by an XRPD pattern having an absence of peaks at any one or more of: 3.0 to 5.8 degrees 2-theta ± 0.2 degrees 2-theta; 8.1 to 8.9 degrees 2-theta ± 0.2 degrees 2-theta; 9.9 to 11.3 degrees 2-theta ± 0.2 degrees 2-theta; 17.8 to 18.3 degrees 2-theta ± 0.2 degrees 2-theta; and / or 19.5 to 19.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0046] In any aspect or embodiment of the present disclosure, crystalline Form B1 of Samuraciclib may be isolated.

[0047] In any aspect or embodiment crystalline Form B1 of Samuraciclib may be polymorphically pure.

[0048] In any aspect or embodiment crystalline Form B1 may be anhydrous.

[0049] In a further embodiment, crystalline Form B1 of Samuraciclib according to the present invention is stable when exposed to high relative humidity.

[0050] In a further embodiment, the present disclosure includes a crystalline polymorph of Samuraciclib hydrochloride salt designated Form H3. The crystalline Form H3 of Samuraciclib hydrochloride salt 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 6.1, 8.0, 9.0, 11.1 and 21.6 degrees 2-theta ± 0.2 degrees 2- theta; and combinations of these data.

[0051] Crystalline Form H3 of Samuraciclib hydrochloride salt may be further characterized by an X-ray powder diffraction pattern having peaks at 6.1, 8.0, 9.0, 11.1 and 21.6 degrees 2- theta ± 0.2 degrees 2-theta, and also having one, two, three, four, or five additional peaks selected from 6.6, 16.3, 18.3, 19.3 and 23.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0052] Crystalline Form H3 of Samuraciclib hydrochloride salt may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 6.1, 6.6, 8.0, 9.0, 11.1, 16.3, 18.3, 19.3, 21.6 and 23.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0053] Crystalline Form H3 of Samuraciclib hydrochloride according to any aspect or embodiment of the present disclosure may be additionally characterized by an XRPD pattern having an absence of peaks at any one or more of: 3.0 to 5.6 degrees 2-theta ± 0.2 degrees 2- theta; 7.1 to 7.5 degrees 2-theta ± 0.2 degrees 2-theta; 9.5 to 10.2 degrees 2-theta ± 0.2 degrees 2-theta; 11.6 to 11.7 degrees 2-theta ± 0.2 degrees 2-theta; 13.8 to 14.0 degrees 2-theta ± 0.2 degrees 2-theta; and / or 17.1 to 17.3 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API031-WO01 (2222-189 PCT)

[0054] In any aspect or embodiment of the present disclosure, crystalline Form H3 of Samuraciclib hydrochloride may be isolated.

[0055] In any aspect or embodiment crystalline Form H3 of Samuraciclib hydrochloride may be polymorphically pure.

[0056] In any of the embodiments disclosed herein, crystalline Form H3 of Samuraciclib hydrochloride may be monohydrochloride salt of Samuraciclib, dihydrochloride salt of Samuraciclib, or trihydrochloride salt of Samuraciclib.

[0057] In another embodiment, the present disclosure provides a crystalline polymorph of Samuraciclib hydrochloride salt characterized by an X-ray powder diffraction pattern having peaks at 7.3, 8.1 and 15.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0058] In another embodiment, the present disclosure includes a crystalline polymorph of Samuraciclib hydrochloride salt designated Form H4. The crystalline Form H4 of Samuraciclib hydrochloride salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 4; an X-ray powder diffraction pattern having peaks at 7.3, 15.0 and 23.1 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0059] Crystalline Form H4 of Samuraciclib hydrochloride salt may be further characterized by an X-ray powder diffraction pattern having peaks at 7.3, 15.0 and 23.1 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, or three additional peaks selected from 8.1, 15.4 and 21.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0060] Alternatively, crystalline Form H4 of Samuraciclib hydrochloride may be characterized by an X ray powder diffraction having peaks at 7.3, 8.1 and 15.4 degrees 2-theta ± 0.2 degrees 2-theta and also having an X-ray powder diffraction pattern substantially as depicted in Figure 4.

