Solid forms of gusacitinib

Abstract

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

Description

[Technical field]

[0001] The present disclosure encompasses solid forms of gusacitinib, in embodiments crystalline polymorphs of gusacitinib, processes for their preparation, and pharmaceutical compositions thereof. [Background technology]

[0002] Gusacitinib, 2-[1-[4-[4-(4-hydroxypiperidin-1-yl)anilino]-5-oxo-6H-pyrimido[4,5-d]pyridazin-2-yl]piperidin-4-yl]acetonitrile, has the following chemical structure: [ka]

[0003] Gusacitinib, an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, is in development for the treatment of moderate to severe chronic hand eczema. It is also in clinical studies for the treatment of moderate to severe atopic dermatitis.

[0004] This compound is disclosed in US Pat. No. 8,729,079.

[0005] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. Single molecules can be characterized by unique crystal structures, as well as melting points, thermal behavior (measured, for example, by thermogravimetric analysis ("TGA") or differential scanning calorimetry ("DSC")), X-ray diffraction (XRD) patterns, infrared absorption fingerprints, and solid state ( 13 C) Various polymorphs may occur that have the physical properties of the NMR spectrum. One or more of these techniques may be used to distinguish various polymorphs of a compound.

[0006] Different salts and solid forms (including solvated forms) of an active pharmaceutical ingredient may have different properties. Such variations in the properties of different salts and solid forms and solvates may provide a basis for improving formulations, for example, by promoting better processing or handling characteristics, favorably changing the dissolution profile, or improving stability (polymorphic as well as chemical stability) and shelf life. These variations in the properties of different salts and solid forms may also improve the final dosage form, for example, if they serve to improve bioavailability. Different salts and solid forms and solvates of an active pharmaceutical ingredient may also give rise to different polymorphs or crystalline forms, thereby providing further opportunities for evaluating the variations in properties and characteristics of the solid active pharmaceutical ingredient.

[0007] The discovery of new solid forms and solvates of a drug can result in materials with desirable processing characteristics, such as ease of handling, processing, storage stability, and purification, or intermediate crystalline forms that facilitate conversion to other polymorphs as desired. New solid forms of a pharma- ceutically useful compound can also provide an opportunity to improve the performance characteristics of a drug. The forms can provide products with different properties, including, for example, different crystal habits, higher crystallinity, or polymorphic stability, thereby expanding the repertoire of materials available to formulation scientists for formulation optimization, by imparting better processing or handling characteristics, improved dissolution profiles, or improved shelf life (chemical / physical stability). For at least these reasons, there is a need for additional solid forms of gusacitinib, including solvated forms. Summary of the Invention

[0008] The present disclosure provides crystalline polymorphs of gusacitinib, processes for their preparation, and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other forms of gusacitinib or salts of gusacitinib.

[0009] The present disclosure provides crystalline polymorphs of gusacitinib for use in the preparation of pharmaceutical compositions and / or formulations for use in medicine, in embodiments for treating skin / inflammatory diseases, in particular for the treatment of moderate to severe chronic hand eczema, or moderate to severe atopic dermatitis, in particular for the treatment of moderate to severe chronic hand eczema.

[0010] The present disclosure provides crystalline polymorphs of gusacitinib for use in medicine, including for the treatment of skin / inflammatory diseases, particularly for the treatment of moderate to severe chronic hand eczema or moderate to severe atopic dermatitis, particularly for the treatment of moderate to severe chronic hand eczema.

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

[0012] In another aspect, the present disclosure provides a pharmaceutical composition comprising any one or combination of crystalline polymorphs of gusacitinib according to the present disclosure.

[0013] The present disclosure includes a process for preparing the above-mentioned pharmaceutical composition, comprising combining any one or a combination of crystalline polymorphs of gusacitinib with at least one pharma- ceutically acceptable excipient.

[0014] The crystalline polymorphs of gusacitinib and pharmaceutical compositions or formulations of the crystalline polymorphs of gusacitinib defined herein can be used as medicaments, such as for the treatment of skin / inflammatory diseases, in particular for the treatment of moderate to severe chronic hand eczema or moderate to severe atopic dermatitis, in particular for the treatment of moderate to severe chronic hand eczema.

[0015] The present disclosure also provides a method of treating a skin disease by administering a therapeutically effective amount of any one or combination of the crystalline polymorphs of gusacitinib disclosed herein, or at least one of the above pharmaceutical compositions, to a subject suffering from or otherwise in need of treatment of a skin disease.

[0016] The present disclosure also provides the use of at least one of the crystalline polymorphs of gusacitinib of the present disclosure or the pharmaceutical compositions described above for the manufacture of a medicament for treating a skin disease / inflammatory disease, particularly for the treatment of moderate to severe chronic hand eczema or moderate to severe atopic dermatitis, particularly for the treatment of moderate to severe chronic hand eczema. [Brief description of the drawings]

[0017] [Figure 1] 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of gusacitinib form GS1.

[0018] [Diagram 2] 1 shows a characteristic XRPD of gusacitinib form GS2.

[0019] [Diagram 3] 1 shows a characteristic XRPD of gusacitinib form GS3.

[0020] [Figure 4] 1 shows a characteristic XRPD of gusacitinib form GS4.

[0021] [Diagram 5] 1 shows a characteristic XRPD of gusacitinib form GS5.

[0022] [Figure 6] 1 shows a characteristic XRPD of gusacitinib form GS6.

[0023] [Figure 7] 1 shows a characteristic XRPD of gusacitinib form GS7.

[0024] [Figure 8] 1 shows a characteristic XRPD of gusacitinib form GS8.

[0025] [Figure 9]1 shows a characteristic XRPD of gusacitinib form GS9.

[0026] [Figure 10] 1 shows a characteristic XRPD of gusacitinib HCl salt form GHCl1.

[0027] [Figure 11] 1 shows a characteristic XRPD of gusacitinib HCl salt form GHCl2.

[0028] [Figure 12] 1 shows a characteristic XRPD of gusacitinib HCl salt form GHCl3.

[0029] [Figure 13] 1 shows a characteristic XRPD of gusacitinib HCl salt form GHCl4.

[0030] [Figure 14] FIG. 1 shows a characteristic XRPD of gusacitinib HCl salt form GHCl5.

[0031] [Figure 15] FIG. 1 shows a characteristic XRPD of gusacitinib HCl salt form GHCl6.

[0032] [Figure 16] 1 shows a characteristic XRPD of gusacitinib HCl salt form GHCl7.

[0033] [Figure 17] 1 shows a characteristic XRPD of gusacitinib HCl salt form GHCl8. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] The present disclosure encompasses solid forms of gusacitinib, processes for its preparation, and pharmaceutical compositions thereof.

[0035] The solid forms or polymorphic forms of gusacitinib or gusacitinib HCl described in any aspect or embodiment of the present disclosure may be polymorphically pure or substantially free of any other forms. A solid form (or polymorph) may be referred to herein as being polymorphically pure or substantially free of any other solid (or polymorphic) forms. As used herein in this context, the phrase "substantially free of any other forms" is understood to mean that the solid 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 form of the subject compound, as measured, for example, by XRPD. For example, any of the solid forms of gusacitinib HCl described herein may be substantially free of any other solid forms of gusacitinib HCl. Similarly, any of the solid forms of gusacitinib described herein may be substantially free of any other solid forms of gusacitinib. Thus, a crystalline polymorph of gusacitinib described herein as being substantially free of any other solid forms will be understood to contain more than about 80% (w / w), more than about 90% (w / w), more than about 95% (w / w), more than about 98% (w / w), more than about 99% (w / w), or about 100% of the subject crystalline polymorph of gusacitinib. Similarly, a crystalline polymorph of gusacitinib HCl according to any aspect or embodiment of the present disclosure that is polymorphically pure or substantially free of any other solid form will 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 gusacitinib HCl. In some embodiments of the present disclosure, the described crystalline polymorph of gusacitinib or salt 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 polymorphs of gusacitinib and / or gusacitinib salts.

[0036] Depending on which other crystalline polymorphs are compared, the crystalline polymorphs 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 with respect to polymorphic transformation and thermal and mechanical stability, stability against dehydration and / or storage stability, low content of residual solvents, lower degree of hygroscopicity, flowability, and advantageous processing and handling properties such as compressibility and bulk density.

[0037] A solid form, e.g., a crystalline or amorphous form, may be referred to herein as being characterized by graphical data "as depicted in" or "substantially depicted in" a figure. Such data include, for example, powder X-ray diffraction patterns and solid-state NMR spectra. As is well known in the art, graphical data potentially provides additional technical means to further define each solid form (a so-called "fingerprint") that cannot necessarily be described by reference to numerical values ​​or peak locations alone. In any event, those skilled in the art will understand that such graphical representations of data may be subject to slight variations, e.g., in the relative intensities of peaks and peak positions, due to certain factors, such as, but not limited to, variations in instrument response and variations in sample concentration and purity, well known to those skilled in the art. Nevertheless, those skilled in the art can easily compare the graphical data of the figures herein with graphical data generated for an unknown crystalline form and can ascertain whether the two sets of graphical data characterize the same crystalline form or two different crystalline forms. Thus, a crystalline form of gusacitinib referred to herein as being characterized by graphical data "as depicted in" or "substantially as depicted in" a figure will be understood to include any crystalline form of gusacitinib characterized using graphical data having such slight variations, as would be known to one of skill in the art, in comparison to the figure.

[0038] As used herein, unless otherwise stated, the term "anhydrous" with respect to a crystalline form of gusacitinib refers to a crystalline form of gusacitinib that does not contain any water of crystallization (or other solvent) in a stoichiometric amount defined within the crystal. Furthermore, an "anhydrous" form generally does not contain more than 1% (w / w) of either water or organic solvent, e.g., as measured by TGA.

[0039] The term "solvate" as used herein, unless otherwise specified, refers to a crystalline form that incorporates a solvent into 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 stoichiometric or non-stoichiometric amounts.

[0040] As used herein, unless otherwise stated, XRPD measurements are made using copper Kα radiation at a wavelength of 1.5418 Å. XRPD peaks reported herein are measured using Cu Kα radiation, λ=1.5418 Å, typically at a temperature of 25±3° C. or about 22-25° C.

[0041] An object, e.g., a reaction mixture, may be characterized herein as being at or at "room temperature" or "ambient temperature," often abbreviated as "RT." This means that the temperature of the object is close to or the same as the temperature of the space in which the object is located, e.g., a room or fume hood. Typically, room temperature is about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0042] The amount of solvent used in a chemical process, such as a reaction or crystallization, may be referred to herein as a numerical "volume" or "vol" or "V". For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10 V) of solvent. In this context, this expression is understood to mean milliliters of solvent per gram of suspended material, whereby suspending 5 grams of material in 10 volumes of solvent means that the solvent is used in an amount of 10 milliliters of solvent per gram of suspended material, or in this example, 50 mL of solvent. In another context, the term "v / v" may be used to indicate the number of volumes of solvent added to a liquid mixture based on the volume of the mixture. For example, adding solvent X (1.5 v / v) to 100 mL of a reaction mixture indicates that 150 mL of solvent X has been added.

[0043] A process or step may be referred to herein as being performed "overnight." This refers, for example, to a process or step, to a time period spanning overnight hours during which the process or step may not be actively observed. This time period may be from about 8 to about 20 hours, or from about 10 to 18 hours, and in some cases, about 16 hours.

[0044] As used herein, the term "reduced pressure" refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is from about 10 mbar to about 50 mbar.

[0045] As used herein, unless otherwise specified, the term "ambient conditions" refers to atmospheric pressure and a temperature of 22-24°C.

[0046] In one embodiment, the present invention provides crystalline gusacitinib and crystalline gusacitinib HCl salt.

[0047] The present disclosure includes a crystalline polymorph of gusacitinib designated GS1. Crystalline form GS1 of gusacitinib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 1; an X-ray powder diffraction pattern having peaks at 6.4, 7.3, 11.8, 17.6, and 23.8 °2θ±0.2 °2θ; and combinations of these data.

[0048] Crystalline form GS1 may be further characterized by an X-ray powder diffraction pattern having peaks at 6.4, 7.3, 11.8, 17.6, and 23.8 °2θ±0.2 °2θ, and also any one, two or three additional peaks selected from 14.6, 18.6, and 25.8 °2θ±0.2 °2θ.

[0049] In one embodiment of the present disclosure, the crystalline form GS1 of gusacitinib is isolated.

[0050] In another embodiment, the crystalline form GS1 may be in a solvated form, in particular a DMF-water solvate.

[0051] Form GS1 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0052] In another embodiment, the disclosure includes a crystalline polymorph of gusacitinib designated GS2. Crystalline form GS2 of gusacitinib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 2; an X-ray powder diffraction pattern having peaks at 4.4, 6.8, 8.9, and 10.3 °2θ ± 0.2 °2θ, and also having additional peaks at any one, two, three, four or five of 3.4, 17.1, 18.3, 20.8, and 23.2 °2θ ± 0.2 °2θ; and combinations of these data.

[0053] Alternatively, gusacitinib form GS2 may be characterized by an X-ray powder diffraction pattern having peaks at 4.4, 6.8, 8.9, 10.3, 20.8 °2θ±0.2 °2θ. Gusacitinib form GS2 may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 4.4, 6.8, 8.9, 10.3, 20.8 °2θ±0.2 °2θ, and optionally, any one, two, three, or four additional peaks at 13.4, 17.1, 18.3, and 23.2 °2θ±0.2 °2θ.

[0054] The crystalline form GS2 of gusacitinib may be further characterized by an X-ray powder diffraction pattern with peaks at 4.4, 6.8, 8.9, 10.3, 13.4, 17.1, 18.3, 20.8, and 23.2 degrees 2θ±0.2 degrees 2θ.

[0055] In one embodiment of the present disclosure, the crystalline form GS2 of gusacitinib is isolated.

[0056] In another embodiment, the crystalline form GS2 of gusacitinib may be anhydrous.

[0057] Form GS2 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0058] Gusacitinib form GS2 is stable under all stress conditions tested (e.g., under vigorous crushing, under 2 tonnes of pressure, high humidity (up to 100% RH for 7 days) and high temperature (up to 100° C.).

[0059] In another embodiment, the disclosure provides a crystalline polymorph of gusacitinib designated GS3. Crystalline form GS3 of gusacitinib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 3; an X-ray powder diffraction pattern having peaks at 4.4, 6.8, 8.9, and 10.3 °2θ ± 0.2 °2θ, and also having any one, two, three, four or five additional peaks selected from 14.2, 16.8, 17.5, 21.1, and 25.2 °2θ ± 0.2 °2θ; and combinations of these data.

[0060] Alternatively, gusacitinib form GS3 may be characterized by an X-ray powder diffraction pattern having peaks at 4.4, 6.8, 8.9, 10.3, and 17.5 °2θ±0.2 °2θ, and optionally having any one, two, three, or four additional peaks at 14.2, 16.8, 21.1, and 25.2 °2θ±0.2 °2θ.

[0061] Gusacitinib form GS3 may alternatively have an X-ray powder diffraction pattern having peaks at 4.4, 6.8, 8.9, 10.3, and 13.1 °2θ ± 0.2 °2θ, and also having any one, two, three, four or five additional peaks selected from 14.2, 16.8, 17.5, 21.1, and 25.2 °2θ ± 0.2 °2θ; or having peaks at 4.4, 6.8, 8.9, 10.3, and 24.1 °2θ ± 0.2 °2θ, and also having any one, two, three, four or five additional peaks selected from 14.2, 16.8, 17.5, 21. or an X-ray powder diffraction pattern having peaks at 4.4, 6.8, 8.9, 10.3, and 28.5 °2θ ± 0.2 °2θ, and also having any one, two, three, four or five additional peaks selected from 14.2, 16.8, 17.5, 21.1, and 25.2 °2θ ± 0.2 °2θ.

[0062] Gusacitinib form GS3 may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 4.4, 6.8, 8.9, 10.3 °2θ ± 0.2 °2θ, and any two or three of 13.1, 24.1 or 28.5 °2θ ± 0.2 °2θ (particularly two peaks at 13.1 and 24.1 °2θ ± 0.2 °2θ, or two peaks at 13.1 and 28.5, or two peaks at 24.1 and 28.5, or three peaks at 13.1, 24.1 and 28.5), and further having any one, two, three, four or five additional peaks selected from 14.2, 16.8, 17.5, 21.1 and 25.2 °2θ ± 0.2 °2θ.

[0063] Alternatively, gusacitinib form GS3 is an X-ray powder diffraction pattern having peaks at 4.4, 6.8, 8.9, 10.3, 13.1, and 17.5 °2θ ± 0.2 °2θ, and optionally with additional peaks at any one, two, three, or four of 14.2, 16.8, 21.1, and 25.2 °2θ ± 0.2 °2θ (particularly, form GS3 may be characterized by an XRPD pattern having peaks at 4.4, 6.8, 8.9, 10.3, 13.1, 14.2, 16.8, 17.5, 21.1, and 25.2); or an X-ray powder diffraction pattern having peaks at 4.4, 6.8, 8.9, 10.3, 17.5, and 24.1 °2θ ± 0.2 °2θ, and optionally with additional peaks at any one, two, three, or four of 14.2, 16.8, 21.1, and 25.2 °2θ ± 0.2 °2θ (particularly, form GS3 can be characterized by an XRPD pattern having peaks at 4.4, 6.8, 8.9, 10.3, 14.2, 16.8, 17.5, 21.1, 24.1, and 25.2 °2θ ± 0.2 °2θ); or an X-ray powder diffraction pattern having peaks at 4.4, 6.8, 8.9, 10.3, 17.5, and 28.5 °2θ ± 0.2 °2θ, and optionally with additional peaks at any one, two, three, or four of 14.2, 16.8, 21.1, and 25.2 °2θ ± 0.2 °2θ (particularly, form GS3 can be characterized by an XRPD pattern having peaks at 4.4, 6.8, 8.9, 10.3, 14.2, 16.8, 17.5, 21.1, 25.2, and 28.5 °2θ ± 0.2 °2θ); or an X-ray powder diffraction pattern having peaks at 4.4, 6.8, 8.9, 10.3, 13.1, and 24.1 °2θ ± 0.2 °2θ, and optionally with additional peaks at any one, two, three, or four of 14.2, 16.8, 21.1, and 25.2 °2θ ± 0.2 °2θ (particularly, form GS3 can be characterized by an XRPD pattern having peaks at 4.4, 6.8, 8.9, 10.3, 13.1, 14.2, 16.8, 17.5, 21.1, 24.1, and 25.2 °2θ ± 0.2 °2θ); or an X-ray powder diffraction pattern having peaks at 4.4, 6.8, 8.9, 10.3, 13.1, 17.5, and 28.5 °2θ ± 0.2 °2θ, and optionally with additional peaks at any one, two, three, or four of 14.2, 16.8, 21.1, and 25.2 °2θ ± 0.2 °2θ (particularly, form GS3 can be characterized by an XRPD pattern having peaks at 4.4, 6.8, 8.9, 10.3, 13.1, 14.2, 16.8, 17.5, 21.1, 25.2, and 28.5 °2θ ± 0.2 °2θ); or an X-ray powder diffraction pattern having peaks at 4.4, 6.8, 8.9, 10.3, 17.5, 24.1, and 28.5 °2θ ± 0.2 °2θ, and optionally with additional peaks at any one, two, three, or four of 14.2, 16.8, 21.1, and 25.2 °2θ ± 0.2 °2θ (particularly, form GS3 can be characterized by an XRPD pattern having peaks at 4.4, 6.8, 8.9, 10.3, 14.2, 16.8, 17.5, 21.1, 24.1, 25.2, and 28.5 °2θ ± 0.2 °2θ); or