[0061] Crystalline Form H4 of Samuraciclib hydrochloride salt may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 7.3, 8.1, 15.0, 15.4, 21.8 and 23.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0062] Crystalline Form H4 of Samuraciclib hydrochloride salt according to any aspect or embodiment of the present disclosure may be additionally characterized by an XRPD pattern having an absence of peaks at any one or more of: 3.0 to 6.8 degrees 2-theta ± 0.2 degrees 2- theta; 8.6 to 9.8 degrees 2-theta ± 0.2 degrees 2-theta; 11.8 to 12.4 degrees 2-theta ± 0.2 degreesAttorney Docket: API031-WO01 (2222-189 PCT) 2-theta; 13.4 to 14.5 degrees 2-theta ± 0.2 degrees 2-theta; 16.8 to 17.7 degrees 2-theta ± 0.2 degrees 2-theta; and / or 18.9 to 19.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0063] In any aspect or embodiment of the present disclosure, crystalline Form H4 of Samuraciclib hydrochloride may be isolated.

[0064] In any aspect or embodiment crystalline Form H4 of Samuraciclib hydrochloride may be polymorphically pure.

[0065] In any of the embodiments disclosed herein, crystalline Form H4 of Samuraciclib hydrochloride may be monohydrochloride salt of Samuraciclib, dihydrochloride salt of Samuraciclib, or trihydrochloride salt of Samuraciclib; preferably, dihydrochloride salt of Samuraciclib.

[0066] In another embodiment, the present invention includes a crystalline polymorph of Samuraciclib hydrochloride salt designated Form H5. Crystalline Form H5 is characterized by an X-ray powder diffraction having peaks at 7.3, 8.1 and 15.4 degrees 2-theta ± 0.2 degrees 2-theta and also having an X-ray powder diffraction pattern substantially as depicted in Figure 7.

[0067] Alternatively crystalline Form H5 of Samuraciclib hydrochloride according to any aspect or embodiment of the present disclosure may be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 7.

[0068] Crystalline Form H5 of Samuraciclib hydrochloride according to any aspect or embodiment of the present disclosure may be additionally characterized by an XRPD pattern having an absence of peaks at any one or more of: 3.0 to 5.2 degrees 2-theta ± 0.2 degrees 2- theta; 7.6 to 7.8 degrees 2-theta ± 0.2 degrees 2-theta; and / or 8.8 to 10.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0069] In another embodiment, the present invention provides a crystalline polymorph of Samuraciclib hydrochloride salt designated Form H1. A characteristic X-ray powder diffraction pattern of Form H1 is substantially as described in Figure 2.

[0070] Form H1 of Samuraciclib hydrochloride salt, may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 6.8, 7.1 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively, Form H1 of Samuraciclib hydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks at 6.8, 7.1 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta; and further characterized by any one, two, or three peaks at 14.9, 18.7 and 28.4 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API031-WO01 (2222-189 PCT)