[0043] In one embodiment, form GS3 is characterized by an X-ray powder diffraction pattern having peaks at 4.4, 6.8, 8.9, 10.3, 13.1, 17.5, 24.1, and 28.5 °2θ ± 0.2 °2θ, and optionally, additional peaks at any one, two, three, or four of 14.2, 16.8, 21.1, and 25.2 °2θ ± 0.2 °2θ (particularly, form GS3 can be characterized by an XRPD pattern having peaks at 4.4, 6.8, 8.9, 10.3, 13.1, 14.2, 16.8, 17.5, 21.1, 24.1, 25.2, and 28.5 °2θ ± 0.2 °2θ).

[0064] The crystalline form GS3 of gusacitinib may be further characterized by an X-ray powder diffraction pattern with peaks at 4.4, 6.8, 8.9, 10.3, 14.2, 16.8, 17.5, 21.1, and 25.2 degrees 2θ±0.2 degrees 2θ.

[0065] In any embodiment or aspect of the present disclosure, the crystalline form GS3 of gusacitinib is isolated. In any embodiment or aspect of the present disclosure, the crystalline form GS3 of gusacitinib is anhydrous.

[0066] In one embodiment of the present disclosure, the crystalline form GS3 of gusacitinib is isolated.

[0067] The crystalline form GS3 can be anhydrous.

[0068] Form GS3 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0069] Gusacitinib form GS3 is stable under all stress conditions tested (e.g., under vigorous crushing, under 2 tonnes of pressure, high humidity (up to 100% RH for 7 days) and high temperature (up to 100° C.).

[0070] In another embodiment, the disclosure includes a crystalline polymorph of gusacitinib designated GS4. Crystalline form GS4 of gusacitinib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 2; an X-ray powder diffraction pattern having peaks at 5.9, 7.4, 11.3, 20.2, 24.4 °2θ ± 0.2 °2θ, and also having additional peaks at any one, two, three, four or five of 11.8, 12.1, 17.0, 17.8, and 23.8 °2θ ± 0.2 °2θ; and combinations of these data.

[0071] Alternatively, form GS4 of gusacitinib may be characterized by an X-ray powder diffraction pattern having peaks at 5.9, 7.4, 11.3, 11.8, 20.2, 24.4 °2θ ± 0.2 °2θ, and also having additional peaks at any one, two, three, or four of 12.1, 17.0, 17.8, and 23.8 °2θ ± 0.2 °2θ; and combinations of these data. Form GS4 of gusacitinib may optionally be characterized by an X-ray powder diffraction pattern having peaks at 5.9, 7.4, 11.3, 12.1, 20.2, 24.4 °2θ ± 0.2 °2θ, and also having additional peaks at any one, two, three, or four of 11.8, 17.0, 17.8, and 23.8 °2θ ± 0.2 °2θ. Alternatively, form GS4 of gusacitinib may optionally be characterized by an X-ray powder diffraction pattern having peaks at 5.9, 7.4, 11.3, 11.8, 12.1, 20.2, 24.4 °2θ±0.2 °2θ, and any one, two or three additional peaks at 17.0, 17.8 and 23.8 °2θ±0.2 °2θ.

[0072] The crystalline form GS4 of gusacitinib may be further characterized by an X-ray powder diffraction pattern with peaks at 5.9, 7.4, 11.3, 11.8, 12.1, 17.0, 17.8, 20.2, 23.8, and 24.4 degrees 2θ±0.2 degrees 2θ.

[0073] In one embodiment of the present disclosure, the crystalline form GS4 of Guanidine is isolated.

[0074] In another embodiment, the crystalline form GS4 of gusacitinib may be anhydrous.

[0075] Form GS4 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0076] Gusacitinib form GS4 is stable under all stress conditions tested (e.g., under vigorous crushing, under 2 tonnes of pressure, high humidity (up to 80% RH for 7 days) and high temperature (up to 100° C.).

[0077] In a further embodiment, the disclosure provides a crystalline polymorph of gusacitinib designated GS5. Crystalline form GS5 of gusacitinib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 5; an X-ray powder diffraction pattern having peaks at 17.4, 18.4, 20.9, 26.2, and 29.8 °2θ ± 0.2 °2θ, and also having any one, two, three, or four additional peaks selected from 8.9, 14.7, 20.1, and 23.6 °2θ ± 0.2 °2θ; and combinations of these data.

[0078] Alternatively, gusacitinib form GS5 may be characterized by an X-ray powder diffraction pattern having peaks at 17.4, 18.8, 20.9, 26.2, and 29.8 °2θ ± 0.2 °2θ, and also having any one, two, three, or four additional peaks selected from 8.9, 14.7, 20.1, and 23.6 °2θ ± 0.2 °2θ; and combinations of these data.

[0079] Alternatively, form GS5 of gusacitinib may be characterized by an X-ray powder diffraction pattern having peaks at 17.4, 18.4, 20.1, 20.9, 26.2, and 29.8 °2θ±0.2 °2θ, and also having any one, two, or three additional peaks selected from 8.9, 14.7, and 23.6 °2θ±0.2 °2θ; and combinations of these data. Further alternatively, form GS5 of gusacitinib may be characterized by an X-ray powder diffraction pattern having peaks at 17.4, 18.8, 20.1, 20.9, 26.2, and 29.8 °2θ±0.2 °2θ, and also having any one, two, three, or four additional peaks selected from 8.9, 14.7, and 23.6 °2θ±0.2 °2θ.

[0080] The crystalline form GS5 of gusacitinib may be further characterized by an X-ray powder diffraction pattern with peaks at 8.9, 14.7, 17.4, 18.4, 20.1, 20.9, 23.6, 26.2, and 29.8 °2θ±0.2 °2θ.

[0081] In one embodiment of the present disclosure, the crystalline form GS5 of gusacitinib is isolated.

[0082] Crystalline form GS5 may be a DMSO solvate.

[0083] Form GS5 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0084] In another embodiment, the disclosure includes a crystalline polymorph of gusacitinib designated GS6. Crystalline form GS6 of gusacitinib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 6; an X-ray powder diffraction pattern having peaks at 11.6, 14.7, 18.3, 19.6, and 23.9 °2θ±0.2 °2θ; and combinations of these data.

[0085] The crystalline form GS6 of gusacitinib may be characterized by an X-ray powder diffraction pattern having peaks at 11.6, 14.7, 18.3, 19.6, and 23.9 °2θ±0.2 °2θ, and also any one, two, three, or four additional peaks selected from 7.4, 13.5, 20.2, and 26.2 °2θ±0.2 °2θ.

[0086] The crystalline form GS6 of gusacitinib may be further characterized by an X-ray powder diffraction pattern with peaks at 7.4, 11.6, 13.5, 14.7, 18.3, 19.6, 20.2, 23.9, and 26.2 degrees 2θ±0.2 degrees 2θ.

[0087] In one embodiment of the present disclosure, the crystalline form GS6 of gusacitinib is isolated.

[0088] In another embodiment, the crystalline form GS6 of gusacitinib may be a hydrate, preferably a hydrate containing water in an amount of about 13 to about 25% by weight; or about 16 to about 22% by weight. More preferably, the crystalline form GS6 of gusacitinib according to any aspect or embodiment of the present disclosure may be a pentahydrate.

[0089] Form GS6 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0090] In a further embodiment, the disclosure provides a crystalline polymorph of gusacitinib designated GS7. Crystalline form GS7 of gusacitinib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 7; an X-ray powder diffraction pattern having peaks at 6.3, 9.6, 16.7, 23.3 and 26.1 °2θ±0.2 °2θ; and combinations of these data.

[0091] Crystalline form GS7 may be characterized by an X-ray powder diffraction pattern having peaks at 6.3, 9.6, 16.7, 23.3, and 26.1 °2θ±0.2 °2θ, and also any one, two or three additional peaks selected from 5.8, 20.1, and 29.5 °2θ±0.2 °2θ.

[0092] The crystalline form of gusacitinib, GS7, may be further characterized by an X-ray powder diffraction pattern with peaks at 5.8, 6.3, 9.6, 16.7, 20.1, 23.3, 26.1, and 29.5 degrees 2θ±0.2 degrees 2θ.

[0093] In one embodiment of the present disclosure, the crystalline form GS7 of gusacitinib is isolated.

[0094] Form GS7 of gusacitinib according to any aspect or embodiment of the present disclosure may contain water in an amount of about 0.5 to about 3.0% by weight; about 0.8 to 3.8% by weight, or about 1.0 to about 2.5% by weight.

[0095] The gusacitinib form GS7 described in any aspect or embodiment of the present disclosure may be a hydrate, preferably a hydrate containing water in an amount of about 0.5 to about 3.0% by weight; about 0.8 to 3.8% by weight, or about 1.0 to about 2.5% by weight. More preferably, the gusacitinib form GS7 described in any aspect or embodiment of the present disclosure may be a hemihydrate.

[0096] The gusacitinib form GS7 may be a hydrate; more preferably a hemihydrate.

[0097] Form GS7 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0098] In a further embodiment, the disclosure provides a crystalline polymorph of gusacitinib designated GS8. Crystalline form GS8 of gusacitinib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 8; an X-ray powder diffraction pattern having peaks at 6.9, 10.2, 23.0, 25.8 and 27.9 °2θ±0.2 °2θ; and combinations of these data.

[0099] Crystalline form GS8 may be characterized by an X-ray powder diffraction pattern having peaks at 6.9, 10.2, 23.0, 25.8, and 27.9 °2θ±0.2 °2θ, and also any one, two or three additional peaks selected from 4.4, 16.9, and 21.1 °2θ±0.2 °2θ.

[0100] The crystalline form GS8 of gusacitinib may be further characterized by an X-ray powder diffraction pattern with peaks at 4.4, 6.9, 10.2, 16.9, 21.1, 23.0, 25.8, and 27.9 degrees 2θ±0.2 degrees 2θ.

[0101] In one embodiment of the present disclosure, the crystalline form GS8 of gusacitinib is isolated.

[0102] The crystalline form GS8 of gusacitinib described in any aspect or embodiment of the present disclosure may contain water in an amount of about 1.8 to about 5.8% by weight; about 2.2 to 5.5% by weight, or about 2.5 to about 5.0% by weight.

[0103] Crystalline form GS8 according to any aspect or embodiment of the present disclosure may be a hydrate, preferably a hydrate containing water in an amount of about 1.8 to about 5.8% by weight; about 2.2 to 5.5% by weight, or about 2.5 to about 5.0% by weight. More preferably, crystal form GS8 according to any aspect or embodiment of the present disclosure is a monohydrate.

[0104] The crystalline form GS8 may be a hydrate, more preferably a monohydrate.

[0105] Form GS8 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0106] In a further embodiment, the disclosure provides a crystalline polymorph of gusacitinib designated GS9. Crystalline form GS9 of gusacitinib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 9; an X-ray powder diffraction pattern having peaks at 5.9, 8.8, 10.3, 16.9 and 25.1 °2θ±0.2 °2θ; and combinations of these data.

[0107] The crystalline form GS9 of gusacitinib may be further characterized by an X-ray powder diffraction pattern having peaks at 5.9, 8.8, 10.3, 16.9, and 25.1 °2θ±0.2 °2θ, and also having any one, two, three, or four additional peaks selected from 17.5, 21.2, 23.7, and 28.0 °2θ±0.2 °2θ.

[0108] The crystalline form GS9 of gusacitinib may be further characterized by an X-ray powder diffraction pattern with peaks at 5.9, 8.8, 10.3, 16.9, 17.5, 21.2, 23.7, 25.1, and 28.0 degrees 2θ±0.2 degrees 2θ.

[0109] In one embodiment of the present disclosure, the crystalline form GS9 of gusacitinib is isolated.

[0110] Form GS9 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0111] In another embodiment, the present invention discloses a crystalline gusacitinib HCl salt.

[0112] In a further embodiment, the disclosure discloses a crystalline polymorph of gusacitinib HCl salt designated as GHCl1. The crystalline form GHCl1 of gusacitinib HCl 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 10; an X-ray powder diffraction pattern having peaks at 5.1, 8.9, 10.1, 15.3, and 27.2 °2θ±0.2 °2θ; and combinations of these data.

[0113] The crystalline form GHCl1 of the gusacitinib HCl salt may be further characterized by an X-ray powder diffraction pattern having peaks at 5.1, 8.9, 10.1, 15.3, and 27.2 °2θ ± 0.2 °2θ, and also having any one, two, three, or four additional peaks selected from 17.5, 21.2, 23.7, and 28.0 °2θ ± 0.2 °2θ. Alternatively, the crystalline form GHCl1 of the gusacitinib HCl salt may be characterized by an X-ray powder diffraction pattern having peaks at 5.1, 8.9, 10.1, 15.3, and 27.2 °2θ ± 0.2 °2θ, and also having any one, two, or three additional peaks selected from 17.1, 20.4, and 24.4 °2θ ± 0.2 °2θ.

[0114] In a further embodiment, the crystalline form GHCl1 of the gusacitinib HCl salt may be characterized by an X-ray powder diffraction pattern with peaks at 5.1, 8.9, 10.1, 15.3, 17.5, 21.2, 23.7, 27.2, and 28.0 °2θ±0.2 °2θ. Alternatively, the crystalline form GHCl1 of the gusacitinib HCl salt may be characterized by an X-ray powder diffraction pattern with peaks at 5.1, 8.9, 10.1, 15.3, 17.1, 20.4, 24.4, and 27.2 °2θ±0.2 °2θ.

[0115] The crystalline form GHCl1 of gusacitinib HCl salt according to any aspect or embodiment of the present disclosure may contain water in an amount of about 6.5 to about 13.5% by weight; about 7.5 to about 12.5% ​​by weight, or about 8.0 to about 12.0% by weight. The crystalline form GHCl1 of gusacitinib HCl salt according to any aspect or embodiment of the present disclosure may be a hydrate, preferably a hydrate containing water in an amount of about 6.5 to about 13.5% by weight; about 7.5 to about 12.5% ​​by weight, or about 8.0 to about 12.0% by weight. More preferably, the crystalline form GHCl1 according to any aspect or embodiment of the present disclosure is a trihydrate.

[0116] In another embodiment, the crystalline form GHCl1 of gusacitinib HCl salt is a hydrate; preferably a trihydrate.

[0117] Form GHCl1 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0118] Gusacitinib HCl salt form GHCl1 is stable under all stress conditions tested (e.g., under vigorous crushing, under 2 tonnes of pressure, high humidity (up to 100% RH for 7 days) and high temperature (up to 100° C.).

[0119] In another embodiment, the present disclosure discloses a crystalline polymorph of gusacitinib HCl salt designated GHCl2. The crystalline form GHCl2 of gusacitinib HCl salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 11; an X-ray powder diffraction pattern having peaks at 6.4, 13.7, 15.6, 22.9 and 27.5 °2θ±0.2 °2θ; and combinations thereof.

[0120] The crystalline form GHCl2 of gusacitinib HCl salt may be further characterized by an X-ray powder diffraction pattern having peaks at 6.4, 13.7, 15.6, 22.9, and 27.5 °2θ±0.2 °2θ, and also having any one, two, three, or four additional peaks selected from 12.7, 14.4, 16.6, and 17.8 °2θ±0.2 °2θ.

[0121] In a further embodiment, the crystalline form GHCl2 of gusacitinib HCl salt may be characterized by an X-ray powder diffraction pattern having peaks at 6.4, 12.7, 13.7, 14.4, 15.6, 16.6, 17.8, 22.9 and 27.5 °2θ±0.2 °2θ.

[0122] The crystalline form GHCl2 of gusacitinib HCl salt may be anhydrous.

[0123] The above crystalline polymorphs of gusacitinib / gusacitinib salts can be used to prepare other crystalline polymorphs of gusacitinib, salts of gusacitinib and their solid forms.

[0124] Form GHCl2 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0125] Gusacitinib HCl salt form GHCl2 is stable under all stress conditions tested (e.g., under vigorous crushing, under 2 tonnes of pressure, high humidity (up to 100% RH for 7 days) and high temperature (up to 100° C.).

[0126] In another embodiment, the present disclosure discloses a crystalline polymorph of gusacitinib HCl salt designated GHCl3. The crystalline form GHCl3 of gusacitinib HCl 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 12; an X-ray powder diffraction pattern having peaks at 5.5, 16.7, 21.0, 22.0 and 26.2 °2θ±0.2 °2θ; and combinations thereof.

[0127] The crystalline form GHCl3 of gusacitinib HCl salt may be further characterized by an X-ray powder diffraction pattern having peaks at 5.5, 16.7, 21.0, 22.0, and 26.2 °2θ ± 0.2 °2θ, and also having any one, two, three, or four additional peaks selected from 14.5, 19.0, 24.8, and 28.6 °2θ ± 0.2 °2θ.

[0128] In a further embodiment, the crystalline form GHCl3 of gusacitinib HCl salt may be characterized by an X-ray powder diffraction pattern having peaks at 5.5, 14.5, 16.7, 19.0, 21.0, 22.0, 24.8, 26.2, and 28.6 °2θ±0.2 °2θ.