[0071] Crystalline Form H1 of Samuraciclib hydrochloride according to any aspect or embodiment of the present disclosure may be additionally characterized by an XRPD pattern having an absence of peaks at any one or more of: at 3.0 to 6.3 degrees 2-theta ± 0.2 degrees 2- theta; 7.6 to 14.3 degrees 2-theta ± 0.2 degrees 2-theta; 15.5 to 17.0 degrees 2-theta ± 0.2 degrees 2-theta; 19.0 to 20.4 degrees 2-theta ± 0.2 degrees 2-theta; and / or 24.0 to 27.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0072] The present disclosure also includes a crystalline polymorph Samuraciclib designated Form B2. The crystalline Form B2 of Samuraciclib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 5; an X-ray powder diffraction pattern having peaks at 10.0, 18.0 and 24.6 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0073] Crystalline Form B2 of Samuraciclib may be further characterized by an X-ray powder diffraction pattern having peaks at 10.0, 18.0 and 24.6 degrees 2-theta ± 0.2 degrees 2- theta, and also having one, two, or three additional peaks selected from 6.7, 12.3 and 17.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0074] Crystalline Form B2 of Samuraciclib may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 6.7, 10.0, 12.3, 17.1, 18.0 and 24.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0075] Crystalline Form B2 of Samuraciclib according to any aspect or embodiment of the present disclosure may be additionally characterized by an XRPD pattern having an absence of peaks at any one or more of: 3.0 to 5.2 degrees 2-theta ± 0.2 degrees 2-theta; 6.9 to 9.5 degrees 2-theta ± 0.2 degrees 2-theta; 10.5 to 11.2 degrees 2-theta ± 0.2 degrees 2-theta; and / or 12.8 to 14.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0076] In any aspect or embodiment of the present disclosure, crystalline Form B2 of Samuraciclib may be isolated.

[0077] In any aspect or embodiment crystalline Form B2 of Samuraciclib may be polymorphically pure.

[0078] In any aspect or embodiment crystalline Form B2 may be anhydrous.

[0079] In a further embodiment, crystalline Form B2 of Samuraciclib according to the present invention is stable when exposed to high relative humidity.Attorney Docket: API031-WO01 (2222-189 PCT)

[0080] The present disclosure provides the above-described crystalline polymorph of Samuraciclib for use in the preparation of pharmaceutical compositions comprising Samuraciclib and / or solid state forms thereof.

[0081] The present disclosure also encompasses the use of crystalline polymorph of Samuraciclib of the present disclosure for the preparation of pharmaceutical compositions of crystalline polymorph Samuraciclib and / or solid state forms thereof.

[0082] The present disclosure includes processes for preparing the above-mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorph of Samuraciclib of the present disclosure with at least one pharmaceutically acceptable excipient.

[0083] Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the solid state form of Samuraciclib 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.

[0084] 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.

[0085] 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, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.Attorney Docket: API031-WO01 (2222-189 PCT)

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] In liquid pharmaceutical compositions of the present invention, Samuraciclib 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.

[0092] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not solubleAttorney Docket: API031-WO01 (2222-189 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.

[0093] 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.

[0094] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.Attorney Docket: API031-WO01 (2222-189 PCT)

[0099] 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.

[0100] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] A pharmaceutical formulation of Samuraciclib can be administered. Samuraciclib may be formulated for administration to a mammal, in embodiments to a human, by injection. Samuraciclib 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 pHAttorney Docket: API031-WO01 (2222-189 PCT) 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.

[0106] The crystalline polymorph of Samuraciclib and the pharmaceutical compositions and / or formulations of Samuraciclib of the present disclosure can be used as medicaments, in embodiments for the treatment of patients with cancer, and in particular breast cancer.

[0107] The present disclosure also provides methods of treating of patients with cancer, and in particular breast cancer, by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Samuraciclib of the present disclosure, or at least one of the above pharmaceutical compositions and / or formulations, to a subject in need of the treatment.

[0108] 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

[0109] Sample, after being powdered in a mortar and pestle, was applied directly on a silicon plate holder. The X-ray powder diffraction pattern was measured with Philips X'Pert PRO X-ray powder diffractometer, equipped with Cu irradiation source =1.54184 Ǻ (Ǻngström), X’Celerator (2.022º 2θ) detector. Scanning parameters: angle range: 3-40 deg., step size 0.0167, time per step 37 s, continuous scan. Peak positions were determined without using silicon powder as an internal standard. Measurement parameters: Scan range: 3 – 40 degrees 2-theta Scan mode: continuous Step size: 0.0167 degrees Step size: 37 sAttorney Docket: API031-WO01 (2222-189 PCT) EXAMPLES Preparation of starting materials