[0129] The crystalline form GHCl3 of gusacitinib HCl salt according to any aspect or embodiment of the present disclosure may contain water in an amount of about 6.5 to about 13.5% by weight; about 7.5 to about 12.5% ​​by weight, or about 8.0 to about 12.0% by weight. The crystalline form GHCl3 of gusacitinib HCl salt according to any aspect or embodiment of the present disclosure may be a hydrate, preferably a hydrate containing water in an amount of about 6.5 to about 13.5% by weight; about 7.5 to about 12.5% ​​by weight, or about 8.0 to about 12.0% by weight. More preferably, the crystalline form GHCl3 according to any aspect or embodiment of the present disclosure is a trihydrate.

[0130] In another embodiment, the crystalline form GHCl3 of gusacitinib HCl salt is a hydrated form; preferably, a trihydrate form.

[0131] Form GHCl3 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0132] The gusacitinib HCl salt form GHCl3 is stable under the stress conditions tested (e.g., under strong crushing); 2 tons pressure and high humidity (up to 60% RH for 7 days).

[0133] In a further embodiment, the disclosure discloses a crystalline polymorph of gusacitinib HCl salt designated GHCl4. The crystalline form GHCl4 of gusacitinib HCl 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 13; an X-ray powder diffraction pattern having peaks at 5.8, 8.0, 14.9, 21.5 and 25.4 °2θ±0.2 °2θ; and combinations of these data.

[0134] The crystalline form GHCl4 of gusacitinib HCl salt may be further characterized by an X-ray powder diffraction pattern having peaks at 5.8, 8.0, 14.9, 21.5, and 25.4 °2θ ± 0.2 °2θ, and also having any one, two, three, four, or five additional peaks selected from 9.4, 12.7, 15.6, 17.8, and 22.9 °2θ ± 0.2 °2θ.

[0135] In a further embodiment, the crystalline form GHCl4 of gusacitinib HCl salt may be characterized by an X-ray powder diffraction pattern having peaks at 5.8, 8.0, 9.4, 12.7, 14.9, 15.6, 17.8, 21.5, 22.9 and 25.4 °2θ±0.2 °2θ.

[0136] In another embodiment, the crystalline form GHCl4 of the gusacitinib HCl salt is anhydrous form. Form GHCl4 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0137] In another embodiment, the present disclosure discloses a crystalline polymorph of gusacitinib HCl salt designated GHCl5. The crystalline form GHCl5 of gusacitinib HCl 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 14; an X-ray powder diffraction pattern having peaks at 5.2, 8.8, 16.6, 23.9 and 25.5 °2θ±0.2 °2θ; and combinations thereof.

[0138] The crystalline form GHCl5 of the gusacitinib HCl salt may be further characterized by an X-ray powder diffraction pattern having peaks at 5.2, 8.8, 16.6, 23.9, and 25.5 °2θ ± 0.2 °2θ, and also having any one, two, or three additional peaks selected from 17.7, 20.1, and 21.7 °2θ ± 0.2 °2θ.

[0139] In a further embodiment, the crystalline form GHCl5 of the gusacitinib HCl salt may be characterized by an X-ray powder diffraction pattern having peaks at 5.2, 8.8, 16.6, 17.7, 20.1, 21.7, 23.9, and 25.5 °2θ±0.2 °2θ.

[0140] In another embodiment, the crystalline form GHCl5 of gusacitinib HCl salt is a solvated form; preferably, a 1,4 dioxane solvate.

[0141] Form GHCl5 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0142] In another embodiment, the present disclosure discloses a crystalline polymorph of gusacitinib HCl salt designated GHCl6. The crystalline form GHCl6 of gusacitinib HCl salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 15; an X-ray powder diffraction pattern having peaks at 6.2, 12.8, 17.3, 20.8 and 26.6 °2θ±0.2 °2θ; and combinations thereof.

[0143] The crystalline form GHCl6 of gusacitinib HCl salt may be further characterized by an X-ray powder diffraction pattern having peaks at 6.2, 12.8, 17.3, 20.8, and 26.6 °2θ ± 0.2 °2θ, and also having any one, two, three, or four additional peaks selected from 14.3, 21.8, 25.7, and 31.7 °2θ ± 0.2 °2θ.

[0144] In a further embodiment, the crystalline form GHCl6 of gusacitinib HCl salt may be characterized by an X-ray powder diffraction pattern having peaks at 6.2, 12.8, 14.3, 17.3, 20.8, 21.8, 25.7, 26.6, and 31.7 °2θ±0.2 °2θ.

[0145] In another embodiment, the crystalline form GHCl6 of gusacitinib HCl salt may be in a solvated form, preferably a mixture of water and 1,3 dioxolane solvate.

[0146] Form GHCl6 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0147] In a further embodiment, the disclosure discloses a crystalline polymorph of gusacitinib HCl salt designated GHCl7. The crystalline form GHCl7 of gusacitinib HCl 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 16; an X-ray powder diffraction pattern having peaks at 6.0, 8.5, 13.9, 16.3, and 27.0 °2θ±0.2 °2θ; and combinations of these data.

[0148] The crystalline form GHCl7 of gusacitinib HCl salt may be further characterized by an X-ray powder diffraction pattern having peaks at 6.0, 8.5, 13.9, 16.3, and 27.0 °2θ ± 0.2 °2θ, and also having any one, two, three, or four additional peaks selected from 17.8, 21.6, 28.6, and 33.3 °2θ ± 0.2 °2θ.

[0149] In a further embodiment, the crystalline form GHCl7 of gusacitinib HCl salt may be characterized by an X-ray powder diffraction pattern having peaks at 6.0, 8.5, 13.9, 16.3, 17.8, 21.6, 27.0, 28.6, and 33.3 °2θ±0.2 °2θ.

[0150] In another embodiment, the crystalline form GHCl7 of gusacitinib HCl salt is a solvated form; preferably, a 1,2-dichloroethane solvate.

[0151] Form GHCl7 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0152] The present disclosure discloses a crystalline polymorph of gusacitinib HCl salt designated GHCl8. The crystalline form of gusacitinib HCl salt, GHCl8, may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 17; an X-ray powder diffraction pattern having peaks at 5.8, 11.4, 17.1, 24.6 and 27.5 °2θ±0.2 °2θ; and combinations of these data.

[0153] The crystalline form GHCl8 of gusacitinib HCl salt may be further characterized by an X-ray powder diffraction pattern having peaks at 5.8, 11.4, 17.1, 24.6, and 27.5 °2θ±0.2 °2θ, and also any one or two additional peaks selected from 9.0 and 28.6 °2θ±0.2 °2θ.

[0154] In a further embodiment, the crystalline form GHCl8 of gusacitinib HCl salt may be characterized by an X-ray powder diffraction pattern having peaks at 5.8, 9.0, 11.4, 17.1, 24.6, 27.5, and 28.6 °2θ±0.2 °2θ.

[0155] The crystalline form GHCl8 of gusacitinib HCl salt according to any aspect or embodiment of the present disclosure may contain water in an amount of about 5.0 to about 10.0% by weight; about 5.5 to about 9.5% by weight, or about 6.0 to about 9.0% by weight. The crystalline form GHCl8 of gusacitinib HCl salt according to any aspect or embodiment of the present disclosure may be a hydrate, preferably a hydrate containing water in an amount of about 5.0 to about 10.0% by weight; about 5.5 to about 9.5% by weight, or about 6.0 to about 9.0% by weight. More preferably, the crystalline form GHCl8 according to any aspect or embodiment of the present disclosure is a dihydrate.

[0156] In another embodiment, the crystalline form of gusacitinib HCl salt GHCl8 is a hydrated form; preferably a dihydrate form.

[0157] Form GHCl8 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0158] Gusacitinib HCl salt form GHCl8 is stable under all stress conditions tested (e.g., under vigorous crushing, under 2 tonnes of pressure, high humidity (up to 100% RH for 7 days) and high temperature (up to 100° C.).

[0159] The present disclosure provides crystalline polymorphs of gusacitinib / gusacitinib salts for use in preparing pharmaceutical compositions.

[0160] The present disclosure also encompasses the use of the disclosed crystalline polymorphs of gusacitinib for the preparation of a pharmaceutical composition of the crystalline polymorphs of gusacitinib.

[0161] The present disclosure includes a process for preparing the above-mentioned pharmaceutical composition, which comprises combining any one or a combination of the crystalline polymorphs of gusacitinib disclosed herein with at least one pharma- ceutically acceptable excipient.

[0162] The pharmaceutical combination or formulation of the present disclosure contains any one or combination of the solid forms of gusacitinib of the present disclosure. In addition to the active ingredient, the pharmaceutical formulation of the present disclosure can contain one or more excipients. Excipients are added to the formulation for various purposes.

[0163] Diluents can increase the bulk of solid pharmaceutical compositions and make pharmaceutical dosage forms containing the compositions easier for patients and caregivers to handle.Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), fine 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.

[0164] Solid pharmaceutical compositions that are compressed into dosage forms such as tablets can contain excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomers (e.g., Carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), hydroxypropylmethylcellulose (e.g., Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0165] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by adding a disintegrant to the composition.Disintegrants include alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose (e.g., Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[0166] Glidants can be added to improve the flowability of non-compacted solid compositions and improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0167] When a dosage form such as a tablet is made by compressing a powder composition, the composition is subjected to pressure from a punch and a die. Some excipients and active ingredients have a tendency to adhere to the surface of the punch and die, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and facilitate 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.

[0168] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceuticals that may be included in the compositions of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0169] Solid and liquid compositions may also be dyed using any pharma- ceutically acceptable colorant to improve their appearance and / or to facilitate patient identification of products and unit dosage levels.

[0170] In liquid pharmaceutical compositions of the present invention, gusacitinib and any other solid excipients may be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0171] Liquid pharmaceutical compositions may contain emulsifiers to disperse active ingredients or other excipients that are not dissolved in liquid carriers uniformly throughout the composition. Emulsifiers that may be useful in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methylcellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0172] The liquid pharmaceutical compositions of the present invention may also contain thickening agents to improve the mouthfeel of the product and / or to coat the lining of the gastrointestinal tract, such agents include acacia, bentonite alginate, carbomer, calcium or sodium carboxymethylcellulose, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum, and combinations thereof.

[0173] Sweetening agents (eg, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar) may be added to improve taste.

[0174] Preservatives and chelating agents (eg, alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid) may be added at levels safe for consumption to improve storage stability.

[0175] According to the present disclosure, the liquid composition may also contain a buffering agent such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. The choice of excipients and the amounts to be used can be readily determined by a formulation scientist based on experience and consideration of standard procedures and reference works in the art.

[0176] The solid compositions of the present disclosure include powders, granules, aggregates, and compressed compositions. Dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, and ocular administration. The most suitable administration in any given case will depend on the nature and severity of the condition being treated, but in embodiments, the route of administration is oral. Dosages are conveniently provided in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical arts.

[0177] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0178] The dosage form of the present disclosure may be a capsule containing a composition, such as a powdered or granulated solid composition of the present disclosure, within either a hard or soft shell. The shell may be made from gelatin and may optionally contain a plasticizer, such as glycerin and / or sorbitol, an opacifying agent, and / or a colorant.

[0179] The active ingredients and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0180] Compositions 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 powder to clump into granules. The granules are sieved and / or milled, dried, and then sieved and / or milled to the desired particle size. The granules can then be tableted, or other excipients, such as glidants and / or lubricants, can be added before tableting.

[0181] Tableting compositions can be conveniently prepared 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 then be compressed into tablets.

[0182] As an alternative to dry granulation, blended compositions can be directly compressed into compacted dosage forms using direct compression technology. Direct compression produces more uniform tablets that do not contain granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray-dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The appropriate use of these and other excipients in direct compression tableting is known to those skilled in the art who have experience and skill in the specific formulation challenges of direct compression tableting.

[0183] Capsule fillings of the present disclosure may include any of the foregoing blends and granules described with respect to tableting, but which are not subjected to a final tableting step.

[0184] A pharmaceutical formulation of gusacitinib can be administered. Gusacitinib can be formulated for administration to a mammal, in embodiments to a human, by injection. Gusacitinib 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 physical and chemical stability, viscosity (allowing for syringeability), flowability, boiling point, miscibility, and purity of the solvent at various pH levels. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and castor oil USP. Additional substances such as buffers, solubilizers, and antioxidants, among others, can be added to the formulation. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

[0185] The disclosed crystalline polymorphs of gusacitinib and pharmaceutical compositions and / or formulations of gusacitinib can be used as medicines.

[0186] The present disclosure also provides a method of treating dermatitis by administering to a subject in need of treatment a therapeutically effective amount of any one or combination of the crystalline polymorphs of gusacitinib disclosed herein, or at least one of the pharmaceutical compositions and / or formulations described above.

[0187] Although the present disclosure has been described with reference to certain preferred embodiments and illustrative examples, those skilled in the art can appreciate modifications to the disclosure described and illustrated that do not depart from the spirit and scope of the disclosure disclosed herein. The examples are set forth to aid in the understanding of the present disclosure, but are not intended to, and should not be construed as, limiting its scope in any way.

[0188] X-ray Powder Diffraction ("XRPD") X-ray diffraction is performed using an X-ray powder diffractometer: The analysis was performed with a Bruker D8 Advance; CuKα radiation (λ = 1.5418 Å); Lynx eye detector; laboratory temperature 22-25 °C; PMMA sample holder ring. Prior to the analysis, the samples were gently ground using a mortar and pestle to obtain a fine powder. The ground sample was adjusted into the cavity of the sample holder and the surface of the sample was smoothed by a cover glass. Measurement parameters: Scanning range: 2~40°2θ; Scan mode: continuous; Step size: 0.05°; Time per step: 0.5 seconds; Sample spin: 30 rpm; Sample holder: PMMA sample holder ring.

[0189] All X-ray powder diffraction peak values ​​are calibrated with respect to standard silicon spiking in the samples. EXAMPLES

[0190] Preparation of starting materials Gusacitinib can be prepared according to methods known from the literature, for example from US Pat. No. 8,729,079.

[0191] A pH 1.2 buffer can be prepared according to any suitable method, in particular according to the United States Pharmacopoeia. A suitable buffer can be prepared using aqueous hydrochloric acid and potassium chloride solutions:

[0192] The following solutions 1 and 2 were prepared: Solution 1: 8.5 mL concentrated HCl + 491.5 mL water Solution 2: 745 g of potassium chloride was made up to 500 mL with water.

[0193] Then, 425 mL of solution 1 was combined with 250 mL of solution 2. Water was added to the combined solution to bring the total volume to 1000 mL. This solution can be used as a pH 1.2 buffer in the examples.

[0194] Example 1: Preparation of Gusacitinib - Form GS1 Gusacitinib (0.05 g) was dissolved in N,N-dimethylformamide (DMF, 12 mL) at 25-30 °C. The solution was filtered and water (10 mL) was added to the clear solution with stirring at 25-30 °C. The reaction mixture was stirred for 1 h and filtered under vacuum for about 15-20 min. The resulting solid was dried under vacuum at 25-30 °C for about 4 h. The solid was analyzed by XRD and designated as form GS1 of gusacitinib, as shown in Figure 1.

[0195] Example 2: Preparation of Gusacitinib - Form GS2 Gusacitinib (1 g) was dissolved in a mixture of dichloromethane:methanol (1:1; 250 mL) at 25-30 °C. The solution was filtered and the clear solution was subjected to distillation under reduced pressure at 60 °C for approximately 30-45 min. The resulting solid was isolated, analyzed by XRD, and designated as gusacitinib form GS2, as shown in Figure 2.

[0196] Example 3: Preparation of Gusacitinib - Form GS3 Gusacitinib (0.05 g) was dissolved in N-methylpyrrolidone (NMP; 5 mL) at 25-30 °C. The solution was filtered to give a clear solution, and water (10 mL) was added with stirring at 25-30 °C. The reaction mixture was stirred for 1 h and filtered under vacuum for 15-20 min. The resulting solid was analyzed by XRD and designated as form GS3 of gusacitinib, as shown in Figure 3.

[0197] Example 4: Preparation of Gusacitinib - Form GS4 Gusacitinib (0.6 g) was dissolved in N,N,dimethylformamide (DMF; 5 mL) at 60° C. The clear solution was added to pre-cooled (approximately 0° C.) cyclopentyl methyl ether (5 mL). The resulting suspension was maintained under stirring at 0° C. for 1 h and filtered at 25° C. The filtered solid was dried under vacuum at 60° C. for 2 h. The resulting solid was analyzed by XRD and designated as gusacitinib form GS4, as shown in FIG. 4.

[0198] Example 5: Preparation of Gusacitinib - Form GS5 Gusacitinib (GS1, 100 mg) was taken in a test tube and dissolved in dimethyl sulfoxide (DMSO, 0.8 mL) at 60 °C. To the clear solution, methyl tert-butyl ether (MTBE, 6 mL) was added at 50 °C and maintained at the same temperature for 10-15 min. The reaction mixture was cooled to 25 °C and after 10-15 min the solution was filtered and suction dried under vacuum for 10-15 min. The solid was analyzed by XRD and named as form GS5 of gusacitinib as shown in Figure 5.

[0199] Example 6: Preparation of Gusacitinib - Form GS6 Gusacitinib (form GS5, 0.1 g) and water (5 mL) were stirred at 25° C. The resulting slurry was stirred at 25° C. for 24 hours. The reaction mixture was filtered and dried under vacuum at 25-30° C. for 20-30 minutes. The resulting solid was analyzed by XRD and was designated as gusacitinib form GS6, as shown in FIG. 6.

[0200] Example 7: Preparation of Gusacitinib - Form GS7 Gusacitinib (form GS5, 0.1 g) and water (5 mL) were stirred at 25° C. The slurry was stirred at 25° C. for 24 h, filtered, and dried under vacuum at 25° C. for 10-15 min. The resulting solid was dried at 60° C. in an air tray dryer for 16 h, analyzed by XRD, and designated as gusacitinib form GS7, as shown in FIG. 7.

[0201] Example 8: Preparation of Gusacitinib - Form GS8 Gusacitinib (GS1, 0.350 g) was dissolved in dioxane (8 mL) at 60° C. and filtered. The clear solution was kept at 25° C. for 2 days without stirring to allow for slow solvent evaporation. After 2 days, hexane (3 mL) was added and the reaction mixture was filtered and dried under vacuum for about 30 minutes. The resulting solid was analyzed by XRD and designated as form GS8 of gusacitinib, as shown in FIG. 8.

[0202] Example 9: Preparation of Gusacitinib - Form GS9 Gusacitinib (GS3, 0.03 g) was dissolved in N,N-dimethylformamide (DMF 0.3 mL) at 60 °C. To the clear solution, methyl tert-butyl ether (MTBE, 6 mL) was added at 50 °C and maintained under stirring for 10 min (the mixture remained clear). The reaction mixture was immediately cooled to -10 °C and after 10-15 min the solution was filtered and dried for 10-15 min. The resulting solid was isolated and analyzed by XRD and named as form GS9 of gusacitinib as shown in Figure 9.