[0110] Samuraciclib can be prepared according to methods known from the literature, for example according to the disclosure in International Publication No. WO 2015 / 124941. Example 1: Preparation of Samuraciclib crystal Form B1 Procedure A

[0111] Samuraciclib base (20 mg) was dissolved in methanol (1 mL) at reflux temperature in a sealed tube. Obtained solution was left overnight to cool to room temperature. The solution was then left open on room temperature to evaporate. After 5 days, the obtained solid was analyzed by XRPD. Form B1 of Samuraciclib was obtained, as shown in Figure 1. Procedure B

[0112] Samuraciclib base (20 mg) was dissolved in acetone / water (2:1 volume ratio, 2 mL) at reflux temperature in a sealed tube. Obtained solution was left overnight to cool to room temperature. The solution was then left open on room temperature to evaporate. After 3 days obtained solid was analyzed by XRPD. Crystalline Form B1 of Samuraciclib was obtained. Procedure C

[0113] Samuraciclib base (20 mg) was dissolved in tetrahydrofuran / water (2:1 volume ratio, 2 mL) at reflux temperature in a sealed tube. Obtained solution was left overnight to cool to room temperature. The solution was then left open to evaporate on room temperature. After 3 days obtained solid analyzed by XRPD. Crystalline Form B1 of Samuraciclib was obtained. Example 2: Preparation of Samuraciclib hydrochloride -Form H1:

[0114] Samuraciclib base (300 mg) was suspended in acetone (3 mL) at 5-10 °C. Aqueous solution of hydrochloric acid (12M; 70 µL) was added to the suspension. The suspension was stirred overnight at 5-10 °C and filtered off under vacuum. The obtained solid was analyzed by XRPD. Form H1 of Samuraciclib hydrochloride salt was obtained, as shown in Figure 2.Attorney Docket: API031-WO01 (2222-189 PCT) Example 3: Preparation of Samuraciclib hydrochloride -Form H3:

[0115] Samuraciclib base (500 mg) was suspended in t-butanol (5 mL) at room temperature. Solution of hydrochloric acid in 2-propanol (5-6M; 484 µL) was added to the suspension. The suspension was stirred for two days at room temperature and filtered off under vacuum. The obtained solid was analyzed by XRPD. Form H3 of Samuraciclib hydrochloride salt was obtained, as shown in Figure 3. Example 4: Preparation of Samuraciclib hydrochloride -Form H4

[0116] Samuraciclib base (500 mg) was suspended in methyl ethyl ketone (3 mL) at room temperature. Solution of hydrochloric acid in 2-propanol (5-6M; 968 µL) was added to the suspension. The suspension was stirred for 12 days at room temperature and then it was filtered off under vacuum. The obtained solid was analyzed by XRPD. Form H4 of Samuraciclib hydrochloride salt was obtained, as shown in Figure 4. Example 5: Preparation of Samuraciclib crystal Form B2

[0117] Samuraciclib base (300 mg, amorphous) was suspended in methyl tert-butyl ether (3 mL) at room temperature (around 25 °C). Suspension was left to stir overnight. It was then filtrated off over a blue ribbon filter paper under vacuum. Obtained solid was analyzed by XRPD. Form B2 of Samuraciclib was obtained, as shown in Figure 5. Example 6: Preparation of amorphous Samuraciclib

[0118] Samuraciclib base (2 grams) was dissolved in methanol (70 mL) at room temperature (around 25 °C). Obtained solution was filtrated over a black ribbon filer paper and the obtained solution was then fast evaporated on rotational evaporator until dryness. Obtained solid was further dried for 2 hours on 50 °C under vacuum. Obtained solid was analyzed by XRPD. Amorphous Samuraciclib base was obtained, as shown in Figure 6. Example 7: Preparation of Samuraciclib hydrochloride-Form H5

[0119] Samuraciclib base (500 mg) was suspended in 2-propanol (5 mL) at room temperature (around 25 °C). Solution of hydrochloric acid in 2-propanol (5-6M; 968 µL) was added to the suspension. The suspension was stirred for 5 days at room temperature, and thenAttorney Docket: API031-WO01 (2222-189 PCT) filtered off over blue ribbon filter paper under vacuum. Obtained solid was analyzed by XRPD. Form H5 of Samuraciclib hydrochloride was obtained, as shown in Figure 7. Example 8: Preparation of Samuraciclib crystal Form B1

[0120] Samuraciclib base (2 g) was dissolved in acetonitrile (40 mL) at reflux temperature. Water (280 mL) was added and the obtained solution was left for 1 h to cool to room temperature. After that, the mixture was filtered through a black ribbon and the solid was dried under vacuum at 50 °C for 10 hours. Crystalline Form B1 of Samuraciclib was obtained. Example 9: Preparation of Samuraciclib crystal Form B2

[0121] Samuraciclib (3 g) was dissolved in methanol (32 mL) at reflux temperature. Water (224 mL) was added to the solution. The heating was turned off and the mixture was left to cool to room temperature. The obtained solid was filtered through a black ribbon and dried at 50 °C under vacuum for 10 hours- Crystalline Form B2 of Samuraciclib was obtained. Example 10: Preparation of Samuraciclib dihydrochloride salt -Form H4:

[0122] Samuraciclib base (amorphous, 2 g) was suspended in methyl ethyl ketone (12 mL) at room temperature. Solution of hydrochloric acid in 2-propanol (3.9 mL; 4.2 eq.) was added dropwise and obtained suspension was stirred overnight, filtered through a black ribbon filter paper under vacuum, and dried under vacuum at 50 °C for 2 h. Obtained powder was analyzed by XRPD – Form H4 of Samuraciclib dihydrochloride salt; as shown in Figure 8. Further aspects and embodiments of the present disclosure are set out in the following clauses: 1. Crystalline Samuraciclib 2. Crystalline form of Samuraciclib designated Form B1, which is characterized by data selected from: (a) an X-ray powder diffraction pattern substantially as depicted in Figure 1; (b) an X-ray powder diffraction pattern having peaks at 7.6, 9.4, 12.7, 19.0 and 20.2 degrees 2-theta ± 0.2 degrees 2-theta;Attorney Docket: API031-WO01 (2222-189 PCT) and combination of these data. Crystalline Samuraciclib according Clause 2, which is further characterized by an X-ray powder diffraction pattern having any one, two, three, four, or five additional peaks selected from 11.8, 16.2, 16.9, 17.3 and 21.2 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib according to Clauses 2 or 3, which is characterized by an XRPD pattern having peaks at 7.6, 9.4, 11.8, 12.7, 16.2, 16.9, 17.3, 19.0, 20.2 and 21.2 degrees 2- theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib according to any of Clauses 2, 3 and 4, which is characterized by an XRPD pattern having an absence of peaks at 3.0 to 5.8 degrees 2-theta ± 0.2 degrees 2- theta. Crystalline Samuraciclib according to any of Clauses 2, 3, 4, and 5, which is characterized by an XRPD pattern having an absence of peaks at 8.1 to 8.9 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib according to any of Clauses 2, 3, 4, 5, and 6, which is characterized by an XRPD pattern having an absence of peaks at 9.9 to 11.3 degrees 2- theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib according to any of Clauses 2, 3, 4, 5, 6, and 7, which is characterized by an XRPD pattern having an absence of peaks at 17.8 to 18.3 degrees 2- theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib according to any of Clauses 2, 3, 4, 5, 6, 7, and 8, which is characterized by an XRPD pattern having an absence of peaks at 19.5 to 19.7 degrees 2- theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib according to any of Clauses 2, 3, 4, 5, 6, 7, 8, and 9, which 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 crystalline forms of Samuraciclib.Attorney Docket: API031-WO01 (2222-189 PCT) Crystalline Samuraciclib according to any of Clauses 2, 3, 4, 5, 6, 7, 8, 9, and 10, which 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 amorphous Samuraciclib. Crystalline Samuraciclib according to any of Clauses 2, 3, 4, 5, 6, 7, 8, and 9, which is substantially free of any other solid state form of Samuraciclib. Crystalline Samuraciclib according to Clause 12, which 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 solid state form of Samuraciclib. Crystalline form of Samuraciclib designated Form B2, which is characterized by data selected from: (a) an X-ray powder diffraction pattern substantially as depicted in Figure 5; (b) an X-ray powder diffraction pattern having peaks at 10.0, 18.0 and 24.6 degrees 2- theta ± 0.2 degrees 2-theta; and combination of these data; Crystalline Samuraciclib according Clause 14, which is further characterized by an X-ray powder diffraction pattern having any one, two, or three additional peaks selected from 6.7, 12.3 and 17.1 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib according to Clause 14 or Clause 15, which is characterized by an XRPD pattern having peaks at 6.7, 10.0, 12.3, 17.1, 18.0 and 24.6 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib according to any of Clauses 14, 15, and 16, which is characterized by an XRPD pattern having an absence of peaks at 3.0 to 5.2 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib according to any of Clauses 14, 15, 16, and 17, which is characterized by an XRPD pattern having an absence of peaks at 6.9 to 9.5 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API031-WO01 (2222-189 PCT) Crystalline Samuraciclib according to any of Clauses 14, 15, 16, 17, and 18, which is characterized by an XRPD pattern having an absence of peaks at 10.5 to 11.2 degrees 2- theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib according to any of Clauses 14, 15, 16, 17, 18, and 19, which is characterized by an XRPD pattern having an absence of peaks at 12.8 to 14.4 degrees 2- theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib according to any of Clauses 14, 15, 16, 17, 18, 19, and 20, which 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 crystalline forms of Samuraciclib. Crystalline Samuraciclib according to any of Clauses 14, 15, 16, 17, 18, 19, 20, and 21, which 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 