[0203] Example 10: Preparation of Gusacitinib HCl Salt - Form GHCl1 Gusacitinib (form GS3, 0.05 g) was placed in a glass vial at 25 °C. A buffer solution (pH 1.2, 2 mL) was added and the reaction mixture was stirred at 37 °C for 24 h. The slurry was filtered and dried under vacuum for 10-15 min. The resulting solid was analyzed by XRD and designated as form GHCl1 of gusacitinib HCl salt, as shown in Figure 10.

[0204] Example 11: Preparation of Gusacitinib HCl Salt - Form GHCl2 Gusacitinib hydrochloride (form GHCl1, 5.00 g) was dissolved in methanol (10 mL) at 60° C. To the clear solution, methyl tert-butyl ether (15 mL) was added at 60° C. with stirring. The reaction mixture was cooled to 25-30° C. in 15-20 minutes and maintained at this temperature for about 1 hour. The reaction mixture was filtered under vacuum for about 15-20 minutes. The solid obtained was dried under vacuum at 25-30° C. for about 30 minutes. The solid obtained was analyzed by XRD and was named as form GHCl2 of gusacitinib HCl salt, as shown in FIG. 11.

[0205] Example 12: Preparation of Gusacitinib HCl Salt - Form GHCl3 A suspension of gusacitinib (form GS2, 0.02 g) in isoamyl alcohol (1 mL) was cooled to 0 °C. Hydrochloric acid in isopropyl alcohol (18%, 20 μL) was added at 0 °C and the mixture was stirred at 0 °C for about 18 h. The slurry was filtered under vacuum at room temperature for about 15-20 min. The resulting solid was analyzed by XRD and designated as form GHCl3 of gusacitinib HCl salt, as shown in Figure 12.

[0206] Example 13: Preparation of Gusacitinib HCl Salt - Form GHCl4 A suspension of gusacitinib hydrochloride (form GHCl2, 0.02 g) in 3 mL of dichloromethane* (3 mL) was heated to 60° C. and maintained under stirring for about 16 hours. The slurry was cooled to about 25° C., filtered, and dried under vacuum for 10-15 minutes. The resulting solid was analyzed by XRD and designated as gusacitinib HCl salt form GHCl4, as shown in FIG. 13. *Form GHCl4 was also obtained when this example was repeated using the following solvents: isobutanol, methanol, ethyl formate, or acetonitrile.

[0207] Example 14: Preparation of Gusacitinib HCl Salt - Form GHCl5 Gusacitinib base (form GS2, 0.2 g) was dissolved in 1,4-dioxane (10 mL) at 60° C. The reaction mixture was cooled to 8-10° C. over 15-20 min and concentrated aqueous HCl (about 37%, 50 μL) was added. The mixture was stirred at 10° C. for about 65 h. The resulting solid was filtered under vacuum over 30-45 min, analyzed by XRD and designated as form GHCl5 of gusacitinib HCl salt, as shown in FIG. 14.

[0208] Example 15: Preparation of Gusacitinib HCl Salt - Form GHCl6 Gusacitinib base (form GS2, 0.03 g) was dissolved in 1,3 dioxolane (10 mL) at 60° C. The reaction mixture was then cooled to about 0° C. in about 15-20 min and concentrated aqueous HCl (about 37%, 20 μL) was added. The reaction mixture was stirred at about 0° C. for about 30 h and filtered under vacuum at room temperature for about 15-20 min. The resulting solid was analyzed by XRD and designated as form GHCl6 of gusacitinib HCl salt, as shown in FIG. 15.

[0209] Example 16: Preparation of Gusacitinib HCl Salt - Form GHCl7 Gusacitinib base (form GS2, 0.03 g) and 1,2-dichloroethane (2 mL) were mixed together at 25° C. The suspension was cooled to about 10° C. in about 5-10 minutes and hydrochloric acid in isopropyl alcohol (18%, 20 μL) was added. The mixture was stirred at about 10° C. for about 18 hours and filtered under vacuum at room temperature for about 15-20 minutes. The resulting solid was analyzed by XRD and designated as form GHCl7 of gusacitinib HCl salt, as shown in FIG. 16.

[0210] Example 17: Preparation of Gusacitinib HCl Salt - Form GHCl8 Gusacitinib free base (GS2, 1 g) was suspended in buffer* (pH=1.2, 10 mL) at about 37° C. The slurry was stirred for about 16 hours, cooled to 25° C., filtered, and dried under vacuum for about 15 minutes. The solid was further dried in a Vacuum Tray Dryer (VTD) at about 60° C. for 5 hours. The resulting solid was analyzed by XRD and designated as form GHCl8 of gusacitinib HCl salt, as shown in FIG. 17. *Complies with USP.

[0211] Example 18: Preparation of Gusacitinib HCl Salt - Form GHCl8 A mixture of gusacitinib hydrochloride (form GHCl3, 0.25 g) in a buffer solution* (pH=1.2, 8 mL) was heated to 37° C. The resulting solution was stirred at 37° C. for about 2 hours, filtered, and dried under vacuum at room temperature for 10-15 minutes. The resulting solid was further dried in a VTD at about 40° C. for 4 hours. The resulting solid was analyzed by XRD and determined to be gusacitinib HCl salt form GHCl8. *Complies with USP.

[0212] Example 19: Preparation of Gusacitinib HCl Salt - Form GHCl2 Gusacitinib (1 g) was dissolved in 1,3-dioxolane (30 mL) at 55 °C (a clear solution was obtained). Concentrated aqueous HCl (approximately 37%, 250 μL) was added and the mixture was stirred at 25 °C for approximately 1 h. The reaction mixture was filtered under vacuum for approximately 15-20 min. The solid was isolated and analyzed by XRD and identified as the crystalline form of gusacitinib HCl salt, GHCl2.

[0213] Example 20: Preparation of Gusacitinib HCl Salt - Form GHCl2 A mixture of gusacitinib (form GS2, 0.03 g) in THF* (2 mL) was cooled to about 10 °C. Hydrochloric acid in isopropyl alcohol (18%, 8 µL) was added and the mixture was stirred at about 10 °C for about 18 h. The resulting solid was filtered under vacuum for 15-20 min and analyzed by XRD, identifying it as the crystalline form of gusacitinib hydrochloride, GHCl2. *This example was repeated using different solvents; for example: sulfolane, diacetone alcohol, dimethyl carbonate, dimethyl carbonate, butyl acetate, diethyl ketone, nitromethane, propionitrile, acetone and acetonitrile. In all cases, crystalline GHCl2 was obtained. Example 21: Preparation of Gusacitinib HCl Salt - Form GHCl2 Gusacitinib hydrochloride (form GHCl2, 0.02 g) was dissolved in trifluoroacetic acid (0.2 mL) at 25-30 °C. After the solution was filtered, n-butanol* (5 mL) was added at 25-30 °C and the mixture was stirred for about 1 h. The reaction mixture was kept under stirring for 2 days and then filtered under vacuum for about 15 min. The obtained solid was analyzed by XRD and identified as gusacitinib HCl salt form GHCl2. *This example was repeated using trifluoroacetic acid as the solvent and 1,2-DME, ethyl formate, ethylene glycol, IPA, methyl acetate, methyl isobutyl ketone and toluene as anti-solvents, consistently yielding the gusacitinib HCl salt form GHCl2.

[0214] Example 22: Preparation of Gusacitinib HCl Salt - Form GHCl3 To a mixture of gusacitinib base (0.05 g) in THF (25 mL) at 0° C. was added aqueous HCl (approximately 37%, 0.25 mL). The mixture was stirred at 0° C. for approximately 16 h, filtered under vacuum for approximately 15-20 min, and analyzed by XRD to determine gusacitinib hydrochloride form GHCl3.

[0215] Example 23: Preparation of Gusacitinib HCl Salt - Form GHCl3 A suspension of gusacitinib (form GS2, 0.02 g) in isoamyl alcohol (1 mL) was cooled to 0 °C. HCl(g) in isopropyl alcohol (18%, 20 μL) was added at 0 °C and the mixture was stirred at 0 °C for about 18 h. The slurry was filtered under vacuum at room temperature for about 15-20 min. The resulting solid was analyzed by XRD and named as gusacitinib HCl salt form GHCl3 (corresponding to Figure 12).

[0216] Example 24: Preparation of Gusacitinib HCl Salt - Form GHCl2 A mixture of gusacitinib (form GS2, 0.03 g) in THF* (2 mL) was cooled to about 10° C. HCl(g) in isopropyl alcohol (18%, 8 μL) was added and the mixture was stirred at about 10° C. for about 18 h. The resulting solid was filtered under vacuum for 15-20 min and analyzed by XRD as crystalline form GHCl2 of gusacitinib hydrochloride. Crystalline form GHCl2 was also formed using the following solvents: sulfolane, diacetone alcohol, dimethyl carbonate, butyl acetate, diethyl ketone, nitromethane, propionitrile, acetone, and acetonitrile.