amorphous Samuraciclib. Crystalline Samuraciclib according to any of Clauses 14, 15, 16, 17, 18, 19, and 20, which is substantially free of any other solid state form of Samuraciclib. Crystalline Samuraciclib according to Clause 23, which 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 solid state form of Samuraciclib. Crystalline Samuraciclib dihydrochloride salt. Crystalline form of Samuraciclib dihydrochloride salt designated Form H4 which is characterized by data selected from: (a) an X-ray powder diffraction pattern substantially as depicted in Figure 4; (b) an X-ray powder diffraction pattern having peaks at 7.3, 15.0 and 23.1 degrees 2- theta ± 0.2 degrees 2-theta; and combination of these data.Attorney Docket: API031-WO01 (2222-189 PCT) Crystalline Samuraciclib dihydrochloride salt according Clause 26, which is further characterized by an X-ray powder diffraction pattern having any one, two, or three additional peaks selected from 8.1, 15.4 and 21.8 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib dihydrochloride salt according to Clauses 26 or 27, which is characterized by an XRPD pattern having peaks at 7.3, 8.1, 15.0, 15.4, 21.8 and 23.1 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib dihydrochloride salt according to any of Clauses 26, 27 and 28, which is characterized by an XRPD pattern having an absence of peaks at 3.0 to 6.8 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib dihydrochloride salt according to any of Clauses 26, 27, 28, and 29, which is characterized by an XRPD pattern having an absence of peaks at 8.6 to 9.8 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib dihydrochloride salt according to any of Clauses 26, 27, 28, 29, and 30, which is characterized by an XRPD pattern having an absence of peaks at 11.8 to 12.4 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib dihydrochloride salt according to any of Clauses 26, 27, 28, 29, 30, and 31, which is characterized by an XRPD pattern having an absence of peaks at 13.4 to 14.5 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib dihydrochloride salt according to any of Clauses 26, 27, 28, 29, 30, 31, and 32, which is characterized by an XRPD pattern having an absence of peaks at 16.8 to 17.7 degrees 2-theta ± 0.2 degrees 2-theta Crystalline Samuraciclib dihydrochloride salt according to any of Clauses 26, 27, 28, 29, 30, 31, 32, and 33, which is characterized by an XRPD pattern having an absence of peaks at 18.9 to 19.2 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Samuraciclib dihydrochloride salt according to any of Clauses 26, 27, 28, 29, 30, 31, 32, 33, and 34, which contains about 20% (w / w) or less, about 10% (w / w) or less,Attorney Docket: API031-WO01 (2222-189 PCT) about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other crystalline forms of Samuraciclib dihydrochloride salt. Crystalline Samuraciclib dihydrochloride salt according to any of Clauses 26, 27, 28, 29, 30, 31, 32, 33, 34, and 35, which 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 amorphous Samuraciclib dihydrochloride salt. Crystalline Samuraciclib dihydrochloride salt according to any of Clauses 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, and 36, which is substantially free of any other solid state form Samuraciclib dihydrochloride salt. Crystalline Samuraciclib according to Clause 37, which 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 solid state form of Samuraciclib dihydrochloride salt. Use of crystalline Samuraciclib or Samuraciclib dihydrochloride salt according to any of Clauses 1-38 for preparing pharmaceutical compositions of Samuraciclib or Samuraciclib salts. A pharmaceutical composition comprising crystalline Samuraciclib or Samuraciclib dihydrochloride salt according to any of Clauses 1-38, and at least one pharmaceutically acceptable excipient. Use of Samuraciclib or Samuraciclib dihydrochloride salt according to any of Clauses 1-38 for the preparation of a pharmaceutical composition and / or formulation. A process for preparing the pharmaceutical composition according to Clause 73, comprising combining crystalline Samuraciclib or Samuraciclib dihydrochloride salt according to any of Clauses 1-38 with at least one pharmaceutically acceptable excipient. Crystalline Samuraciclib or Samuraciclib dihydrochloride salt according to any of Clauses 1-38, or a pharmaceutical composition according to Clause 40, for use as a medicament.Attorney Docket: API031-WO01 (2222-189 PCT) Crystalline Samuraciclib or Samuraciclib dihydrochloride salt according to and of Clauses 1 to 38, or a pharmaceutical composition according to Clause 40, for use as a medicament for treat cancer; preferably breast cancer. A method of treating cancer comprising administering a therapeutically effective amount of crystalline Samuraciclib or Samuraciclib dihydrochloride salt according to any of Clauses 1-38, or a pharmaceutical composition according to Clause 40, to a subject in need of the treatment.

Claims

Attorney Docket: API031-WO01 (2222-189 PCT) Claims 1. Crystalline Samuraciclib.

2. Crystalline form of Samuraciclib designated Form B1, which is characterized by data selected from: (a) an X-ray powder diffraction pattern substantially as depicted in Figure 1; (b) an X-ray powder diffraction pattern having peaks at 7.6, 9.4, 12.7, 19.0 and 20.2 degrees 2-theta ± 0.2 degrees 2-theta; and combination of these data.

3. Crystalline Samuraciclib according Claim 2, which is further characterized by an X-ray powder diffraction pattern having any one, two, three, four, or five additional peaks selected from 11.8, 16.2, 16.9, 17.3 and 21.2 degrees 2-theta ± 0.2 degrees 2-theta.

4. Crystalline Samuraciclib according to Claims 2 or 3, which is characterized by an XRPD pattern having peaks at 7.6, 9.4, 11.8, 12.7, 16.2, 16.9, 17.3, 19.0, 20.2 and 21.2 degrees 2- theta ± 0.2 degrees 2-theta.

5. Crystalline Samuraciclib according to any of Claims 2, 3, or 4 which is substantially free of any other solid state form of Samuraciclib.

6. Crystalline form of Samuraciclib designated Form B2, which is characterized by data selected from: (a) an X-ray powder diffraction pattern substantially as depicted in Figure 5; (b) an X-ray powder diffraction pattern having peaks at 10.0, 18.0 and 24.6 degrees 2- theta ± 0.2 degrees 2-theta; and combination of these data; 7. Crystalline Samuraciclib according Claim 6, which is further characterized by an X-ray powder diffraction pattern having any one, two, or three additional peaks selected from 6.7, 12.3 and 17.1 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API031-WO01 (2222-189 PCT) 8. Crystalline Samuraciclib according to Claims 6 or 7, which is characterized by an XRPD pattern having peaks at 6.7, 10.0, 12.3, 17.1, 18.0 and 24.6 degrees 2-theta ± 0.2 degrees 2- theta.

9. Crystalline Samuraciclib according to any of Claims 6, 7, or 8 which is substantially free of any other solid state form of Samuraciclib.

10. Crystalline Samuraciclib dihydrochloride salt.

11. Crystalline form of Samuraciclib dihydrochloride salt designated Form H4 which is characterized by data selected from: (a) an X-ray powder diffraction pattern substantially as depicted in Figure 4; (b) an X-ray powder diffraction pattern having peaks at 7.3, 15.0 and 23.1 degrees 2- theta ± 0.2 degrees 2-theta; and combination of these data.

12. Crystalline Samuraciclib dihydrochloride salt according Claim 11, which is further characterized by an X-ray powder diffraction pattern having any one, two, or three additional peaks selected from 8.1, 15.4 and 21.8 degrees 2-theta ± 0.2 degrees 2-theta.

13. Crystalline Samuraciclib dihydrochloride salt according to Claims 11 or 12, which is characterized by an XRPD pattern having peaks at 7.3, 8.1, 15.0, 15.4, 21.8 and 23.1 degrees 2-theta ± 0.2 degrees 2-theta.

14. Crystalline Samuraciclib according to any of Claims 11, 12, or 13 which is substantially free of any other solid state form of Samuraciclib or Samuraciclib hydrochloride.

15. Use of crystalline Samuraciclib or Samuraciclib dihydrochloride salt according to any of Claims 1-14 for preparing pharmaceutical compositions of Samuraciclib or Samuraciclib salts.

16. A pharmaceutical composition comprising crystalline Samuraciclib or Samuraciclib dihydrochloride salt according to any of Claims 1-14, and at least one pharmaceutically acceptable excipient.Attorney Docket: API031-WO01 (2222-189 PCT) 17. Use of Samuraciclib or Samuraciclib dihydrochloride salt according to any of Claims 1-14 for the preparation of a pharmaceutical composition and / or formulation.

18. A process for preparing the pharmaceutical composition according to Claim 16, comprising combining crystalline Samuraciclib or Samuraciclib dihydrochloride salt according to any of Claims 1-14 with at least one pharmaceutically acceptable excipient.

19. Crystalline Samuraciclib or Samuraciclib dihydrochloride salt according to any of Claims 1-14, or a pharmaceutical composition according to Claim 16, for use as a medicament.

20. Crystalline Samuraciclib or Samuraciclib dihydrochloride salt according to and of Claims 1 to 14, or a pharmaceutical composition according to Claim 16, for use as a medicament for treating cancer; preferably breast cancer.

21. A method of treating cancer comprising administering a therapeutically effective amount of crystalline Samuraciclib or Samuraciclib dihydrochloride according to any of Claims 1- 14, or a pharmaceutical composition according to Claim 16, to a subject in need of the treatment.

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