[0217] Example 25: Stability Studies Storage stability at different relative humidities Gusacitinib forms: GS2, GS3, GS4 and gusacitinib HCl salt forms GHCl1, GHCl2, GHCl8 were subjected to different relative humidity conditions at ambient temperature. XRPD analysis was performed on the samples after 7 days. The results are shown in Table 1 below: [Table 1]

[0218] A sample of gusacitinib HCl salt form GHCl3 was subjected to 60% relative humidity for 7 days. XRPD analysis did not show any polymorphic conversion.

[0219] The above data demonstrate that forms GS2, GS3 and GS4, and gusacitinib HCl salt forms GHCl1, GHCl2, GHCl3, and GHCl8 are particularly stable to high relative humidity conditions and are particularly suitable for pharmaceutical dosage forms.

[0220] Crushing experiment Samples of gusacitinib forms: GS2, GS3, GS4 and gusacitinib HCl salt forms: GHCl1, GHCl2, GHCl3, GHCl8 were subjected to vigorous grinding and solvent drop grinding in isopropanol, ethanol and water. Grinding was performed on the sample alone or in the presence of a solvent. In these experiments, approximately 20 mg of sample is placed in a mortar and ground with a pestle for 2 minutes. When a solvent is used, the solvent was added to the crystalline material in a volume of 10 microliters before grinding. XRPD analysis performed on the samples after the grinding experiments confirmed that there was no conversion of the starting material (Table 2): [Table 2]

[0221] The results demonstrate that gusacitinib forms GS2, GS3, GS4 as well as gusacitinib HCl salt forms GHCl1, GHCl2, GHCl3, GHCl8 are resistant to polymorphic change and are highly suitable for preparing pharmaceutical formulations.

[0222] thermal stability Samples of gusacitinib forms: GS2, GS3, GS4 and gusacitinib HCl salt forms GHCl1, GHCl2 and GHCl8 were subjected to heating to 100° C. for 30 minutes. XRPD analysis of the samples confirmed no changes to the starting materials (Table 3): [Table 3]

Claims

1. Crystalline gusacitinib HCl salt.

2. A crystalline form of gusacitinib HCl salt designated as Form GHCl1, (a) an X-ray powder diffraction pattern substantially as shown in Figure 10; or (b) X-ray powder diffraction pattern with peaks at 5.1, 8.9, 10.1, 15.3 and 27.2°2θ±0.2°2θ 1. The crystalline gusacitinib HCl salt characterized by data selected from at least one of:

3. 3. The crystalline gusacitinib HCl salt of claim 2, further characterized by an X-ray powder diffraction pattern having any one, two or three additional peaks selected from 17.1, 20.4 and 24.4 °2θ±0.2 °2θ.

4. The crystalline gusacitinib HCl salt of claim 2 or 3, characterized by an X-ray powder diffraction pattern having peaks at 5.1, 8.9, 10.1, 15.3, 17.1, 20.4, 24.4, and 27.2°2θ±0.2°2θ.

5. A crystalline gusacitinib HCl salt according to claim 2 or 3, which is a hydrate.

6. 4. The crystalline gusacitinib HCl salt of claim 2 or 3, which is substantially free of any other solid forms of gusacitinib and / or gusacitinib salts.

7. A crystalline form of gusacitinib HCl salt designated as Form GHCl2, comprising: (a) an X-ray powder diffraction pattern substantially as shown in Figure 11; or (b) X-ray powder diffraction pattern with peaks at 6.4, 13.7, 15.6, 22.9, and 27.5°2θ±0.2°2θ 1. The crystalline gusacitinib HCl salt characterized by data selected from at least one of:

8. 8. The crystalline gusacitinib HCl salt of claim 7, further characterized by an X-ray powder diffraction pattern having any one, two, three or four additional peaks selected from 12.7, 14.4, 16.6 and 17.8°2θ±0.2°2θ.

9. 9. The crystalline gusacitinib HCl salt of claim 7 or 8, characterized by an XRPD pattern with peaks at 6.4, 12.7, 13.7, 14.4, 15.6, 16.6, 17.8, 22.9, and 27.5 °2θ±0.2 °2θ.

10. 9. The crystalline gusacitinib HCl salt of claim 7 or 8, which is anhydrous.

11. 9. The crystalline gusacitinib HCl salt of claim 7 or 8, which is substantially free of any other solid forms of gusacitinib and / or gusacitinib salts.

12. A crystalline form of gusacitinib HCl salt designated as Form GHCl3, (a) an X-ray powder diffraction pattern substantially as shown in Figure 12; or (b) X-ray powder diffraction pattern with peaks at 5.5, 16.7, 21.0, 22.0, and 26.2°2θ±0.2°2θ 1. The crystalline gusacitinib HCl salt characterized by data selected from at least one of:

13. 13. The crystalline gusacitinib HCl salt of claim 12, further characterized by an X-ray powder diffraction pattern having any one, two, three or four additional peaks selected from 14.5, 19.0, 24.8 and 28.6 °2θ±0.2 °2θ.

14. 14. The crystalline gusacitinib HCl salt of claim 12 or 13, characterized by an XRPD pattern with peaks at 5.5, 14.5, 16.7, 19.0, 21.0, 22.0, 24.8, 26.2, and 28.6 °2θ±0.2 °2θ.

15. The crystalline gusacitinib HCl salt of claim 12 or 13, which is a hydrate.

16. 14. The crystalline gusacitinib HCl salt of claim 12 or 13, which is substantially free of any other solid forms of gusacitinib and / or gusacitinib salts.

17. A crystalline form of gusacitinib HCl salt designated as Form GHCl4, (a) an X-ray powder diffraction pattern substantially as shown in Figure 13; or (b) X-ray powder diffraction pattern with peaks at 5.8, 8.0, 14.9, 21.5, and 25.4°2θ±0.2°2θ 1. The crystalline gusacitinib HCl salt characterized by data selected from at least one of:

18. 18. The crystalline gusacitinib HCl salt of claim 17, further characterized by an X-ray powder diffraction pattern having any one, two, three or four additional peaks selected from 9.4, 12.7, 15.6, 17.8 and 22.9 °2θ ± 0.2 °2θ.

19. 19. The crystalline gusacitinib HCl salt of claim 17 or 18, characterized by an XRPD pattern with peaks at 5.8, 8.0, 9.4, 12.7, 14.9, 15.6, 17.8, 21.5, 22.9, and 25.4 °2θ±0.2 °2θ.

20. 19. The crystalline gusacitinib HCl salt of claim 17 or 18, which is anhydrous.

21. 19. The crystalline gusacitinib HCl salt of claim 17 or 18, which is substantially free of any other solid forms of gusacitinib and / or gusacitinib salts.

22. A crystalline form of gusacitinib HCl salt designated as Form GHCl8, comprising: (a) an X-ray powder diffraction pattern substantially as shown in Figure 17; or (b) X-ray powder diffraction pattern with peaks at 5.8, 11.4, 17.1, 24.6, and 27.5°2θ±0.2°2θ 1. The crystalline gusacitinib HCl salt characterized by data selected from at least one of:

23. 23. The crystalline gusacitinib HCl salt of claim 22, further characterized by an X-ray powder diffraction pattern having any one or two additional peaks selected from 9.0 and 28.6°2θ±0.2°2θ.

24. 24. The crystalline gusacitinib HCl salt of claim 22 or 23, characterized by an XRPD pattern with peaks at 5.8, 9.0, 11.4, 17.1, 24.6, 27.5, and 28.6 °2θ±0.2 °2θ.

25. The crystalline gusacitinib HCl salt of claim 22 or 23, which is a hydrate.

26. 24. The crystalline gusacitinib HCl salt of claim 22 or 23, which is substantially free of any other solid forms of gusacitinib and / or gusacitinib salts.

27. A method for preparing other crystalline forms of gusacitinib, salts of gusacitinib, or crystalline forms thereof, using the crystalline gusacitinib HCl salt of any one of claims 1 to 3, 7, 8, 12, 13, 17, 18, 22, and 23.

28. A pharmaceutical composition comprising the crystalline gusacitinib HCl salt of any one of claims 1 to 3, 7, 8, 12, 13, 17, 18, 22 and 23, and at least one pharmaceutically acceptable excipient.

29. A process for preparing a pharmaceutical composition and / or formulation using the crystalline gusacitinib HCl salt of any one of claims 1 to 3, 7, 8, 12, 13, 17, 18, 22 and 23.

30. A process for preparing a pharmaceutical composition comprising the crystalline gusacitinib HCl salt of any one of claims 1 to 3, 7, 8, 12, 13, 17, 18, 22 and 23, the process comprising combining the crystalline gusacitinib HCl salt of any one of claims 1 to 3, 7, 8, 12, 13, 17, 18, 22 and 23 with at least one pharmaceutically acceptable excipient.

31. A method for treating a disease, comprising administering a therapeutically effective amount of the crystalline gusacitinib HCl salt of any one of claims 1 to 3, 7, 8, 12, 13, 17, 18, 22 and 23 as a pharmaceutical to a subject in need of treatment.

32. 24. A method for treating chronic hand eczema or moderate to severe atopic dermatitis, in particular for the treatment of moderate to severe chronic hand eczema, comprising administering a therapeutically effective amount of the crystalline gusacitinib HCl salt of any one of claims 1 to 3, 7, 8, 12, 13, 17, 18, 22 and 23.

33. 26. A method of treating a tumor, comprising administering a therapeutically effective amount of the crystalline gusacitinib HCl salt of any one of claims 1 to 3, 7, 8, 12, 13, 17, 18, 22 and 23 to a subject in need of treatment.

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